EORTC Soft Tissue and Bone Sarcoma Group Phase II study of ...€¦ · EORTC-1317-STBSG Ph II CABOGIST in GIST Version 3.2 7 / 97 March 29, 2017 8.2 Statistical analysis plan 68 8.2.1

EORTC Avenue E. Mounierlaan 83/11 Brussel 1200 Bruxelles België – Belgique Tel: +32 2 774 16 11 e-mail: [email protected] www.eortc.org

EORTC Soft Tissue and Bone Sarcoma Group

Phase II study of cabozantinib in patients with metastatic gastrointestinal stromal

tumor (GIST) who progressed during neoadjuvant, adjuvant or palliative therapy

with imatinib and sunitinib

EORTC protocol 1317-STBSG (EudraCT number 2014-000501-13)

(NCT02216578)

Study Coordinator: Patrick Schöffski

Protocol version

Date of PRC approval/notification

Amendment reference

N° Classification

Outline October 25, 2013 ---- ----

1.0 July 31, 2014 ---- ----

2.0 April 29, 2016 1 Scientific

3.0 August 12, 2016 2 Scientific

3.1 December 20, 2016 3 Administrative

3.2 March 29, 2017 4 Administrative

Version 3.2 / March 29, 2017 Copyright EORTC 2017

EORTC-1317-STBSG Ph II CABOGIST in GIST

Version 3.2 2 / 97 March 29, 2017

Contact addresses Writing Committee: Schöffski P., U.Z. Leuven - Campus Gasthuisberg, Leuven,

Belgium Wozniak A., U.Z. Leuven - Campus Gasthuisberg, Leuven, Belgium EORTC Headquarters Team, Brussels, Belgium.

Study Coordinator: Patrick Schöffski Phone: +32 16 346900 E-mail: [email protected]

Clinical Research Physician:

Sandrine Marréaud Phone: +32 2 774 16 85 E-mail: [email protected]

Project Manager: Ward Sents Phone: +32 2 774 15 33 E-mail: [email protected]

Data Manager: Catherine Hermans Phone: +32 2 774 10 70 E-mail: [email protected]

Statistician: Saskia Litière Phone: +32 2 774 10 73 E-mail: [email protected]

Pharmacovigilance Unit:

Phone: +32 2 774 16 76 Fax: +32 2 772 80 27 E-mail: [email protected]

mailto:[email protected]






http://www.eortc.org/



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Table of contents: Protocol summary 9

1 Background and introduction 16

1.1 GIST 16

1.2 Cabozantinib 17

1.2.1 Introduction 17

1.2.2 Pharmacokinetic Data 18

1.2.3 Drug-Drug interactions 19

1.2.4 Dosing 20

1.2.4.1 Investigators Study driven 20

1.2.4.2 Cancer Therapy Evaluation Program of US National Cancer Institute 24

1.2.4.3 Dosing for GIST patients 25

1.2.4.4 Recommended dosing for this trial 26

1.2.5 Safety profile 26

1.2.6 Anti-tumor activity 27

1.3 Rationale 28

2 Objectives of the trial 29

2.1 General objective 29

2.2 End-points 29

2.2.1 Primary endpoint 29

2.2.2 Secondary endpoints 29

2.2.3 Exploratory endpoints 29

3 Patient selection criteria 30

3.1 Disease status 30

3.2 Patient status 31

4 Trial Design 34

5 Therapeutic regimens, expected toxicity, dose modifications 36

5.1 Drug information 36

5.1.1 General information 36

5.1.1.1 Pharmaceutical presentation 36

5.1.2 Drug supply 36

5.1.3 Packaging, dispensing and storage 36

5.1.4 Drug reconciliation procedures 36

5.2 Initial dose and schedule 36

5.3 Withdrawal criteria 37

5.4 Dose and schedule modifications 38

5.4.1 General recommendations for cabozantinib 38


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5.4.2 General guidance for dose and treatment interruption 39

5.4.2.1 Dose reduction 39

5.4.2.2 Cabozantinib Dose Reinstitution and Reescalation 39

5.4.2.3 Dose interruption 39

5.4.3 General guidelines for treatment related adverse events 40

5.4.4 Guidelines for management of specific adverse events 41

5.4.4.1 Gastrointestinal disorders 41

5.4.4.1.1 Diarrhea 41

5.4.4.1.2 Nausea and vomiting 43

5.4.4.2 Stomatitis and mucositis 43

5.4.4.3 Hepatobiliary disorders 43

5.4.4.4 Fatigue, anorexia, and weight loss 44

5.4.4.5 Hematological disorders 44

5.4.4.6 Palmar-plantar erythrodysesthesia syndrome (PPES) 44

5.4.4.7 Wound healing and surgery 45

5.4.4.8 Hypertension 46

5.4.4.9 Thromboembolic events (venous and arterial) 47

5.4.4.10 Proteinuria 47

5.4.4.11 Corrected QT (QTc) prolongation 48

5.4.4.12 Hypophosphatemia 50

5.4.4.13 Thyroid function disorders 50

5.4.4.14 Hemorrhagic events 50

5.4.4.15 GI perforation/fistula and non-GI fistula formation 51

5.4.4.16 Osteonecrosis of the jaw 51

5.4.4.17 Angioedema 52

5.4.4.18 Nervous system disorders 52

5.4.4.19 Muscoloskeletal and connective tissue disorders 52

5.4.4.20 Respiratory, thoracic and mediastinal disorders 52

5.5 Concomitant treatments 52

5.5.1 Allowed medications 52

5.5.2 Prohibited or restricted medications 53

5.5.3 Potential drug interactions 54

5.5.3.1 Cytochrome P450 (CYP) 54

5.5.3.2 Protein Binding 55

5.5.3.3 Other Interactions 55

6 Clinical evaluation, laboratory tests and follow-up 56

6.1 Before treatment start 56


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6.1.1 Investigations performed within 28 days prior to start of treatment 56



6.1.4 Investigations performed within 72 hours prior to start of treatment 57

6.2 During treatment 57

6.2.1 Every cycle (3 weeks, day 1 +/- 3 days of each cycle) 57

6.2.2 Every 6 weeks (+/- 3 days) 57

6.2.3 Translational research 58

6.3 Upon permanent discontinuation of treatment 58

6.4 After end of treatment (Follow-up) 58

6.4.1 For patients who discontinued protocol treatment due to disease progression 59

6.4.2 For patients who discontinued treatment in the absence of per protocol progression 59

6.5 Summary table 60

7 Criteria of evaluation 62

7.1 Progression free survival at 12 weeks (binary) 62

7.2 Progression free survival 62

7.3 Overall survival 62

7.4 Objective response rate 62

7.4.1 Measurability of tumor lesions at baseline 63

7.4.1.1 Definitions 63

7.4.1.2 Methods of measurements 63

7.4.2 Tumor response evaluation 64

7.4.2.1 Frequency of tumor re-evaluation 66

7.4.2.2 Date of progression 66

7.4.3 Reporting of tumor response 66

7.5 Clinical benefit rate 66

7.6 Total duration of treatment 66

7.7 Evaluation of safety 66

7.7.1 Adverse events 66

7.7.2 General evaluation of adverse events 67

7.7.3 Serious adverse events 67

7.7.4 Toxic death 67

7.7.5 Evaluability for safety 67

7.8 Evaluation of exploratory endpoints 67

8 Statistical considerations 68

8.1 Statistical design 68

8.1.1 Sample size 68


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8.2 Statistical analysis plan 68

8.2.1 Primary and secondary endpoints 68

8.2.2 Analysis populations 68

8.2.3 Statistical methods 69

8.2.4 Pre-planned sensitivity or exploratory analyses 69

8.2.5 Follow-up analyses 69

8.2.6 Data recoding and display 69

8.3 End of study 70

9 Data Monitoring 70

10 Translational research 70

10.1 Introduction 70

10.2 Efficacy of cabozantinib in different molecular subtypes of GIST 71

10.2.1 Archival fixed tissue collection for tumor characterization 71

10.2.2 Instructions for preparing slides from FFPE blocks (mandatory) 71

10.2.3 Statistical analysis 72

10.3 Exploration of plasma cell-free DNA (cfDNA), originating from the tumor 72

10.3.1 Blood sample collection for characterization of circulating cell-free DNA (mandatory) 73

10.3.2 Statistical analyses 73

10.4 Data storage, transfer and development of technical appendices 74

10.5 General principles for human biological material (HBM) collection 74

11 Investigator authorization procedure 75

12 Patient registration procedure 76

13 Forms and procedures for collecting data 77

13.1 Case report forms and schedule for completion 77

13.2 Data flow 77

14 Reporting of Serious Adverse Events 78

14.1 Definitions 78

14.2 Exceptions 79

14.3 Severity assessment 80

14.4 Causality assessment 80

14.5 Expectedness assessment 80

14.6 Reporting procedure for investigators 80

14.7 Reporting responsibilities for EORTC 81

14.8 Pregnancy reporting 81

15 Quality assurance 82

15.1 Control of data consistency 82


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15.2 On-site quality control 82

15.3 Audits 82

15.4 External review of histology 83

15.4.1 Forms 83

15.4.2 Material to be shipped to reference pathologists 83

15.4.3 Reference pathologist 83

15.4.4 The list of reference pathologists 84

15.5 External review of responses 84

15.5.1 Storage 84

16 Ethical considerations 85

16.1 Patient protection 85

16.2 Subject identification 85

16.3 Informed consent 85

17 Administrative responsibilities 86

17.1 The study coordinator 86

17.2 The EORTC Headquarters 86

17.3 The EORTC group 86

18 Trial sponsorship and financing 87

19 Trial insurance 87

20 Publication policy 88

Table of appendices: Appendix A: References 89

Appendix B: Abbreviations 92

Appendix C: ECOG performance status scale 95

Appendix D: Hy's Law criteria 96

Appendix E: MRP2 inhibitors 97


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Protocol summary Title of the Study Phase II study of cabozantinib in patients with metastatic gastrointestinal

stromal tumor (GIST) who progressed during neoadjuvant, adjuvant or palliative therapy with imatinib and sunitinib.

Objective(s) The main objective is to assess the safety and activity of cabozantinib in patients with metastatic GIST who have previously progressed on imatinib and sunitinib and have not yet been exposed to other KIT- or PDGFR-directed tyrosine kinase inhibitors such as regorafenib or similar agents.

Methodology Multi-center, multi-national, open label, single arm Phase II study of single-agent cabozantinib. Patients will receive cabozantinib until they experience no further benefit from the treatment, become intolerant to the drug or wish to discontinue the treatment. Treatment beyond RECIST 1.1 progression is allowed in patients deriving clinical benefit, upon investigator’s discretion, provided that no other criteria for treatment withdrawal are met.

Number of patients Number planned (Statistical design)

Number analyzed

The A’Hern one-stage design will be applied: 41 eligible and evaluable patients are required, for the decision rule. To allow for a sufficient number of patients to be assessable, enrollment can continue beyond 41 patients, but will be capped at 50.

Diagnosis and main criteria for inclusion

Disease status

♦ Histologically confirmed diagnosis of GIST that is metastatic. Patients with the primary tumor still in place are excluded from the trial, due to the risk for intestinal perforation reported for cabozantinib.

♦ Presence of at least one non-previously irradiated, measurable metastatic lesion as defined by RECIST 1.1.

♦ No evidence of tumor or metastatic lesion invading the gastrointestinal tract (esophagus, stomach, small or large bowel, rectum or anus) within 28 days prior to the first dose of cabozantinib.

♦ No current evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib.

♦ Radiographic absence of a cavitating pulmonary lesion within 28 days prior to the first dose of cabozantinib.

♦ No patient with tumor in contact with, invading or encasing a major blood vessel.

♦ Consent of the patient ♦ Archival tumor tissue available from primary tumor or

metastatic site (10 unstained slides with archived tumor tissue of 10 micrometer thickness and two hematoxylin and eosin (H&E) stained slides) for central mutational analysis and (5 unstained slides of 4 micrometer thickness) for pathology review.

♦ To allow sequential sampling of blood for the circulating cell-free DNA isolation for central mutational analysis


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♦ Failure on prior therapy with imatinib and sunitinib ♦ An interval from prior tyrosine kinase inhibitor (TKI) therapy to

the first dose of cabozantinib of at least 14 days

♦ Radiological progression on imatinib during neoadjuvant, adjuvant or palliative treatment of GIST or within 3 months after completing adjuvant treatment with imatinib AND radiological progression on sunitinib for the treatment of advanced GIST

Note: progression is assessed by local radiologist/oncologist without central confirmation of pre-baseline progression.

♦ No other prior use of tyrosine kinase inhibitors for the treatment of advanced GIST with the exception of imatinib and sunitinib.

♦ No other investigational agents within 28 days before the first dose of study treatment

Patient status

♦ Male or female patient ≥ 18 years of age.

♦ ECOG performance status (PS) of 0-1 (See Appendix C).

♦ Adequate bone marrow and organ function prior to receiving the first dose of study treatment:

♦ Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (no prophylactic administration of G-CSF or GM-CSF allowed).

♦ Platelet count ≥ 100 x 109/L or x 103/μL (transfusion allowed).

♦ Hemoglobin ≥ 9.0 g/dL or 5.6 mmol/L (transfusion and erythropoietin allowed).

♦ Prothrombin time (PT)/INR or partial thromboplastin time (PTT) test < 1.3 × ULN within 7 days before the first dose of study treatment.

♦ Serum phosphorus, calcium, magnesium and potassium within normal range.

♦ Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 50 mL/min or glomerular filtration rate (GFR) >30 mL/min (as assessed per local standard).

♦ Serum bilirubin within normal range (or ≤ 1.5 x ULN if liver metastases are present; or total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in patients with Gilbert’s syndrome).

♦ Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within ≤ 3.0 x ULN or ≤ 5.0 x ULN if liver metastases.

♦ Serum albumin ≥ 2.8 g/dL.

♦ Serum lipase < 2 x ULN and no radiologic or clinical evidence


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of pancreatitis.

♦ Urine protein/creatinine ratio (UPCR) ≤ 1.

♦ Clinically normal cardiac function based on the institutional lower limit of normal for-left ventricular ejection fraction as assessed either by multi-gated acquisition scan or cardiac ultrasound, 12 lead ECG without clinically relevant abnormalities.

♦ No history of congenital long QT syndrome.

♦ No (Fridericia's formula) QTcF > 500 msec within 1 month before the first dose of study treatment: three ECGs must be performed for eligibility determination. If the average of these three consecutive results for QTcF is ≤ 500 msec, the patient meets eligibility in this regard.

♦ No congestive heart failure (CHF): New York Heart Association (NYHA) Class III (moderate) or Class IV (severe) at the time of screening;

♦ No history of any of the following cardiovascular conditions within 6 months prior to the first dose of protocol treatment:

♦ Unstable angina.

♦ Clinically significant cardiac arrhythmias.

♦ Myocardial infarction.

♦ No poorly controlled hypertension defined at baseline as blood pressure (BP) >150/100 mmHg despite optimal antihypertensive treatment within 7 days of the first dose of study treatment

♦ No concomitant anticoagulation at therapeutic doses with oral anticoagulants (eg, warfarin, direct thrombin and Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel);

Note: Low-dose aspirin for cardioprotection (per local applicable guidelines), low-dose warfarin (< 1 mg/day), and low dose, low molecular weight heparins (LMWH) are permitted. Anticoagulation with therapeutic doses of LMWH is allowed in subjects who are on a stable dose of LMWH for at least 12 weeks before registration, and who have had no complications from a thromboembolic event or the anticoagulation regimen.;

♦ Patients must be able to swallow and retain oral film-coated tablets.

♦ Recovery to baseline or ≤ Grade 1 CTCAE v.4.0 from toxicities related to any prior treatments, unless AE(s) are clinically non-significant and/or stable on supportive therapy.

♦ No specific contraindications for treatment with cabozantinib (e.g. no known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to cabozantinib).

♦ No stroke (including transient ischemic attack (TIA), or other ischemic event) and no thromboembolic event requiring therapeutic


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anticoagulation within 6 months before the first dose of study treatment

Note: subjects with a venous filter (eg, vena cava filter) are not eligible for this study.

♦ No gastrointestinal disorders associated with a high risk of perforation or fistula formation, including the following:

♦ Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (eg, ulcerative colitis, Crohn’s disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction

♦ Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess within 6 months before registration.

♦ Ongoing visceral complications from prior therapy

♦ Prior GI surgery (particularly when associated with delayed or incomplete healing)

Note: Complete healing of an intra-abdominal abscess must be confirmed prior to registration.

♦ No other clinically significant disorders that would preclude safe study participation.

♦ No evidence of significant active bleeding (including gastrointestinal (GI) bleeding) or bleeding diathesis within 6 months before the first dose of study treatment.

♦ No hemoptysis ≥ 0.5 teaspoon (2.5 ml) of red blood within 3 months before the first dose of study treatment.

♦ No signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment.

♦ Prior radiation therapy ♦ No radiation therapy for bone metastasis within 2 weeks, or any

other external radiation therapy within 4 weeks before the first dose of study treatment.

♦ No systemic treatment with radionuclides within 6 weeks before the first dose of study treatment.

♦ Patients with clinically relevant ongoing complications from prior radiation therapy are not eligible.

♦ Prior surgery ♦ No major surgery or trauma within 12 weeks prior to first dose

of study drug and/or presence of any non-healing wound, fracture or ulcer. Complete wound healing from major surgery must have occurred one month before the first dose of study treatment.

♦ Minor surgery (including uncomplicated tooth extractions)


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within 28 days before the first dose of study treatment with complete wound healing at least 10 days before the first dose of study treatment is permitted.

♦ Patients with clinically relevant ongoing complications from prior surgery are not eligible.

♦ None of the following clinically significant disorders such as: ♦ Active infection requiring systemic treatment within 28 days

before the first dose of study treatment.

♦ History of organ transplant.

♦ Concurrent severe, clinically relevant hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment.

♦ No history of other malignancy in the past 5 years with the exception of treated carcinoma in situ of the cervix and non-metastatic, non-melanoma skin cancer. Patients with desmoid fibromatosis or neurofibromas, which can be associated with GIST, are allowed to enter the trial, under the provision that they do have a measurable GIST lesion that can be distinguished from the other lesions.

♦ Patients requiring chronic concomitant treatment with strong Cytochrome P450 (CYP) 3A4 inducers (e.g. dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John’s Wort) are not eligible.

♦ Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other study procedures.

♦ Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial

♦ Women of child bearing potential (WOCBP) must have a negative serum pregnancy test within 72 hours prior to the first dose of study treatment.

Note: women of childbearing potential are defined as premenopausal females capable of becoming pregnant (i.e. females who have had evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy). However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body weight, ovarian suppression or other reasons.

♦ Patients of childbearing / reproductive potential should use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 4 months after the last study treatment. A highly effective method of birth control is defined as a method which results in a low failure rate (i.e. less than 1% per year) when used consistently and correctly. Such methods include:


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♦ Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal)

♦ Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)

♦ Intrauterine device (IUD)

♦ Intrauterine hormone-releasing system (IUS)

♦ Bilateral tubal occlusion

♦ Vasectomized partner

♦ Sexual abstinence

♦ Lactating females are not eligible.

♦ Before patient registration, written informed consent must be given according to international conference on harmonization/Good clinical practice (ICH/GCP), and national/local regulations.

Important note: All eligibility criteria must be adhered to, in case of deviation discussion with EORTC Headquarters and the study

coordinator is mandatory.

Treatment Test product, dose and mode of administration

Duration of treatment

Cabozantinib tablets will be administered as an oral single agent once daily at 60 mg (expressed as the freebase weight). Patients should fast at least 2 hours before and 1 hour after taking cabozantinib.

Patients will receive cabozantinib until they experience no further benefit from the treatment, are becoming intolerant to the drug or wish to discontinue the treatment. Treatment beyond RECIST 1.1 progression is allowed in patients deriving clinical benefit upon investigator’s discretion, provided that no other criteria for treatment withdrawal as defined by protocol are met. Subjects may discontinue study treatment or withdraw their consent to participate in the study at any time without prejudice.

Criteria for evaluation

Efficacy Primary end point: progression free survival (PFS) at 12 weeks (binary) according to RECIST 1.1.

For this purpose, the tumor size must be evaluated 12 weeks after start of treatment in all patients (even if protocol therapy has been discontinued, unless progression has been documented at an earlier time point).

Secondary end points include

PFS according to RECIST 1.1. Overall survival (OS).

Objective response rate (ORR), defined as complete response (CR) or partial response (PR) according to RECIST 1.1.

Clinical benefit rate (CBR), defined as CR, PR or SD (stable disease) according to RECIST 1.1;


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Total duration of treatment (including treatment beyond RECIST progression).

Safety Adverse events will be graded according to the NCI CTCAE, version 4.0.

Statistical methods A’Hern one-stagedesign with P0 = 40%, P1 = 60%, and alpha = beta = 0.1.

If at least 21 out of 41 eligible and evaluable patients are progression-free at the week 12 assessment (see Section 7.1), the activity of cabozantinib in this trial will be deemed sufficient to warrant further exploration of the drug in metastatic GIST.

Translational research

Translational research is mandatory and exploratory

The objectives of the translational research are:

♦ To assess the relative efficacy of cabozantinib in different molecular subtypes of GIST based on KIT/PDGFRA mutations. To explore the use of of cell-free DNA (cfDNA) in plasma originating from the tumor

Biological material collected:

♦ Archival tumor tissue available from primary tumor or metastatic site (10 unstained slides with archived tumor tissue of 10 micrometer thickness and two hematoxylin and eosin (H&E) stained slides).

♦ cfDNA isolated from plasma samples at multiple time points.


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1 Background and introduction 1.1 GIST Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and are thought to have a common precursor with the interstitial cells of Cajal. GISTs are malignant tumors driven by activating mutations in the genes encoding for the receptor tyrosine kinase KIT (CD117) or the related kinase called platelet-derived growth factor receptor alpha (PDGFRA) (Ref. 1).

Approximately 75-80% of immunohistochemically KIT-positive GISTs harbor an activating mutation in the KIT oncogene, and 13% of GISTs have a mutated PDGFRA gene. Mutations in KIT exon 11 are the most common (61-67%) subtype of GIST, while KIT exon 9 mutations are found in 10-12% of GISTs. Mutations in KIT exons 13 and 17 are rare. The remaining cases harbor no mutation in these genes, and were traditionally referred to as “wildtype” GIST (Ref. 2). These rare cancers represent a heterogeneous family of diseases with other underlying genetic abnormalities.

GISTs can arise anywhere along the gastrointestinal tract but are most common in the stomach (50-60%) and small intestine (20-30%). The majority of KIT exon 9 mutations arise in small intestinal GISTs, while most PDGFRA mutations are found in gastric primaries. KIT exon 11 mutations are distributed throughout the gastrointestinal tract. The mutational subtype of GIST has both prognostic and predictive relevance. Response and resistance to systemic therapies in metastatic/inoperable GIST is related to the identified activating mutations and the according structural changes of the encoded transmembranous receptors (Ref. 2).

The mainstay of therapy for patients with operable primary GIST is surgical resection. Surgery alone is curative in about half of patients with 5-year disease specific survival rates around 54% (Ref. 3). Recurrence rates exceeding 50% within 2 years of resection of primary GIST and approximating 90% after re-excision (Ref. 3) underscore the need for effective systemic treatment.

Imatinib (Glivec®, Gleevec®, Novartis) is a small molecule receptor tyrosine kinase inhibitor which received worldwide approval for the treatment of adult patients with unresectable and/or metastatic GIST. The availability of imatinib dramatically changed the prognosis of GIST patients by prolonging overall survival (OS), progression-free survival (PFS) and the 5-year survival rate (Ref. 4, Ref. 5). The oral drug is currently used at doses ranging from 400 mg/day to 800 mg/day p.o. for the treatment of patients with unresectable and/or metastatic KIT-positive GIST. In addition, it has been shown that imatinib 800 mg/day significantly improves the PFS of patients with advanced GIST harboring KIT exon 9 mutations as compared to 400 mg/day.

As a result of the impressive activity of imatinib in the treatment of patients with unresectable and/or metastatic GIST, a number of more recent randomized phase III trials have established the role of adjuvant treatment of adult patients with GIST following complete resection. Treatment with imatinib 400 mg/day for 12 months was found to improve recurrence-free survival (RFS) over control. Imatinib was approved worldwide for the adjuvant treatment of adult patients following resection of GIST. Results from trial SSGXVIII/AIO in patients at high risk of disease recurrence after resection of GIST showed that prolonged adjuvant imatinib (36 months) is superior to 12 months in improving both RFS and OS. (Ref. 6). Despite the unprecedented efficacy of imatinib in advanced GIST and the proven prognostic impact of adjuvant therapy, treatment of metastatic disease remains an area of unmet medical need with more than 50% of patients progressing after two years of starting imatinib first line therapy.


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For patients whose disease has progressed during treatment with imatinib, or in patients who are intolerant to imatinib, sunitinib (Sutent®; Pfizer) is approved as second line standard treatment (Ref. 7). Median time to progression (TTP) achieved on therapy with this multi-targeted tyrosine kinase inhibitor is 27 weeks and the PFS is 24 weeks in GIST failing imatinib (Ref. 8).

Presently, standard therapeutic options for GIST patients in the European Union, who have failed prior therapy with both imatinib and sunitinib, are limited to the use of regorafenib, which is not yet available or reimbursed in all European countries.The tyrosine kinase inhibitor regorafenib gained approval by the US Food and Drug Administration (FDA) based on the results of the GRID Phase III trial (Ref. 9). In that study, patients with histologically confirmed, metastatic or unresectable GIST, with failure of at least previous imatinib and sunitinib were randomized in a 2:1 ratio, stratified by treatment line and geographical region, to receive either oral regorafenib 160 mg daily or placebo, plus best supportive care in both groups, for the first 3 weeks of each 4 week cycle. The primary endpoint was PFS. At disease progression, patients assigned to the placebo group could crossover to open-label regorafenib. Analyses were by intention to treat.A total of 199 patients were randomized to receive regorafenib (n=133) or matching placebo (n=66). Median PFS per independent blinded central review was 4.8 months (IQR 1.4-9.2) for regorafenib and 0.9 months (0.9-1.8) for placebo (hazard ratio [HR] 0.27, 95% CI 0.19-0.39; p<0.0001). After progression, 56 patients (85%) assigned placebo crossed over to regorafenib. Drug-related adverse events were reported in 130 (98%) patients received regorafenib and 45 (68%) patients assigned placebo. The most common regorafenib-related adverse events of grade 3 or higher were hypertension, hand-foot skin reaction, and diarrhea. The European Medicines Agency (EMA) recently approved regorafenib for the treatment of adult patients with unresectable or metastatic GIST who progressed on or are intolerant to prior treatment with imatinib and sunitinib

Given this high unmet medical need many patients are treated off label with other tyrosine kinase inhibitors based on limited scientific evidence, using drugs such as sorafenib, pazopanib or other compounds. The development of treatment options with proven efficacy for patients with multi-drug resistant GIST remains a high priority, also after the introduction of regorafenib.

1.2 Cabozantinib

1.2.1 Introduction The tyrosine kinase inhibitor cabozantinib (XL184) is a new oral anticancer agent developed by Exelixis Inc. The established molecular targets of cabozantinib are MET, VEGFR2/KDR, RET, KIT, AXL, and FLT3. These targets are important mediators of tumor growth, angiogenesis, invasiveness and metastasis. In vivo pharmacodynamic activity of cabozantinib against these targets has been demonstrated in studies and has been associated with tumor growth inhibition and tumor regression. In preclinical models of different malignancies, cabozantinib treatment was found to inhibit tumor angiogenesis, invasiveness and metastasis, and the progression of tumors in bone.

Cabozantinib has been studied in multiple Phase I, II and III trials in a variety of solid tumors. Since 2012 cabozantinib capsules have been approved by the FDA for treatment of progressive, metastatic medullary thyroid cancer (MTC), and in the European Union in 2014 for treatment of progressive, unresectable locally advanced or metastatic medullary thyroid carcinoma (Ref. 10). Since April 2016, cabozantinib tablets are approved by FDA for patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy. Cabozantinib is commercially available as both capsules and tablets in the United States and is currently available only as capsules in the European Union.

The kinase inhibitor showed very broad anti-tumoral effects in a multi-tumor randomized discontinuation trial (NCT00940225). The kinase profile of cabozantinib strongly suggests that the drug may also be active in GIST, due to the well-established role of KIT and vascular endothelial growth factor receptor 2 (VEGFR2) in the pathogenesis and evolution of this disease. Based on this rationale, the in vivo efficacy


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of cabozantinib in GIST has been explored in patient-derived mouse xenografts established by the Laboratory of Experimental Oncology (LEO) at the University Hospitals Leuven (UZ Leuven), KU Leuven, Leuven, Belgium (Ref. 11). In imatinib- and sunitinib-sensitive GIST models with KIT exon 11 mutation the drug had similar or even better antiproliferative activity than the standard agent imatinib. In KIT exon 9 mutated model cabozantinib reduced tumor volume, while it led to the tumor size stabilisation in the imatinib-resistant model. In all models the cell proliferation was significantly reduced. In addition cabozantinib reduced the microvessel density compared to both control and imatinib groups, revealing the anti-angiogenic effect. Tumors treated with cabozantinib showed also consistent inhibition of the KIT signaling pathway mainly in models with KIT exon 11 and with KIT exon 9, to the lesser extent in the imatinib resistant model. Cabozantinib was well tolerated in the tumor-bearing mice and could be given safely as a single agent (Ref. 11). The enhanced activity of cabozantinib in imatinib resistant GIST preclinical models may be attributed to the parallel inhibition of MET receptor. Recently researchers at Memorial Sloan-Kettering Cancer Center have shown that the pharmacological inhibition of KIT activates MET signaling in GIST, and have seen promising activity with MET inhibitors such as cabozantinib in preclinical models (Ref. 12). Cabozantinib has not been studied in disease-specific GIST clinical trials yet. Four GIST patients, however, were enrolled in a Japanese solid tumor dose finding study (NCT01553656) and derived durable therapeutic benefit from treatment with the novel tyrosine kinase inhibitor (Tamura, National Cancer Center Hospital, Tokyo, personal communication; Ref. 13). All four patients (2 male, 2 female) had typical GISTs arising from stomach or small intestine, had previously been exposed to imatinib and sunitinib, and remained on active treatment with cabozantinib for 6, 8, 9 and 21 months. All patients achieved RECIST stable disease (SD) as best response and three patients had shrinkage of target lesions of 8, 15 and 25 %, respectively. The mutational profile of the treated tumors is not available.

1.2.2 Pharmacokinetic Data Information based on the Investigator's brochure (Ref. 14).

Two population pharmacokinetics (PopPK) analyses have been conducted using cabozantinib clinical data. The first included data from subjects with MTC, glioblastoma (GB), and other solid tumors who received repeated oral daily dosing of cabozantinib capsules at 140 mg. From this analysis, the predicted effective half-life is was approximately 55 h, the oral volume of distribution (V/F) was approximately 349 L, and the oral clearance (CL/F) at steady-state was estimated to be 4.4 L/h. The terminal half-life (for predicting drug washout) was approximately 120 hours h. Following oral administration of cabozantinib, median time to maximum plasma concentrations (Tmax) for cabozantinib ranged from 2 to 5 h post-dose. Repeat daily dosing of cabozantinib at 140 mg for 19 days resulted in 4- to 5-fold higher mean cabozantinib accumulation (based on area under the plasma concentration-vs-time curve [AUC]) compared with a single dose administration; steady state was achieved by Day 15. Cabozantinib is highly protein bound in human plasma (≥ 99.7%). The analysis did not identify clinically relevant differences in clearance of cabozantinib between females and males or between Whites (89%) and non-Whites (11% [<4% were Asian]). Cabozantinib pharmacokinetics (PK) was not affected by age (20-86 years).

A second PopPK analysis was conducted in subjects with RCC who received repeated oral daily cabozantinib tablet dosing at 60 mg (with protocol-permitted dose reductions to 40 mg and 20 mg) combined with healthy subjects who received a single oral cabozantinib tablet dose of 20, 40, or 60 mg. That analysis indicated that for a White male subject the predicted terminal plasma half-life of cabozantinib was approximately 99 h; the terminal phase volume of distribution (Vz) was approximately 319 L; and the CL/F at steady-state was estimated to be approximately 2.2 L/h. Female gender and Asian race were significant covariates on CL/F, and while the attributes were statistically significant, they were not deemed clinically meaningful given the magnitude of the effects. Further evaluation of the differences in the two PopPK analyses revealed that compared with other cancer patient groups (ie, RCC, CRPC, GB), MTC subjects cleared cabozantinib faster and thus had lower dose-normalized steady-state plasma


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exposures. Several possible factors may underlie the higher cabozantinib clearance observed in MTC patients in the first PopPK analysis; however, an exact cause has yet to be identified.

Within a 48-day collection period after a single dose of 14C-cabozantinib in healthy subjects, approximately 81% of the total administered radioactivity was recovered with 54% in feces and 27% in urine.

Results from a PK study of cabozantinib in subjects with renal impairment indicated that the ratios of geometric least squares (LS) mean for maximum plasma concentration (Cmax) and AUCs (AUC from 0 h to the last sampling time point [AUC0-t] and AUC from 0 h to infinity [AUC0-inf]) were 19% and 30% higher, respectively, for subjects with mild renal impairment compared to subjects with normal renal function. For subjects with moderate renal impairment, both Cmax and AUCs appeared to be similar when compared to with subjects with normal renal function (differences: < 3% and < 7%, respectively). Results from a PK evaluation of cabozantinib in subjects with hepatic impairment indicated that exposure (AUC0-inf) to cabozantinib was increased by about 81% and 63% in subjects with mild and moderate hepatic impairment, respectively. There are no PK data in subjects with severe renal or hepatic impairment.

A high-fat meal increased Cmax and AUC values by 41% and 57%, respectively, relative to fasted conditions in healthy subjects administered a single 140-mg oral cabozantinib dose.Cabozantinib is administered as either capsules or tablets. In a bioequivalence study comparing capsules with tablets in healthy adult subjects (Study XL184-010), the geometric mean ratios for both AUC parameters (AUC0-t and AUC0-inf) comparing 140 mg cabozantinib doses of the tablet formulation with the capsule formulation were 108% (90% confidence interval [CI]%: 101, 117). The ratio of geometric means for Cmax (119%; 90% CI%: 107, 132) had a 90% CI upper bound that slightly exceeds the standard accepted limit of 125%. Therefore, bioequivalence of the cabozantinib capsule and tablet formulations cannot be concluded, and the two formulations are not interchangeable.

1.2.3 Drug-Drug interactions Cabozantinib should be administered without food (patients should fast at least two hours before and one hour after taking cabozantinib). Cabozantinib is highly protein bound in vitro in human plasma (> 99.9% at 0.2 and 1.0 μM, and 99.7% at 10 μM). Cabozantinib at clinically-relevant steady-state plasma concentrations (≥ 125 mg/day daily for a minimum of 21 days) showed no statistically-significant effect on single-dose plasma PK exposure values (C max and AUC) for the CYP2C8 substrate rosiglitazone in patients with solid tumors. Thus, cabozantinib appears to present low potential for inhibiting the metabolism of concomitant medications that are substrates of CYP2C8 or CYP isozymes, which have been shown to be less potently inhibited by cabozantinib in vitro (i.e., CYP2C9, CYP2C19, CYP2D6, CYP1A2, and CYP3A4).

Cabozantinib is a substrate of cytochrome P450 (CYP)3A4 in vitro. Inhibition of CYP3A4 reduced the formation of the cabozantinib N-oxide metabolite by > 80%. Inhibition of CYP2C9 had a minimal effect on cabozantinib metabolite formation (ie, a < 20% reduction). Inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP2E1 had no effect on cabozantinib metabolite formation. In healthy subjects, cabozantinib AUC was increased 38% with coadministration of the strong CYP3A4 inhibitor ketoconazole and decreased 77% with coadministration of the strong CYP3A4 inducer rifampin (rifampicin).

Cabozantinib is a noncompetitive inhibitor of CYP2C8 (Kiapp = 4.6 μM), a mixed-type inhibitor of both CYP2C9 (Kiapp = 10.4 μM) and CYP2C19 (Kiapp = 28.8 μM), and a weak competitive inhibitor of CYP3A4 (estimated Kiapp = 282 μM) in human liver microsome (HLM) preparations. Concentration associated with 50% inhibition (IC50) values > 20 μM were observed for CYP1A2, CYP2D6, and CYP3A4 isozymes in both recombinant and HLM assay systems. Cabozantinib at steady-state plasma concentrations (≥ 100 mg/day daily dosing for a minimum of 21 days) showed no effect on single-dose rosiglitazone (a CYP2C8 substrate) plasma exposure (Cmax and AUC) in subjects with solid tumors.


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Cabozantinib is an inducer of CYP1A1 mRNA in human hepatocyte incubations (ie, 75 100% of CYP1A1 positive control β-naphthoflavone induction) but not of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP3A4 mRNA or isozyme-associated enzyme activities.

Concomitant administration of proton pump inhibitor (PPI) esomeprazole resulted in no clinically- relevant effect on cabozantinib plasma PK in healthy subjects.

Cabozantinib is an inhibitor (IC50 = 7.0 μM), but not a substrate, of P-glycoprotein (P-gp) transport activities in a bi-directional assay system using MDCK-MDR1 cells. In addition, cabozantinib was shown to be a substrate of drug transporter multidrug resistance-associated protein 2 (MRP2) in an in vitro assay.

1.2.4 Dosing For single agent cabozantinib tablets, the recommended dose is cabozantinib 60 mg free-base equivalent (FBE) once daily by mouth which is included in the prescribing information for the treatment of renal cell carcinoma. This is less than the approved dose for medullary thyroid cancer which has a recommended dose of 140 mg (FBE), however, that is with the capsule formulation which is not bioequivalent to the tablets and is not being used in Exelixis' current development plan for solid tumors beyond thyroid cancer.

There have been many studies which examined the dose of cabozantinib at 60 mg (FBE) per day. For company sponsored studies, the list includes completed studies; XL184-306, XL184-307, and XL184-308 as well as ongoing studies; XL184-309 and XL184-401. These are summarized in the Investigator's Brochure.

In addition to Company trials, the investigator initiated studies in the Tables below also include a 60 mg (FBE) dose.

1.2.4.1 Investigators Study driven Study Number Indication Countries

Involved Full Enrollment

Current Enrolled Study Title NCT #

XL184-IST1

Prostate Cancer

USA 36 36 Dose-Finding Pilot Study of XL184 in Men With Castrate-Resistant Prostate Cancer and Bone Metastases

NCT01347788

XL184-IST4

Prostate Cancer

USA 25 25 A Phase 2 trial of XL184 in patients with castrate-resistant prostate cancer metastatic to bone (chemotherapy naïve population)

NCT01428219


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Study Number Indication Countries



XL184-IST5

Prostate Cancer

USA 19 19 A Phase II study of MRI based functional imaging for the evaluation of bone metastasis in men with castrate resistant prostate cancer receiving XL184

NCT01599793

XL184-IST7

Neuroendocrine Tumors

USA 62 62 An open-label, phase II study of cabozantinib (XL184) in patients with advanced pancreatic neuroendocrine and carcinoid tumors after progression on prior therapies

NCT01466036

XL184-IST8

CRPC with bone mets

USA 20 20 Pilot trial of oral XL184 in metastatic castrate resistant prostate cancer to explore the changes in bone and tumor imaging related pathways

NCT01812668

XL184-IST9

Multiple solid tumor types

USA 38 38 Phase II trial of X184 in patients with advanced solid malignancies (non-breast, non-prostate) and bony metastases

NCT01588821

XL184-IST15

Breast Cancer

USA 35 35 A Phase 2 Study of XL184 for metastatic triple-negative breast cancer

NCT01738438

XL184-IST20

Prostate Cancer

USA 40 17 A phase II study of cabozantinib (XL184) therapy in castrate resistant prostate cancer (CRPC) with visceral disease

NCT01834651


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XL184-IST21

NSCLC USA 68 36 A Phase II Study of Cabozantinib in Patients with KIF5B/RET-Positive Advanced Non-Small Cell Lung Cancers

NCT01639508

XL184-IST23

Prostate Cancer

USA 34 9 A pilot study of the effects of cabozantinib (XL184) on bone turnover and the microenvironment in men with non-metastatic and metastatic castration-resistant prostate cancer

NCT01703065

XL184-IST25

High Grade Uterine Sarcoma

Belgium France Italy Netherlands Spain UK

90 5 62113-55115: A randomized phase II study evaluating the role of maintenance therapy with XL184 in High Grade Uterine Sarcoma (HGUS) after stabilization or response to chemotherapy following surgery or in metastatic first line treatment

NCT01979393

XL184-IST26

Cholangiocarcinoma

USA 19 19 A Phase II Study of Cabozantinib (XL-184) Monotherapy in Patients with Advanced Cholangiocarcinoma after Progression on First or Second Line Systemic Therapy

NCT01954745


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XL184-IST27

AML USA 18 18 A phase I study of cabozantinib for patients with relapsed or refractory acute myeloid leukemia (AML)

NCT01961765

XL184-IST30

Merkel Cell Carcinoma

USA 8 8 Pilot Study with Cabozantinib in Recurrent/Metastatic Merkel Cell Carcinoma

NCT02036476

XL184-IST31

NSCLC USA 54 2 A single-arm phase II clinical trial of cabozantinib in patients with previously treated non-small cell lung cancer (NSCLC) with brain metastases with and without c-MET amplification

NCT02132598

XL184-IST34

Differentiated Thyroid Cancer

USA 35 32 A Phase II Trial of Cabozantinib for the Treatment of Radioiodine (RAI)-refractory Differentiated Thyroid Carcinoma (DTC) in the First-line Setting

NCT02041260

XL184-IST35

Pheochromocytomas and Paragangliomas

USA 22 14 A Pilot Study to Evaluate the Effects of Cabozantinib in Patients with Unresectable Metastatic Pheochromocytomas and Paragangliomas

NCT02302833


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1.2.4.2 Cancer Therapy Evaluation Program of US National Cancer Institute

Study Number

Indication Lead Institution

Full enrollment

Total Enrolled

Study Title NCT#

L9236 Urothelial Cancer

NCI 69 69 A phase II study of XL184 in patients with advanced/metastatic urothelial carcinoma

NCT01688999

9284 Soft Tissue Sarcomas

NCI 50 24 A Phase 2 Study of XL184 (Cabozantinib), a Dual Inhibitor of MET and VEGFR, in Patients With Metastatic Refractory Soft Tissue Sarcoma.

NCT01755195

9312 Differentiated Thyroid Cancer

OSU 25 25 Phase II Study of Cabozantinib in Patients with Radioiodine-Refractory Differentiated Thyroid Cancer Who Failed Prior First-Line VEGFR-Targeted Therapy

NCT01811212

9322 Endometrial Cancer

PMH 80 101 A Phase 2 Study of XL184 (Cabozantinib) in Recurrent or Metastatic Endometrial Cancer.

NCT01935934

L9620 Osteosarcomas & Ewing Sarcomas

Institut Bergonie

90 64 Phase 2 Trial of Cabozantinib in Treating Patients With Relapsed Osteosarcomas and Ewing Sarcomas

NCT02243605


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Study Number

Indication Lead Institution

Full enrollment

Total Enrolled

Study Title NCT#

9299/ Alliance number AO31203

Renal Cell Carcinoma

DFCI 157 157 Randomized Phase II Study Comparing Cabozantinib with commercially supplied Sunitinib in Patients with Previously-Untreated Metastatic Renal Cell Carcinoma

NCT01835158

AO91201

Uveal Melanoma

DFCI 69 47 Randomized Phase II Study comparing the MET inhibitor cabozantinib to temozolomide/dacarbazine in ocular melanoma

NCT01835145

9301 Ovarian Cancer

DFCI 111 111 Randomized Phase II Study of cabozantinib versus weekly paclitaxel in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer.

NCT01716715

S1500

Papillary Renal Cell Cancer

SWOG 164 30

A randomized phase II efficacy assessment of multiple MET knase inhibitors in metastatic papillary renal carcinoma (PAPMET)

NCT02761057

1.2.4.3 Dosing for GIST patients There were 4 GIST patients who were enrolled on the Japanese dose finding study (NCT01553656). Three of these patients received 75mg of Cabozantinib malate salt in capsule, which corresponds to a FBE of 60 mg and one of the patients received 100 mg of Cabozantinib malate salt in capsule, which corresponds to a FBE of 80 mg. The 60 mg tablet formulation has a FBE of 60 mg. The Table below summarizes the strength conversions.


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1.2.4.4 Recommended dosing for this trial In addition to the above considerations, the mode of action for cabozantinib is similar to other drugs targeting RTKs: binding in a fully reversible manner to a region of the kinase domain (including the ATP-binding site) which forces the kinase activation loop into a pseudo-inactive conformation, thereby inhibiting subsequent catalytic activity. The cell-based target inhibition profile of cabozantinib is shown in the Table below.

In conclusion, it appears to be a reasonable hypothesis to investigate cabozantinib tablets 60 mg (FBE) per day given the low IC50 for cKIT (5nM) in conjunction with the demonstrated efficacy of cabozantinib tablets at 60 mg (FBE) per day in RCC where the IC50s for the most relevant targets (VEGFR2 (2nM), MET (8nM) and AXL (77nM)) are similar to that of cKIT.

1.2.5 Safety profile Common side effects experienced by patients treated with cabozantinib in clinical trials include gastrointestinal symptoms (such as nausea, vomiting, and diarrhea), fatigue/asthenia, anorexia, weight loss, skin rash, and mucosal inflammation/stomatitis.

Common laboratory abnormalities reported as adverse events include elevated liver function tests (including ALT and AST), thyroid stimulating hormone (TSH) increase, hypokalemia, hypomagnesemia, hypophosphatemia, hypocalcemia, increase in serum lipase, and thrombocytopenia. In many patients, these adverse events have required treatment interruption or dose reduction.


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Effects that may be related to inhibition of the vascular endothelial growth factor pathway, including hypertension, thromboembolic events, gastrointestinal tract perforation, fistula formation, hemorrhage, wound healing complications, and proteinuria, have been observed in clinical studies with cabozantinib.

Reversible posterior leukoencephalopathy has occurred in a cabozantinib-treated patient.

The most commonly reported serious adverse events (experienced by ≥1% of patients) with single agent cabozantinib regardless of causality are pulmonary embolism, dehydration, pneumonia, diarrhea, vomiting, deep vein thrombosis, convulsion, abdominal pain, nausea, dyspnea, mental status changes, hyponatremia, asthenia, acute renal failure, confusional state, urinary tract infection (Ref. 14).

A single case of possible drug-induced liver injury (which met Hy’s law screening criteria) with no clinical sequelae was observed in the pooled single-agent study grouping. A mean increase from baseline in Fridericia’s correction of QT (QTcF) values of 10 ms (upper bound of one-sided 95% confidence interval [CI] <15 ms) within the first 4 weeks of initiating cabozantinib treatment was observed in one study. This effect was not associated with a change in cardiac wave form morphology or new rhythms. No cabozantinib-treated patients had a QTcF >500 ms (Ref. 14).

As of 29 February 2016, the incidence of grade 5 adverse events from pooled single-agent studies was 10.5% (254 subjects/2410). The grade 5 adverse events that occurred at ≥ 1% frequency were prostate cancer (2.9%) and general physical health deterioration (1.0%). Only one of these events (an event of general physical health deterioration on Study XL184-307) was assessed as related to study treatment. 33 subjects had grade 5 adverse events that were assessed as related to study treatment. The only fatal events that occurred more than once were pulmonary embolism (four patients), death (unspecified; three patients), haemorrhage (two patients), respiratory failure (two patients), and sudden death (two patients). In the ongoing company-sponsored double-blind Study XL184-309 (N = 450) in subjects with advanced hepatocellular carcinoma, 58 grade 5 adverse events (regardless of causality) were reported as of 29 February 2016 (Ref. 14).

1.2.6 Anti-tumor activity Cabozantinib has demonstrated broad clinical activity in multiple tumor types, including thyroid, breast, ovarian, prostate, and lung cancers and melanoma, glioblastoma, hepatocellular and renal cell carcinoma. Observations of clinical activity have included shrinkage of soft tissue tumor lesions including visceral metastases, effects on metastatic lesions on bone scan (partial or complete bone scan resolution) and reduction in serum tumor markers and in circulating tumor cells.

In the placebo-controlled Phase III study XL184-301 in 330 patients with medullary thyroid carcinoma a significant increase in PFS was seen in the cabozantinib arm compared with placebo (11.2 vs 4.0 months; hazard ratio [HR] =0.28; 95 confidence intervals [CIs]: 0.19, 0.40) (Ref. 10). Confirmed partial responses (PR) occurred in 28% of cabozantinib-treated patients and none in the placebo arm; responses were durable (median duration 14.6 months) (Ref. 10).

In the Phase II randomized discontinuation study XL184-203 in multiple solid tumors, cabozantinib demonstrated broad clinical activity in men with castration-resistant prostate adenocarcinoma. In the randomized discontinuation cohort an increase in PFS was observed in the cabozantinib arm compared with placebo (23.9 vs 5.9 weeks). The objective response rate (ORR) at 12 weeks was 5% with stable disease (SD) in 75%. Seventy-two percent of patients had regression in soft tissue lesions. Activity was also observed in the randomized discontinuation trial in other disease-specific cohorts: disease control/patient benefit rates (defined as SD, PR, or complete response (CR)) at week 12 ranged from 38-66%: non-small cell lung cancer, 38%; breast cancer, 48%; melanoma, 46%; ovarian cancer, 47%; and hepatocellular carcinoma, 66% (Ref. 15).

Based on the results of the above mentioned Phase II studies the kinase inhibitor is also in advanced stages of clinical testing in renal cell carcinoma (NCT01865747). Exelixis recently reported positive results from


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a Phase III pivotal trial of cabozantinib versus everolimus in patients with metastatic renal cell carcinoma (METEOR, XL184-308). The trial met its primary endpoint of demonstrating a median PFS of 7.4 months in patients treated with cabozantinib and 3.8 months with everolimus. Cabozantinib reduced the risk of disease progression or death by 42 percent compared to the everolimus arm (hazard ratio [HR]=0.58, 95% CI 0.45-0.75, p<0.0001). The objective response rate was 17% with cabozantinib and 3% with everolimus (P<0.001). A planned interim analysis at the time of the primary analysis of PFS showed that overall survival was longer with cabozantinib than with everolimus (HR for death 0.68; 95% CI, 0.51 to 0.90; P=0.006) but did not cross the significance boundary for the interim analysis (Ref. 16). Following those results, an unplanned second interim OS analysis was specified, with a prospectively-defined cutoff date of 31 December 2015 to provide at least 12 months of follow-up from the last subject randomized. The second interim OS analysis with a minimum follow-up of 13 months demonstrated a highly statistically significant prolongation of OS for subjects in the cabozantinib arm compared with the everolimus arm: the HR, adjusted for stratification factors was 0.66 (95% CI: 0.53, 0.83; stratified log-rank p-value 0.0003). Kaplan-Meier estimates for median duration of OS were 21.4 months in the cabozantinib arm and 16.5 months in the everolimus arm. Results for extensive subgroup analyses of PFS, OS, and ORR showed a consistent benefit for cabozantinib treatment. (Ref. 36).

Final results of the Phase III, randomized double-blind, controlled trial XL184-307 (COMET-1) have been presented during the 2015 ASCO meeting (Ref. 17). The study enrolled 1028 subjects with advanced castration resistant prostate cancer with bone metastases. The prespecified primary analysis of the primary endpoint (OS) was based on an ITT analysis of all randomized subjects. The analysis included 614 events (578 were required) and did not demonstrate a statistically significant improvement in OS for subjects in the cabozantinib arm compared with the prednisone arm: the hazard ratio, adjusted for prior cabazitaxel use, baseline Brief Pain Inventory (BPI; Item 3) score, and baseline ECOG performance status was 0.90 (95% CI: 0.76, 1.06; stratified logrank p-value 0.213).

Although there was no improvement in survival, cabozantinib significantly improved bone scan response (measured as a 30% reduction in lesion volume): 42% vs 3% with prednisone (P < 0.001). In addition, cabozantinib significantly improved investigator-assessed PFS: Median PFS was 5.6 months vs 2.8 months, respectively (P < 0.001). Also, time to first on-study skeletal-related event was longer with cabozantinib (Ref. 17).

Based on the results of XL184-307 (COMET-1), XL184-306 (COMET-2) randomization was concluded prior to reaching the planned sample size of 246. The study enrolled subjects with advanced prostate cancer with bone metastases. The primary endpoint was proportion of subjects with a pain response ( ≥30% reduction in BPI item 3) at week 6, confirmed at week 12. A total of 119 subjects were enrolled. The primary analysis for the ITT population (n=119) did not demonstrate an improvement in the proportion of subjects with a pain response in the cabozantinib arm compared with the mitoxantrone plus prednisone arm (Ref. 18).

1.3 Rationale Patients with metastatic GIST who failed imatinib and sunitinib have very limited treatment options. The European Medicines Agency (EMA) recently approved regorafenib for the treatment of adult patients with unresectable or metastatic GIST who progressed on or are intolerant to prior treatment with imatinib and sunitinib. In this setting, regorafenib achieves a median PFS per independent blinded central review of only 4.8 months. The off label use of other tyrosine kinase inhibitors is common practice (Ref. 19). Another generally accepted treatment option which is supported by randomized prospective trial evidence is a re-challenge with imatinib (Ref. 20). Imatinib re-challenge, however, is associated with only a 1.8 month PFS, a DCR at 12 weeks of 32% and a median OS of only 8.2 months. An effective treatment for refractory GIST thus remains an unmet medical need, even after introduction of regorafenib.


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Cabozantinib is a novel compound that inhibits relevant molecular targets that play an important role in GIST pathogenesis and progression. The drug is active in patient-derived GIST xenografts and was associated with patient benefit in all 4 imatinib/sunitinib-resistant GIST patients in an ongoing Japanese Phase I trial. The current Phase II study will primarily assess the safety and activity of cabozantinib in patients with metastatic GIST who previously progressed on imatinib and sunitinib and have not been exposed yet to other tyrosine kinase inhibitors.

2 Objectives of the trial 2.1 General objective The main objective is to assess the safety and activity of cabozantinib in patients with metastatic GIST who have previously progressed on imatinib and sunitinib and have not yet been exposed to other KIT- or PDGFR-directed tyrosine kinase inhibitors such as regorafenib or similar agents.

Secondary objectives of the trial include:

♦ To assess the relative efficacy of cabozantinib in different mutational subtypes of GIST based on both archived tumor material derived from the primary tumor or a metastatic site, and mutations detected in circulating cell-free DNA using centralized mutational analysis.

♦ To explore the use of circulating cell-free DNA (“liquid biopsy”) for centralized mutational analysis in GIST.

2.2 End-points

2.2.1 Primary endpoint Progression free survival at 12 weeks (binary) according to RECIST 1.1.

2.2.2 Secondary endpoints The secondary endpoints include:

♦ PFS according to RECIST 1.1.

♦ Overall survival (OS).

♦ Objective response rate (ORR), defined as a complete or partial response (CR or PR) according to RECIST 1.1.Clinical benefit rate (CBR) defined as CR, PR, or SD according to RECIST 1.1.Total duration of treatment (including treatment beyond RECIST progression).

♦ Safety (graded according to the Common Terminology Criteria for Adverse Events, CTC-AE, version 4.0).

2.2.3 Exploratory endpoints The exploratory endpoints include:

♦ Prevalence of different mutational subtypes of GIST in archived tumor material derived from the primary tumor or a metastatic site and relative efficacy (ORR, CBR, PFS and PFS [binary]) of cabozantinib in recruited mutational subsets.

♦ Feasibility of using circulating plasma DNA as “liquid biopsy” for mutational analysis in metastatic GIST with assessment of the concordance of results with conventional tissue-based mutational analysis.


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♦ Prevalence of different mutational subtypes of GIST circulating cell-free DNA and relative efficacy (ORR, CBR, PFS and PFS [binary]) of cabozantinib in recruited mutational subsets.

♦ Longitudinal assessment of circulating cell-free DNA in patients with metastatic GIST as a potential prognostic/predictive marker.

3 Patient selection criteria 3.1 Disease status ♦ Histologically confirmed diagnosis of GIST that is metastatic. Patients with the primary tumor still in

place are excluded from the trial, due to the risk for intestinal perforation reported for cabozantinib.

♦ Presence of at least one non-previously irradiated, measurable metastatic lesion as defined by RECIST 1.1.

♦ No evidence of tumor or metastatic lesion invading the gastrointestinal tract (esophagus, stomach, small or large bowel, rectum or anus) within 28 days prior to the first dose of cabozantinib.

♦ No current evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib.

♦ Radiographic absence of a cavitating pulmonary lesion within 28 days prior to the first dose of cabozantinib.

♦ No patient with tumor in contact with, invading or encasing a major blood vessel.

♦ Consent of the patient ♦ Archival tumor tissue available from primary tumor or metastatic site (10 unstained slides with

archived tumor tissue of 10 micrometer thickness and two hematoxylin and eosin (H&E) stained slides) for central mutational analysis (Refer to chapter 10) and (5 unstained slides of 4 micrometer thickness) for pathology review.

♦ To allow sequential sampling of blood for the circulating cell-free DNA isolation for central mutational analysis

♦ Failure on prior therapy with imatinib and sunitinb ♦ An interval from prior tyrosine kinase inhibitor (TKI) therapy to the first dose of cabozantinib

of at least 14 days

♦ Radiological progression on imatinib during neoadjuvant, adjuvant or palliative treatment of GIST or within 3 months after completing adjuvant treatment with imatinib AND radiological progression on sunitinib for the treatment of advanced GIST.

Note: progression is assessed by local radiologist/oncologist without central confirmation of pre-baseline progression.

♦ No other prior use of tyrosine kinase inhibitors for the treatment of advanced GIST with the exception of imatinib and sunitinib.

♦ No other investigational agents within 28 days before the first dose of study treatment.


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3.2 Patient status ♦ Male or female patient ≥ 18 years of age.

♦ ECOG performance status (PS) of 0-1 (See Appendix C)

♦ Adequate bone marrow and organ function prior to receiving the first dose of study treatment: ♦ Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (no prophylactic administration of G-CSF or

GM-CSF allowed).

♦ Platelet count ≥ 100 x 109/L or x 103/μL (transfusion allowed).

♦ Hemoglobin ≥ 9.0 g/dL or 5.6 mmol/L (transfusion and erythropoietin allowed).

♦ Prothrombin time (PT)/INR or partial thromboplastin time (PTT) test < 1.3 × ULN within 7 days before the first dose of study treatment.

♦ Serum phosphorus, calcium, magnesium and potassium within normal range.

♦ Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 50 mL/min or glomerular filtration rate (GFR) >30 mL/min (as assessed per local standard).

♦ Serum bilirubin within normal range (or ≤ 1.5 x ULN if liver metastases are present; or total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in patients with Gilbert’s syndrome).

♦ Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within ≤ 3.0 x ULN or ≤ 5.0 x ULN if liver metastases.

♦ Serum albumin ≥ 2.8 g/dL.

♦ Serum lipase < 2 x ULN and no radiologic or clinical evidence of pancreatitis.

♦ Urine protein/creatinine ratio (UPCR) ≤ 1.

♦ Clinically normal cardiac function based on the institutional lower limit of normal for-left ventricular ejection fraction as assessed either by multi-gated acquisition scan or cardiac ultrasound, 12 lead ECG without clinically relevant abnormalities.

♦ No history of congenital long QT syndrome.

♦ No QTcF (Fridericia's formula) > 500 msec within 1 month before the first dose of study treatment: three ECGs must be performed for eligibility determination. If the average of these three consecutive results for QTcF is ≤ 500 msec, the patient meets eligibility in this regard.

♦ No congestive heart failure (CHF): New York Heart Association (NYHA) Class III (moderate) or Class IV (severe) at the time of screening;

♦ No history of any of the following cardiovascular conditions within 6 months prior to the first dose of study treatment:

♦ Unstable angina.

♦ Clinically significant cardiac arrhythmias.

♦ Myocardial infarction.

♦ No poorly controlled hypertension defined at baseline as blood pressure (BP) >150/100 mmHg despite optimal antihypertensive treatment within 7 days of the first dose of study treatment

♦ No concomitant anticoagulation at therapeutic doses with oral anticoagulants (eg, warfarin, direct thrombin and Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel);


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Note: Low-dose aspirin for cardioprotection (per local applicable guidelines), low-dose warfarin (< 1 mg/day), and low dose, low molecular weight heparins (LMWH) are permitted. Anticoagulation with therapeutic doses of LMWH is allowed in subjects who are on a stable dose of LMWH for at least 12 weeks before registration, and who have had no complications from a thromboembolic event or the anticoagulation regimen.;

♦ Patients must be able to swallow and retain oral film-coated tablets.

♦ Recovery to baseline or ≤ Grade 1 CTCAE v.4.0 from toxicities related to any prior treatments, unless AE(s) are clinically non-significant and/or stable on supportive therapy.

♦ No specific contraindications for treatment with cabozantinib (e.g. no known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to cabozantinib).

♦ No stroke (including transient ischemic attack (TIA), or other ischemic event) and no thromboembolic event requiring therapeutic anticoagulation within 6 months before the first dose of study treatment.

Note: subjects with a venous filter (eg, vena cava filter) are not eligible for this study.

♦ No gastrointestinal disorders associated with a high risk of perforation or fistula formation including the following:

♦ Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (eg, ulcerative colitis, Crohn’s disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction.

♦ Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess within 6 months before registration.

♦ Ongoing visceral complications from prior therapy

♦ Prior GI surgery (particularly when associated with delayed or incomplete healing)

Note: Complete healing of an intra-abdominal abscess must be confirmed prior to registration.

♦ No other clinically significant disorders that would preclude safe study participation.

♦ No evidence of significant active bleeding (including gastrointestinal (GI) bleeding) or bleeding diathesis within 6 months before the first dose of study treatment.

♦ No hemoptysis ≥ 0.5 teaspoon (2.5 ml) of red blood within 3 months before the first dose of study treatment.

♦ No signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment.

♦ Prior radiation therapy ♦ No radiation therapy for bone metastasis within 2 weeks, or any other external radiation therapy

within 4 weeks before the first dose of study treatment.

♦ No systemic treatment with radionuclides within 6 weeks before the first dose of study treatment.

♦ Patients with clinically relevant ongoing complications from prior radiation therapy are not eligible.

♦ Prior surgery:


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♦ No major surgery or trauma within 12 weeks prior to first dose of study drug and/or presence of any non-healing wound, fracture or ulcer. Complete wound healing from major surgery must have occurred one month before the first dose of study treatment.

♦ Minor surgery (including uncomplicated tooth extractions) within 28 days before the first dose of study treatment with complete wound healing at least 10 days before the first dose of study treatment is permitted.

♦ Patients with clinically relevant ongoing complications from prior surgery are not eligible.

♦ None of the following clinically significant disorders such as: ♦ Active infection requiring systemic treatment within 28 days before the first dose of study

treatment.

♦ History of organ transplant.

♦ Concurrent severe, clinically relevant hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment.

♦ No history of other malignancy in the past 5 years with the exception of treated carcinoma in situ of the cervix and non-metastatic, non-melanoma skin cancer. Patients with desmoid fibromatosis or neurofibromas, which can be associated with GIST, are allowed to enter the trial, under the provision that they do have a measurable GIST lesion that can be distinguished from the other lesions.

♦ Patients requiring chronic concomitant treatment with strong Cytochrome P450 (CYP3A4) inducers (e.g. dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John’s Wort) are not eligible.

♦ Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other study procedures.

♦ Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.

♦ Women of child bearing potential (WOCBP) must have a negative serum pregnancy test within 72 hours prior to the first dose of study treatment.

Note: women of childbearing potential are defined as premenopausal females capable of becoming pregnant (i.e. females who have had any evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy). However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body weight, ovarian suppression or other reasons.

♦ Patients of childbearing / reproductive potential should use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 4 months after the last study treatment. A highly effective method of birth control is defined as a method which results in a low failure rate (i.e. less than 1% per year) when used consistently and correctly. Such methods include:

♦ Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal)

♦ Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)

♦ Intrauterine device (IUD)

♦ Intrauterine hormone-releasing system (IUS)


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♦ Bilateral tubal occlusion

♦ Vasectomized partner

♦ Sexual abstinence

♦ Lactating females are not eligible.

♦ Before patient registration, written informed consent must be given according to ICH/GCP, and national/local regulations.

Important note: All eligibility criteria must be adhered to, in case of deviation discussion with EORTC Headquarters and the study coordinator is mandatory.

4 Trial Design This trial is a Phase II, multi-center, multi-national, open label, single arm study of cabozantinib in patients with metastatic GIST whose primary tumor has been removed, who have failed imatinib and sunitinib, and who have not received other tyrosine kinase inhibitors for the treatment of advanced GIST.

Patients will be registered at the EORTC Headquarters prior to the start of treatment, and after verification of all eligibility criteria. Patients will receive cabozantinib until they experience no further benefit from the treatment, become intolerant to the drug or wish to discontinue the treatment. Treatment beyond RECIST 1.1 progression is allowed in patients deriving clinical benefit upon investigator’s discretion, provided no other criteria for treatment withdrawal are met. This is considered to be part of the study protocol treatment.

An A'Hern single stage design will be applied (Ref. 21, Ref. 22). The decision rule will require 41 eligible and evaluable* GIST patients. If at least 21 out of these 41 patients are progression-free at the week 12 assessment (see chapter 7.1), the activity of cabozantinib in this trial will be deemed sufficient to warrant further exploration of the drug in metastatic GIST. To allow for a sufficient number of patients to be assessable for the decision rule, enrollment can continue beyond 41 patients, but will be capped at 50. * A patient will be considered as "evaluable" for the primary endpoint if he/she started the study treatment (at least one dose) and he/she had an imaging assessment at baseline.


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Figure 1 Trial Design


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5 Therapeutic regimens, expected toxicity, dose modifications

5.1 Drug information

5.1.1 General information

5.1.1.1 Pharmaceutical presentation Laboratory code name: XL184, EXEL-7184, EXEL-02977184

International nonproprietary name (INN): cabozantinib

Molecular formula: C28H24FN3O5.C4H6O5

Chemical name: N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (2S)-hydroxybutanedioate

5.1.2 Drug supply Cabozantinib will be adequately provided by Exelixis free of charge as 60-mg and 20-mg yellow film-coated tablets. The 60-mg tablets are oval and the 20-mg tablets are round. Initial drug supply shipment is to be distributed upon site activation. Subsequent drug resupply shipment will be based on site's enrollment. The drug ordering will be made following submission of a drug shipment order form from EORTC site to the distribution vendor. Further practicalities for drug supply will be detailed in the pharmacy guidelines.

5.1.3 Packaging, dispensing and storage Refer to the study pharmacy guidelines for details on packaging, dispensing, and storage and handling of cabozantinib.

5.1.4 Drug reconciliation procedures Accountability of the investigational study drug is under the responsibility of the investigator but can be delegated to an appropriately qualified person. Study drug accountability should be maintained by each site. Accountability records should include receipt date, lot numbers, expiry dates, patient sequential identification number, use by patient, issue dates, quantities (lowest unit) and stock balance.

At the end of the study, when all patients have stopped protocol treatment, complete drug reconciliation per batch should be available at the site for verification by EORTC in order to allow drug destruction or return procedure. Standard accountability forms can be provided to the sites for the record of drug accountability. However, the sites are permitted to use their own template providing they included all the required fields.

5.2 Initial dose and schedule One cycle of treatment is defined as 21 days.

Cabozantinib tablets will be administered as an oral single agent once daily dose at 60 mg (expressed as the freebase weight). NOTE: all dosing instructions in this protocol refer to the freebase weight.

♦ Cabozantinib must be taken on an empty stomach. Patients must be instructed not to eat for at least 2 hours before and at least 1 hour after taking cabozantinib.


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♦ Patients should be instructed to take their cabozantinib dose at approximately the same time every day. If a patient misses a dose, the dose may be taken later only if it is within 12 hours of when the missed dose should have been taken. The missed dose should not be made up if it is within 12 hours of the next scheduled dose.

♦ Cabozantinib tablets should be swallowed whole with at least 8 ounces or 225 mL of water. The tablets should not be crushed. Grapefruit, grapefruit juice, Seville oranges and their products should be avoided by patients taking cabozantinib.

In all patients, dose reductions and delays to manage toxicity are allowed under the guidelines in chapter 5.4 below.

5.3 Withdrawal criteria Patients will receive cabozantinib until they experience no further benefit from the treatment, are becoming intolerant to the drug or wish to discontinue the treatment.

Treatment beyond RECIST 1.1 progression is allowed in patients deriving clinical benefit upon investigator’s discretion, provided that no other criteria for treatment withdrawal, as summarized below, are met. This is considered to be part of the study protocol treatment. Patients may discontinue study treatment or withdraw their consent to participate in the study at any time without prejudice.

The following conditions require patient discontinuation from study treatment:

♦ An AE or intercurrent illness that, in the opinion of the investigator, warrants the patient’s withdrawal from study treatment.

♦ Specific conditions described in the Management of Adverse Events in chapter 5.4.

♦ Necessity for treatment with other anticancer treatment prohibited by protocol.

♦ Sexually active patients who refuse to use medically accepted effective/adequate methods of contraception as described in the patient selection criteria during the course of the study and for 4 months following discontinuation of study treatment.

♦ Women who become pregnant.

♦ The investigator feels it is not in the best interest of the patient to continue on study.

♦ Specific conditions described in the management of toxicities (refer to chapter 5.4)

♦ Request by regulatory agencies for termination of treatment of an individual patient or all patients under the protocol.

♦ Significant non-compliance/non-adherence with the protocol schedule in the opinion of the investigator.

♦ The minimum daily dose of study treatment will be 20 mg. Patients who cannot tolerate 20 mg per day will have study treatment discontinued.

♦ RECIST 1.1 progressive disease (PD) and no further clinical benefit from the treatment as determined by the investigator. If cabozantinib is continued beyond progression, it may not be combined with other anticancer agents.

The reason for study treatment discontinuation should be documented. For patients who discontinue or are withdrawn from study treatment, every effort must be made to undertake protocol-specified follow-up procedures and end-of-treatment assessments, if possible, unless consent to participate in the study is also withdrawn.


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If a patient fails to return for the protocol-defined visits, an effort must be made to determine the reason. If a patient withdraws consent to participate in the study, the reason for withdrawal will be documented, no further study procedures or assessments will be performed, and no further study data will be collected for this patient.

After definitive cabozantinib discontinuation, the treatment will be left to the discretion of the treating physician. Any anti-cancer therapy other than the study drug given as single agent will not be considered as part of the protocol treatment. Follow up must be continued for survival as per protocol

5.4 Dose and schedule modifications

5.4.1 General recommendations for cabozantinib The most frequent adverse events experienced by ≥ 20% of subjects treated with cabozantinib in descending order of frequency were diarrhea, fatigue, nausea, decreased appetite, vomiting, weight decreased, PPE, constipation, hypertension, dysgeusia, dysphonia, and asthenia.

Adverse events associated with laboratory abnormalities experienced by ≥ 5% of patients treated with cabozantinib in descending order of frequency wereanemia, AST increased, ALT increased, hypothyroidism, hypokalemia, hypomagnesemia, thrombocytopenia, hypocalcemia, hypophosphatemia, LDH increased, lipase increased, neutropenia, hyponatremia, ALP increased, leukopenia, and hyperglycemia. Mild to moderate QTc interval prolongation (10-15ms) has also been observed with a QT interval calculated by the Fridericia formula (QTcF) not exceeding 500 ms.

Patients may also experience other medically important but less frequent adverse events including arterial and venous thrombotic AEs (eg, DVT, pulmonary embolism, transient ischemic attack and myocardial infarction), severe hemorrhagic events, proteinuria, wound healing complications, GI perforation, abscesses including intra-abdominal and pelvic abscess, GI and non-GI fistula formation, osteonecrosis, and reverse posterior leukoencephalopathy syndrome.

The predicted effective plasma half-life of cabozantinib is 55 hours. Thus, when initiating therapy with cabozantinib, it will take most patients 2 to 3 weeks to reach steady state level. If AEs attributable to cabozantinib occur within the initial 3-week period of dosing, early intervention with dose modifications may be justified for AEs that, if worsened, could potentially be dangerous or debilitating, because without a dose adjustment, systemic exposure of cabozantinib might be expected to increase after the onset of the AE.

Events that generally have an early onset include hypocalcemia, hypokalemia, thrombocytopenia, hypertension, PPE, abdominal pain, mucosal inflammation, constipation, diarrhea and vomiting. In addition, earlier onset for events of dehydration was observed in subjects with castration resistant prostate carcinoma when compared with subjects with other tumor types.

All AEs should also be managed with supportive care at the earliest signs of toxicity considered related to study treatment.

If study treatment of cabozantinib is restarted after being withheld or interrupted, the patient should be instructed not to make up the missed doses of cabozantinib.

The reason for treatment delay and reduced dose must be recorded on the case report form (CRF) and will be assessed according to CTCAE 4.0.

Guidelines for the management of AEs (i.e. dose interruptions and dose reductions) are presented in the next sections.


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5.4.2 General guidance for dose and treatment interruption

5.4.2.1 Dose reduction Each dose reduction of cabozantinib should be to one dose level lower that the current dose. Dose reductions of more than one dose level are acceptable per Investigator judgment.

Table-1

Assigned dose First Dose Level Reduction Second Dose Level Reduction

60 mg cabozantinib oral qd 40 mg cabozantinib oral qd 20 mg cabozantinib oral qd

qd, once daily

Cabozantinib should be discontinued if a qd dose of 20 mg cabozantinib (minimum dose) is not tolerated

5.4.2.2 Cabozantinib Dose Reinstitution and Reescalation Recommendations are based on the dose modifications which Exelixis employs in its research programs with cabozantinib tablets.

If the patient recovers from the toxicities to CTCAE v.4.0 Grade ≤ 1 or to the baseline value (or lower) and the toxicity was unrelated to study treatment, then study treatment may be restarted with no change in dose.

If the patient recovers from the toxicities to Grade ≤ 1 or to the baseline value (or lower) the toxicity was deemed possibly related to study treatment, then study treatment may be restarted at a reduced dose (see Table 1 for the schedule of dose reductions).

Patients receiving a daily dose of 20 mg may be restarted at the same dose if deemed safe at the discretion of the investigator. Patients unable to tolerate a daily dose of 20 mg should discontinue study treatment.

Re-escalation to the previous dose, (but not higher than 60 mg/day) may be allowed at the discretion of the investigator and agreement of the Study coordinator and EORTC team for AEs which have resolved or recovered to Grade 1 (or baseline value) and deemed tolerable and easily managed by optimized supportive treatment.

Dose re-escalation is not allowed for a drug-related dose reduction triggered by Grade 4 hematologic toxicities or by Grade 4 AEs affecting major organs (eg, central nervous system, cardiac, hepatic, renal).

5.4.2.3 Dose interruption

Dose interruption

Due to AEs

If treatment is interrupted due to AEs for more than 6 weeks, cabozantinib should be discontinued unless there is unequivocal evidence that the patient is benefitting. In this situation, a patient may be able to restart therapy with a dose reduction upon resolution of the toxicity, that is to be determined by the investigator and the study coordinator in agreement with EORTC medical monitor.

For reason(s) other than related AEs

(eg, surgical procedures)

It can be longer than 6 weeks per the discretion of the investigator. Before re-starting treatment please discuss the case with the study coordinator and the EORTC medical monitor.


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Cabozantinib treatment should be permanently discontinued for the following adverse events:

♦ visceral perforation or fistula formation,

♦ severe hemorrhage,

♦ serious arterial thromboembolic events,

♦ nephrotic syndrome,

♦ hypertensive emergency,

♦ persistent uncontrolled hypertension despite optimal medical management, reverse posterior leukoencephalopathy syndrome

Dose reductions or interruptions are permitted in the setting of lower grade toxicity than defined in the following sections at the discretion of the investigator if the investigator feels it is in the interest of a patient’s safety.

5.4.3 General guidelines for treatment related adverse events As a general approach, it is suggested that all AEs be managed with supportive care when possible at the earliest signs of toxicity. Calcium, magnesium, potassium and phosphorus should be kept above the lower limits of the laboratory normal values.

Table 2: Dose modifications of cabozantinib for treatment related AEs

CTCAE v4.0 Recommended Guidelines for management*

Grade 1 Add supportive care as indicated. Continue cabozantinib at the current dose level if the AE is manageable and tolerable.

Grade 2 AEs which are tolerable and are easily managed

Continue cabozantinib treatment at the current dose level with supportive care.

Grade 2 AEs which are intolerable and cannot be adequately managed

At the discretion of investigator, cabozantinib should be reduced or Interrupted. Note: It is recommended that dose holds be as brief as possible

Grade 3 AEs (except clinically non-relevant laboratory abnormalities)

Cabozantinib should be interrupted unless the toxicity can be easily managed with a dose reduction and optimal medical care.

Note: It is recommended that dose holds be as brief as possible.

Grade 4 AEs (except clinically non-relevant laboratory abnormalities)

Patients should have cabozantinib interrupted immediately. Discontinue cabozantinib unless the following criteria are met:

♦ Patient is deriving clear clinical benefit as determined by the investigator and agreed by the Sponsor

♦ Toxicity can be managed with a dose reduction following recovery to Grade 1 (or baseline) and optimal medical care

* Study treatment dose adjustment is only needed if the toxicity was deemed related to cabozantinib treatment or had an unclear relationship to cabozantinib treatment.


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5.4.4 Guidelines for management of specific adverse events Guidelines or warnings/precautions for the following cabozantinib treatment-emergent adverse events/serious adverse events are of particular interest for:

♦ Gastrointestinal disorders (diarrhea, nausea, vomiting, stomatitis, mucositis) ♦ Hepatobiliary disorders (elevated ALT and AST)

♦ Hematologic disorders

♦ Fatigue

♦ Anorexia and weight loss

♦ Skin disorders (palmar-plantar erythrodysesthesia syndrome and rash)

♦ Wound healing and surgery

♦ Hypertension

♦ Thromboembolic events (venous and arterial)

♦ Proteinuria

♦ QTc prolongation

♦ Hypophosphatemia

♦ Thyroid function disorders

♦ Hemorrhagic events

♦ Osteonecrosis of jaw

♦ Angioedema

♦ Musculoskeletal and connective tissue disorders

♦ Respiratory, thoracic and mediastinal disorders Please refer to the Investigator’s Brochure (Ref. 14) for additional practice guidelines and management recommendations for side effects potentially related to cabozantinib treatment (such as asymptomatic elevations of amylase and lipase, pancreatitis, rectal and perirectal abscess, cardiac disorders, endocrine disorders, eye disorders, musculoskeletal and connective tissue disorders, nervous system disorders, respiratory, thoracic and mediastinal disorders); available information on potential risk of congenital, familial and genetic disorders; and guidelines on management of overdose of cabozantinib study treatment.

5.4.4.1 Gastrointestinal disorders The most common non-hepatobiliary GI AEs reported in clinical studies with cabozantinib regardless of causality are diarrhea, nausea, decreased appetite, vomiting, constipation, stomatitis and abdominal pain.

5.4.4.1.1 Diarrhea Patients should be instructed to notify their physician immediately at the first signs of poorly formed or loose stool or an increased frequency of bowel movements. Administration of antidiarrheal/antimotility agents is recommended at the first sign of diarrhea as initial management. Some patients may require concomitant treatment with more than one antidiarrheal agent. When therapy with antidiarrheal agents does not control the diarrhea to tolerable levels, study treatment should be temporarily interrupted or dose reduced per Table 3. When the diarrhea is controlled, retreatment with cabozantinib may be acceptable per investigator decision.


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In addition, general supportive measures should be implemented including continuous oral isotonic hydration, correction of fluid and electrolyte abnormalities, small frequent meals, and stopping lactose-containing products, high fat meals, and alcohol.

Recurrent or prolonged diarrhea can be associated with anal or perianal skin erosions which increase the risk for anal abscesses, fistulas, or proctitis. Good personal hygiene should be emphasized. Regular examinations of the perianal region should be performed whenever diarrhea has occurred during treatment with cabozantinib. Infections of the perianal region should be treated per local guidelines.

Table 3. Guidelines and management of treatment-emergent diarrhea

Status Management

Tolerable Grade 1-2

(duration < 48 h)

Continue with study treatment and consider dose reduction

Initiate treatment with an antidiarrheal agent (eg, loperamide 4 mg followed by 2 mg after each episode of diarrhea [maximum: 16 mg loperamide per day])

Dietary modifications (eg, small lactose-free meals, bananas and rice)

Intake of isotonic fluids (1-1.5 L/day)

Re-assess after 24 hours:

Diarrhea resolving to baseline bowel habits: gradually add solid foods and discontinue or decrease antidiarrheal treatment after 12 h diarrhea-free interval

Diarrhea not resolving: Continue/resume antidiarrheal treatment

Intolerable Grade 2,

Grade 2 > 48 h,

or ≥ Grade 3

Interrupt study treatment

Ask subject to attend clinic

Rule out infection (eg, stool sample for culture)

Administer antibiotics as needed (eg, if fever or Grade 3-4 neutropenia persists > 24 h)

Administer fluids (1-1.5 L/day, orally or IV, as appropriate) for hydration or to correct electrolyte abnormalities

For Grade 3-4 or complicated lower grade diarrhea consider hospitalization and IV hydration

Re-assess after 24 h

Diarrhea resolving to baseline bowel habits or Grade ≤ 1: consider restarting study treatment at reduced dose


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Status Management

Diarrhea not resolving:

♦ Start and or continue an antidiarrheal agent (eg, loperamide 4 mg followed by 2 mg after each episode of diarrhea [maximum: 16 mg loperamide per day])

♦ Consider starting second line antidiarrheal or referral to gastroenterologist

5.4.4.1.2 Nausea and vomiting Antiemetic agents are recommended as clinically appropriate at the first sign of nausea and vomiting or as prophylaxis to prevent emesis, along with supportive care in accordance to clinical practice guidelines.

The 5-HT3 receptor antagonists are recommended over chronic use of NK-1 receptor antagonists and dexamethasone (NK-1 receptor antagonists can induce or inhibit CYP3A4, and glucocorticoids induce CYP3A4 and thus could lower cabozantinib exposure (see chapter 5.5). Caution is also recommended with the use of nabilone, which is a weak inhibitor of CYP3A4. When therapy with antiemetic agents does not control the nausea or vomiting to tolerable levels, study treatment should be temporarily interrupted or dose reduced per Table 2.

Dehydration and electrolyte abnormalities may be associated with vomiting and monitoring for and correction of fluid and electrolyte disturbances should be implemented.

5.4.4.2 Stomatitis and mucositis Preventive measures include a comprehensive dental examination to identify any potential complications before study treatment is initiated. Appropriate correction of local factors should be instituted as indicated, such as modification of ill-fitting dentures and appropriate care of gingivitis.

During treatment with cabozantinib good oral hygiene and standard local treatments such as non-traumatic cleansing and oral rinses (e.g. with a weak solution of salt and baking soda) should be maintained. The oral cavity should be rinsed after meals, and dentures should be cleaned and brushed often to remove plaque. Lips should be kept moisturized with lip balm. The use of lipstick, lip-gloss, and Vaseline should be avoided.

Local treatment should be instituted at the earliest onset of symptoms. Obtain bacterial/viral culture if oral infection is suspected and treat infection as indicated by local guidelines. When stomatitis interferes with adequate nutrition and local therapy is not adequately effective, dose reduction or temporary withholding of cabozantinib should be considered per Table 1 and Table 2.

5.4.4.3 Hepatobiliary disorders Elevations of transaminases have also been observed during treatment with cabozantinib. In general, it is recommended that patients with elevation of ALT, AST, and/or bilirubin have more frequent laboratory monitoring of these parameters. Evaluation of patients with elevated transaminases or bilirubin should be individualized and guided by the presence of specific risk factors such as liver conditions (eg, liver cirrhosis, thrombosis of portal or hepatic vein, HCC, hepatitis). If possible, hepatotoxic concomitant medications should be discontinued in patients who develop increased values of ALT, AST, or bilirubin.

Patients on this study may enter with increased ALT/AST serum levels up to 3 × ULN.


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Cabozantinib should be interrupted for related CTCAE Grade 3 or higher hepatic injury (transaminase increase to > 5 × ULN) and when transaminase increases are accompanied by progressive elevations of total bilirubin, and/or elevations of coagulation tests (eg, International Normalized Ratio [INR]).

More frequent monitoring of transaminases should be considered and cabozantinib should be held until the etiology of the abnormalities is determined and these abnormalities are corrected or stabilize at clinically acceptable levels.

Cabozantinib should be discontinued if hepatic dysfunction is not reversed despite interruption of study treatment. Elevations of aminotransferases when hepatic metastases are present may not require dose modifications if there are no progressive changes in the aminotransferases (less than a doubling) and if there are no progressive elevations in serum bilirubin concentration or coagulation factors.

Elevations >3 × ULN of ALT or AST concurrent with >2 × ULN total bilirubin without other explanation can indicate DILI and drug should be permanently discontinued.

5.4.4.4 Fatigue, anorexia, and weight loss Fatigue has been reported during treatment with cabozantinib. Common causes of fatigue such as anemia, deconditioning, emotional distress (depression and/or anxiety),poor nutrition, sleep disturbance, and hypothyroidism should be ruled out and/or these causes treated in accordance to standard of care. Individual non-pharmacological and/or pharmacologic interventions directed to the contributing and treatable factors should be given. Note: chronic use of modafinil should be avoided because of its potential to reduce cabozantinib exposure refer to investigator's brochure (Ref. 14). Refer to Table 2.

Anorexia and weight loss should be managed in accordance to local standard of care including nutritional support. If fatigue, anorexia, or weight loss cannot be adequately managed, study treatment should be temporarily interrupted or dose reduced per Table 1 and Table 2.

5.4.4.5 Hematological disorders Hematological toxicities (ie, neutropenia and thrombocytopenia) and associated complications have been observed after administration of cabozantinib and may be managed with dose interruptions and/or dose reductions. Use of granulocyte colony-stimulating factor support for neutrophil recovery is allowed per investigator discretion and in accordance with accepted guidelines after the first incidence of clinically relevant cytopenia.

Complete blood counts with differentials and platelets should be performed regularly. Patients with hematologic toxicities may require additional or more frequent laboratory tests according to institutional guidelines.

Febrile neutropenia or evidence of infection associated with neutropenia must be assessed immediately and treated appropriately and in a timely manner according to institutional guidelines.

Dose reductions or dose interruptions for anemia are not mandated but can be applied as clinically indicated. Supportive care such as red blood cell transfusions may be managed according to institutional guidelines.

5.4.4.6 Palmar-plantar erythrodysesthesia syndrome (PPES) Palmar-plantar erythrodysesthesia syndrome (also known as hand-foot syndrome), skin rash (including blisters, erythematous rash, macular rash, skin exfoliation, dermatitis acneiform, and papular rash), pruritus, dry skin, and erythema, pigmentary changes, and alopecia have been reported in cabozantinib-treated patients.

All patients on study should be advised on prophylactic skin care including the use of emollients, removal of calluses, avoidance of exposure of hands and feet to hot water leading to vasodilatation,


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protection of pressure-sensitive areas of hands and feet, and use of cotton gloves and socks to prevent injury and keep the palms and soles dry. Patients with skin disorders should be carefully monitored for signs of infection (e.g. abscess, cellulitis, or impetigo).

Early signs of hand-foot syndrome could be tingling, numbness, and symmetrical red and swollen areas on the palms and soles or mild hyperkeratosis. The lateral sides of the fingers or peri-ungual zones may also be affected. Adequate interventions are required to prevent worsening of skin symptoms such as blisters, desquamations, ulcerations, or necrosis of affected areas.

Aggressive management of symptoms is recommended, including early dermatology referral. Treatment guidelines for PPE related to study treatment are presented in Table 4.

In the case of study treatment-related skin changes (e.g. rash, hand-foot syndrome), the investigator may request that additional assessments be conducted with the patient's consent. These assessments may include digital photographs of the skin changes and/or a biopsy of the affected skin and may be repeated until the skin changes resolve.

Table 4: Management of treatment-emergent PPE syndrome

Hand-Foot Skin Reaction and Hand Foot Syndrome (PPE)

CTCAE v. 4.0 Grade Actions to be taken

Grade 1 Cabozantinib may be continued at current dose if PPES is clinically insignificant and tolerable. Otherwise, study treatment should be reduced to the next lower dose level (Table 1).Start urea 20% cream twice daily AND clobetasol 0.05% cream once daily. Reassess patient at least weekly. If PPES worsens at any time or does not improve after 2 weeks, proceed to the intervention guidelines for Grade 2.

Grade 2 Cabozantinib may be continued if PPES is tolerated. Cabozantinib should be dose reduced or interrupted if PPES is intolerable. Continue urea 20% cream twice daily AND high potency steroid cream (e.g. clobetasol 0.05%) once daily and add analgesics (eg, NSAIDs/gamma-aminobutyric acid agonists) for pain control if needed. Reassess at least weekly; if PPES worsens or affects self-care, proceed to the intervention guidelines for Grade 3.

Grade 3 Interrupt Cabozantinib until severity decreases to Grade 1 or 0. Continue treatment of skin reaction with high potency steroid cream (e.g. clobetasol 0.05%) twice daily AND analgesics. Resume study drug at a reduced dose if PPES recovers to Grade ≤ 1. Discontinue patient from study treatment if PPES does not improve within 6 weeks.

5.4.4.7 Wound healing and surgery VEGFR inhibitors can cause wound healing complications and wound dehiscence which may occur even long after a wound has been considered healed. Therefore, surgical and traumatic wounds must have completely healed before starting cabozantinib treatment and be monitored for wound dehiscence or wound infection while the patient is being treated with cabozantinib. If possible, cabozantinib treatment should be stopped for at least 28 days prior to major surgery.

The decision to resume treatment with cabozantinib after surgery should be based on clinical judgment of adequate wound healing.


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5.4.4.8 Hypertension Hypertension is a common class effect of drugs that inhibit VEGF pathways and has been reported among patients treated with cabozantinib.

Treatment guidelines for hypertension deemed related to cabozantinib are presented in the investigator brochure (Ref. 14). Blood pressure should be monitored in a constant position at each visit (either sitting or supine). In general, patients with known hypertension should be optimally managed before study entry. Decisions to decrease or hold the dose of study treatment must be based on blood pressure readings taken by a medical professional and must be confirmed with a second measurement at least 5 minutes after the first measurement. Other than for hypertension requiring immediate therapy, the presence of new or worsened hypertension should be confirmed at a second visit before taking therapeutic action. It is recommended that this second visit occurs within 1 week.

Cabozantinib should be discontinued in subjects with hypertensive emergency.

Table 5: Management of hypertension related to cabozantinib

Criteria for dose modifications Treatment/cabozantinib dose modification

Patients not receiving optimized anti-hypertensive therapy

> 150 mm Hg (systolica) and < 160 mmHg

OR

> 100 mm Hg (diastolic) and < 110 mmHg

Optimize antihypertensive medications by adding new or additional antihypertensive medications and/or increase dose of existing medications.

Reduce cabozantinib by one dose level if optimal antihypertensive therapy (usually to include 3 agents) does not result in BP <150 mm Hg systolic or <100 mm Hg diastolic

If patient is symptomatic interrupt cabozantinib

≥ 160 mm Hg (systolic)

OR

≥ 110 mm Hg (diastolic)

Reduce cabozantinib by one dose level (Table 1) or interrupt cabozantinib per investigator discretion

Add new or additional anti-hypertensive medications and/or increase dose of existing medications and monitor patient closely for hypotension. If optimized antihypertensive therapy (usually to include 3 agents) does not result in BP < 150 mm Hg systolic or < 100 mm Hg diastolic, cabozantinib should be dose reduced further or interrupted

Cabozantinib should be dose interrupted if upper limits of systolic BP (≥ 160 mm Hg) are sustained and not adequately manageable or if systolic BP is > 180 mm Hg or diastolic BP > 110 mm Hg, or if patient is symptomatic

Re-start cabozantinib at the most tolerable dose and re-escalate only if BP falls to and is sustained at < 150 mm Hg systolic and < 100 mm Hg diastolic

Hypertensive emergency b Discontinue cabozantinib


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Criteria for dose modifications Treatment/cabozantinib dose modification

a The investigator may decide to initiate or adjust antihypertensive treatment at a lower threshold than systolic BP >150 or diastolic BP >100 based on their clinical judgment and assessment of the individual patient.

b Hypertensive emergency is defined as uncontrolled elevated blood pressure with clinical evidence of progressive or impending end-organ damage (eg, myocardial infarction/ischemia, intracranial hemorrhage, cerebral ischemia, pulmonary edema, encephalopathy, kidney damage).

5.4.4.9 Thromboembolic events (venous and arterial) Thromboembolic complications are frequent in cancer patients due to procoagulant changes induced by the malignancy or anticancer therapy including inhibitors of VEGF pathways. Deep vein thrombosis (DVT) and pulmonary embolism (PE) have been observed in clinical studies with cabozantinib, including fatal events (refer to investigator's brochure. Patients who develop a PE or DVT should have cabozantinib treatment held until therapeutic anticoagulation with heparins (e.g. low molecular weight heparin [LMWH]) is established. LMWH are the preferred management for thrombotic events, warfarin is not recommended Cabozantinib treatment may be resumed in patients who are stable and have uncomplicated PE or DVT and are deriving clinical benefit from cabozantinib treatment that anticoagulation does not place them at a significant risk that outweighs the benefit of resuming treatment per discretion of the investigator. During anticoagulation treatment, patients need to be monitored on an ongoing basis for bleeding risk and signs of bleeding which may require additional or more frequent laboratory tests in accordance to institutional guidelines. If there are any signs of clinically significant bleedings, cabozantinib treatment should be permanently discontinued. Arterial thrombotic events (e.g. transient ischemic attack, myocardial infarction) have been observed in studies with cabozantinib. Patients should be evaluated for preexisting risk factors for arterial thrombotic events such as diabetes mellitus, hyperlipidemia, hypertension, coronary artery disease, history of tobacco use, and cardiac or thromboembolic events that occurred before initiation of study treatment. Cabozantinib treatment should be discontinued in patients who develop an acute myocardial infarction or any other clinically relevant arterial thromboembolic complication.

5.4.4.10 Proteinuria Proteinuria is an anticipated AE with the inhibition of VEGF pathways and has been observed in cabozantinib clinical studies, and nephrotic syndrome has been reported with cabozantinib and other inhibitors of VEGF pathways. Management guidelines are provided in Table 6.

Proteinuria should be monitored by measuring UPCR.

Cabozantinib should be discontinued in patients who develop nephrotic syndrome (proteinuria > 3.5 grams per day in combination with low blood protein levels, high cholesterol levels, high triglyceride levels, and edema).


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Table 6: Management of treatment-emergent proteinuria

Urine protein/creatinine Ratio (UPCR)

Management of proteinuria

≤ 1 mg/mg

(≤ 113.1 mg/mmol)

No change in treatment or monitoring.

> 1 and < 3.5 mg/mg (> 113.1 and < 395.9 mg/mmol)

Consider confirming with a 24-hour protein assessment within 7 days.

No change in cabozantinib treatment required if UPCR ≤ 2 mg/mg or urine protein ≤ 2 g/24 hours on 24-hour urine collection.

Dose reduce or interrupt cabozantinib treatment if UPCR > 2 mg/mg on repeat UPCR testing or urine protein > 2 g/24 hours on 24-hour urine collection. Continue cabozantinib on a reduced dose if UPCR decreases to < 2 mg/mg. Consider holding cabozantinib treatment if UPCR remains > 2 mg/mg despite a dose reduction until UPCR decreases to < 2 mg/mg. Restart cabozantinib treatment at a reduced dose after a dose hold unless otherwise approved by study coordinator and EORTC medical monitor.

Repeat UPCR within 7 days and once per week. If UPCR < 1 mg/mg on 2 consecutive readings, UPCR monitoring can revert to protocol-specific times. (Second reading is confirmatory and can be done within 1 week of first reading).

If UPCR remains > 1 mg/mg and < 2 mg/mg for 1 month or is determined to be stable (< 20% change) for 1 month, check urine protein/creatinine per protocol or as clinically indicated.

≥ 3.5 mg/mg (≥ 395.9 mg/mmol)

Hold cabozantinib treatment pending repeat UPCR within 7 days and/or 24-hour urine protein.

If ≥ 3.5 on repeat UPCR, continue to hold cabozantinib treatment and check UPCR every 7 days. If UPCR decreases to < 2 mg/mg, restart cabozantinib treatment at a reduced dose and monitoring of urine protein/creatinine should continue weekly until the UPCR decreases to < 1mg/mg. If UPCR remains > 1 mg/mg and < 2 mg/mg for 1 month or is determined to be stable (< 20% change) for 1 month, check urine protein/creatinine per protocol or as clinically indicated.

Nephrotic syndrome Discontinue all study treatment

5.4.4.11 Corrected QT (QTc) prolongation The effect of orally administered cabozantinib at 140 mg/day (free-base equivalent) on QTc interval was evaluated in a randomized, double-blinded, placebo-controlled phase III study in patients with medullary thyroid carcinoma. A mean increase in QTcF of 10 - 15 ms was observed after 4 weeks after initiating cabozantinib. A concentration-QTc relationship could not be definitively established. Changes in cardiac wave form morphology or new rhythms were not observed. No cabozantinib-treated patients in this study had a QTcF > 500 ms. Only patients with a baseline QTcF ≤ 500 msec are eligible for this study. Review of the larger safety database (~5000 patients exposed to cabozantinib in clinical trials and in post-marketing experience) confirmed the absence of safety concerns associated with QT prolongation. There were no events of torsades de pointes reported. Cabozantinib should be used with caution in patients with


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QT prolongation risk, a history of QT interval prolongation, or who are taking antiarrhythmics or drugs known to prolong the QT interval. Concomitant treatment with strong CYP3A4 inhibitors, which may increase cabozantinib plasma concentrations, should be avoided.

If at any time on study there is an increase in QTc to an absolute value > 500 msec or an increase of > 60 ms above baseline, two additional ECGs must be performed with intervals not less than 3 min apart within 30 min after the initial ECG.

If the average QTc calculated by the Fridericia formula (QTcF) from the three ECGs is > 500 msec or increased by > 60 ms above baseline, the following actions must be taken:

♦ Withhold study treatment

♦ Immediately notify the EORTC medical monitor

♦ Hospitalize symptomatic patients (eg, with palpitations, dizziness, syncope, orthostatic hypotension, a significant ventricular arrhythmia on ECG) for a thorough cardiology evaluation and management

♦ Consider cardiology consultation for asymptomatic patients for evaluation and management

♦ Check electrolytes, especially magnesium, potassium and calcium; correct abnormalities as clinically indicated

♦ Check concomitant medications for any medication that may have contributed to QT prolongation, and if possible, discontinue these medications (http://www.qtdrugs.org)

♦ Repeat ECG triplicates hourly until the average QTcF is ≤ 500 msec, or otherwise determined by consultation with a cardiologist or appropriate expert.

Patients with QTc prolongation and symptoms must be monitored closely until the QTc elevation and symptoms have resolved. Cabozantinib may be restarted at a reduced dose level if all of the following conditions are met:

♦ Symptoms are determined to be unrelated to the QT interval prolongation

♦ The QTcF value > 500 ms or increase of > 60 ms above baseline is not confirmed according to protocol procedures

♦ Study treatment has been interrupted through a minimum of 1 week following the return of the QTcF to ≤ 500 msec or return to ≤ 60 ms above baseline.

♦ QT prolongation can be unequivocally associated with an event other than cabozantinib administration and is treatable/has been resolved

♦ EORTC Medical monitor has reviewed all available information and has agreed to the continuation of study treatment.

Following reinitiation of study treatment, ECGs must be repeated weekly for 2 weeks, then every 2 weeks for 1 month, then according to the protocol-defined time points.

Cabozantinib must be permanently discontinued if either of the following applies:

♦ Cardiac evaluation confirms that symptoms are the consequence of QT interval prolongation

♦ Recurrence of QTcF prolongation (confirmed by central ECG lab) after reinitiation of study treatment at a reduced dose

http://www.qtdrugs.org/


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5.4.4.12 Hypophosphatemia Hypophosphatemia has been reported during treatment with cabozantinib. Serum phosphorus should be monitored frequently while receiving cabozantinib. Other causes of hypophosphatemia should be ruled out and/or these causes treated in accordance to standard of care. Mild to moderate hypophosphatemia should be managed by oral replacement including food that is high in phosphate (dairy items, meat, beans) and/or oral phosphate supplements in accordance to standard clinical practice guidelines.

Clinically relevant hypophosphatemia should be managed in accordance to the dose modification guidelines as outlined in Table 1 and Table 2 or as clinically indicated.

5.4.4.13 Thyroid function disorders Changes in thyroid function tests (TFTs) and hypothyroidism have been reported with cabozantinib and other tyrosine kinase inhibitor treatment as a result of altered thyroid hormone regulation by mechanisms that seem to be specific for each agent (Ref. 23). Currently available data are insufficient to determine the mechanism of TFT alterations and its clinical relevance. Routine monitoring of thyroid function and assessments for signs and symptoms associated with thyroid dysfunction is recommended before initiation and during treatment with cabozantinib. Management of thyroid dysfunction (e.g. symptomatic hypothyroidism) should follow accepted clinical practice guidelines and dose modification guidelines as outlined in Table 1 and Table 2.

5.4.4.14 Hemorrhagic events Hemorrhagic events have been reported with cabozantinib. In order to mitigate risk of severe hemorrhage, patients should be evaluated for potential bleeding risk factors before initiating cabozantinib treatment and monitored for bleeding events with serial complete blood counts and physical examination while on study.

Risk factors for hemorrhagic events may include (but may not be limited to) the following:

♦ Tumor of the lung with cavitary lesions or tumor lesions which invade, encase major blood vessels. The anatomic location and characteristics of the tumor as well as the medical history must be carefully reviewed in the selection of patients for treatment with cabozantinib.

♦ Recent or concurrent radiation to the thoracic cavity.

♦ Active peptic ulcer disease, GI diseases including Crohn's disease and ulcerative colitis;

♦ Underlying medical conditions which affect normal hemostasis (e.g. deficiencies in clotting factors and/or platelet function, or thrombocytopenia).

♦ Concomitant medication with anticoagulants or other drugs which affect normal hemostasis;

♦ History of clinically significant hemoptysis.

The risk of hemorrhage in cabozantinib-treated patients with brain metastases has not been thoroughly analyzed but patients with brain metastases should be monitored with a high index of suspicion if symptoms that could be due to a CNS hemorrhage occur.

Cabozantinib should be discontinued in patients with serious and life-threatening bleeding events or recent hemoptysis (≥ 2.5 mL of red blood).


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5.4.4.15 GI perforation/fistula and non-GI fistula formation 1) Gastrointestinal perforation, GI fistula and intra-abdominal and pelvic abscess:

Prior to initiation of treatment with cabozantinib, patients should be carefully evaluated for potential risk factors including (but not limited to) the following:

♦ Tumors invading GI or respiratory tracts. ♦ Active peptic ulcer disease, inflammatory bowel disease (eg, ulcerative colitis, Crohn’s disease),

diverticulitis, cholecystitis or symptomatic cholangitis, or appendicitis.

♦ History of abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess.

♦ Prior GI surgery (particularly when associated with delayed or incomplete healing). Complete healing following abdominal surgery and/or resolution of intra-abdominal abscess must be confirmed before initiating treatment with cabozantinib.

♦ Ongoing visceral complications from prior radiation therapy. After starting cabozantinib, patients should be monitored for early signs of GI perforation such as abdominal pain, nausea, emesis, constipation, and fever especially if known risk factors for developing GI perforation or fistula (Ref. 15) are present.

Discontinue cabozantinib treatment in patients who have been diagnosed with GI perforation/fistula.

2) Non-GI fistula: Complications from radiation therapy has been identified as a possible predisposing risk factor for fistula formation in patients undergoing treatment with cabozantinib.

Patients with any clinically relevant ongoing complications from prior radiation therapy (ie, radiation esophagitis or other inflammation of the viscera) should not be treated with cabozantinib.

Radiation therapy to the thoracic cavity (including mediastinum) should be avoided within 3 months of starting treatment with cabozantinib (excluding local radiation for bone metastases). Fistula should be ruled out as appropriate in cases of onset of severe mucositis or difficulty swallowing after start of therapy. Discontinue cabozantinib and initiate appropriate management in patients who have been diagnosed with a non GI fistula.

5.4.4.16 Osteonecrosis of the jaw Osteonecrosis of the jaw (ONJ) has been reported with cabozantinib. Additional risk factors for ONJ have been identified including the use of bisphosphonates and denosumab, chemotherapy and anti-angiogenic drugs, use of corticosteroids, chemotherapy, local radiotherapy, dental or orofacial surgery procedures.

Osteonecrosis of the jaw can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ.

Perform an oral examination prior to initiation of cabozantinib and periodically during cabozantinib therapy. Advise patients regarding oral hygiene practice and to quickly report symptoms to investigator. Caution should be used in patients receiving bisphosphonates.

Invasive dental procedures should be avoided. In cases where dental procedures are unavoidable, treatment with cabozantinib should be held for approximately 4 weeks prior to the procedure and resumed after complete wound healing has occurred. Bone healing may often require a protracted time.


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5.4.4.17 Angioedema Angioedema should be managed according to standard practice. The patient should be observed until symptoms resolve, with particular attention to maintaining an open airway.

5.4.4.18 Nervous system disorders Cabozantinib appears to represent minimal risk of adverse neurological effects based on nonclinical GLP-compliant toxicology studies. Dysphonia, dysgeusia, headache, dizziness, confusional state, convulsion, depression, memory impairment, hypoesthesia, peripheral neuropathy, insomnia, ataxia, and encephalopathy have been observed in clinical studies with cabozantinib. The development of any new or progressive, unexplained neurological symptoms should be assessed for underlying causes.

Posterior reversible encephalopathy syndrome has been reported and should be considered in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Cabozantinib treatment should be discontinued in subjects with RPLS.

5.4.4.19 Muscoloskeletal and connective tissue disorders Cabozantinib appears to represent minimal risk of adverse musculoskeletal effects based on nonclinical GLP-compliant toxicology studies. The development of new or progressive, unexplained musculoskeletal symptoms such as pain or weakness should be assessed for underlying causes.

Rhabdomyolysis has been reported. Cabozantinib should be discontinued in patients with serious and life-threatening rhabdomyolysis and interrupted if less severe forms occur when there are no other clear causes. Reinitiation of cabozantinib treatment must be discussed with and approved by the EORTC medical monitor. Therapy of rhabdomyolysis should include supportive care and standard medical intervention

5.4.4.20 Respiratory, thoracic and mediastinal disorders Dyspnea has been reported in clinical studies with cabozantinib. Symptoms should be managed according to locally accepted clinical practice including an assessment for underlying causes. Pulmonary embolism should be considered as possible causes for new onset dyspnea given the risk of thrombosis associated with inhibition of VEGF signaling. Furthermore, fistula formation and pneumonia have been reported in patients treated with cabozantinib and should be considered as clinically indicated in patients presenting with pulmonary symptoms.

5.5 Concomitant treatments All concomitant medications used by the subject (including prescription and over-the-counter medications, transfusions, vitamins, herbal remedies, and nutritional supplements) during the period from 28 days before the first dose of study treatment through 30 days after the date of the last dose of study treatment are to be recorded in the case report forms.

5.5.1 Allowed medications ♦ Antiemetics and antidiarrheal medications are allowed prophylactically in accordance to standard

clinical practice if clinically indicated;

♦ Granulocyte colony-stimulating factors (G-CSF or GM-CSF) are allowed if used per clinical guidelines (eg, American Society of Clinical Oncology [ASCO] or [European Society for Medical Oncology] ESMO guidelines), these growth factors are not allowed for prophylactic use at study entry (see patient selection criteria);


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♦ Drugs used to control bone loss (eg, bisphosphonates and denosumab) are allowed if started before screening activities but may not be initiated or exchanged during the course of the study and require Sponsor approval;

♦ For Belgium: drugs used to control bone loss (eg, bisphosphonates and denosumab) may not be initiated or used during the course of the study. If already started before screening activities, it is recommended to stop treatment with these drugs.

♦ Transfusions, hormone replacement, and short term higher doses of corticosteroids should be utilized as indicated by standard clinical practice;

♦ Individualized anticoagulation therapy with heparin is allowed during the study if it can be provided safely and effectively under the following circumstances:

♦ Low dose heparins for prophylactic use are allowed if clinically indicated and the benefit outweighs the risk per the investigator’s discretion.

♦ Therapeutic doses of low molecular weight heparins (LMWH) at the time of first dose are allowed if the patient has no evidence of brain metastasis, has been on a stable dose of LMWH for at least 12 weeks, and has had no complications from a thromboembolic event or the anticoagulation regimen.

♦ Therapeutic doses of low molecular weight heparins (LMWH) after first dose are allowed if clinically indicated (eg, for the treatment of deep venous thrombosis), and the benefit outweighs the risk per the investigator’s discretion. For management of thromboembolic complications while on study, refer to Section 5.4.4.8.

♦ Accepted clinical guidelines regarding appropriate management while receiving anticoagulation therapy with heparins must be followed. This includes, but is not limited to, patient education regarding potential adverse drug reactions, monitoring laboratory parameters, dose adjustments (eg, due to kidney dysfunction);

♦ For restrictions on oral anticoagulants see Section 5.5.2.

♦ Administration of the proton pump inhibitors esomeprazole resulted in no clinically-relevant effect on cabozantinib plasma PK in healthy volunteers (Study XL184-018). Therefore, concomitant use of gastric pH modifying agents (ie, proton pump inhibitors, H2 receptor antagonists, and antacids) is not contraindicated in patients administered cabozantinib. Cimetidine should be avoided due to potential CYP interactions.

5.5.2 Prohibited or restricted medications ♦ Anticancer therapy other than cabozantinib

♦ Any investigational agent or investigational medical device

♦ Anticoagulation therapy: concomitant anticoagulation at therapeutic doses with oral anticoagulants (eg, warfarin, direct thrombin and Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel).

EXCEPT: Low-dose aspirin for cardioprotection (per local applicable guidelines), low-dose warfarin (< 1 mg/day), and low dose, low molecular weight heparins (LMWH) are permitted. Anticoagulation with therapeutic doses of LMWH is allowed in patients without radiographic evidence of brain metastasis, who are on a stable dose of LMWH for at least 12 weeks before registration, and who have had no complications from a thromboembolic event or the anticoagulation regimen


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The following therapies should be avoided if possible, while the patient is on study:

♦ Palliative external radiation to bone metastasis for bone pain should not be performed while on study. Patients who have such an intervention may be considered not evaluable (and may be assigned a censoring or progression date) for certain efficacy endpoints;

♦ Erythropoietic stimulating agents (eg, epoetin alfa and darbepoetin alfa) should not be used based on a report of increased risk of tumor recurrence and/or progression associated with erythropoietin (Ref. 24);

♦ Chronic co-administration of cabozantinib with strong inducers of the CYP3A4 family (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John’s Wort) may significantly decrease cabozantinib concentrations and should be avoided. Selection of alternate concomitant medications with no or minimal CYP3A4 enzyme induction potential is recommended;

♦ Caution must be used when discontinuing treatment with a strong CYP3A4 inducer in a subject who has been concurrently receiving a stable dose of cabozantinib, because this could significantly increase the exposure to cabozantinib;

♦ Co-administration of cabozantinib with strong inhibitors of the CYP3A4 family (eg, ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, and ritonavir) may increase cabozantinib concentrations and should be avoided. Grapefruit and Seville oranges may also increase plasma concentrations of cabozantinib and should be avoided.

5.5.3 Potential drug interactions

5.5.3.1 Cytochrome P450 (CYP) Data from a clinical drug interaction study (Study XL184-008) show that clinically relevant steady-state concentrations of cabozantinib appear to have no marked effect on the area under the plasma drug concentration time curve (AUC) of co-administered rosiglitazone, a CYP2C8 substrate. Therefore, cabozantinib is not anticipated to markedly inhibit CYP2C8 in the clinic, and by inference, is not anticipated to markedly inhibit other CYP450 isozymes that have lower [I]/Ki values compared with CYP2C8 (ie, CYP2C9, CYP2C19, CYP2D6, CYP1A2, and CYP3A4). In vitro data indicate that cabozantinib is unlikely to induce cytochrome P450 enzymes, except for possible induction of CYP1A1 at high cabozantinib concentrations (30 μM).

Cabozantinib is a CYP3A4 substrate and a weak substrate for CYP2C9 (but not a CYP2D6, CYP2C8, CYP2C19, CYP2B6, or CYP1A2 substrate), based on data from in vitro studies. Results from a clinical pharmacology study, XL184-006, showed that concurrent administration of cabozantinib with the strong CYP3A4 inducer, rifampin, resulted in an approximately 77% reduction in cabozantinib exposure (AUC values) after a single dose of cabozantinib in healthy volunteers.

Chronic co-administration of cabozantinib with strong inducers of the CYP3A4 family (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John’s Wort) may significantly decrease cabozantinib concentrations. The chronic use of strong CYP3A4 inducers should be avoided. Other drugs that induce CYP3A4 should be used with caution because these drugs have the potential to decrease exposure (AUC) to cabozantinib. Selection of alternate concomitant medications with no or minimal CYP3A4 enzyme induction potential is recommended.

Results from a clinical pharmacology study, XL184-007, showed that concurrent administration of cabozantinib with the strong CYP3A4 inhibitor, ketoconazole, resulted in a 38% increase in the cabozantinib exposure (AUC values) after a single dose of cabozantinib in healthy volunteers. Co-administration of cabozantinib with strong inhibitors of the CYP3A4 family (eg, ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, and ritonavir) may increase


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cabozantinib concentrations. Grapefruit and Seville oranges may also increase plasma concentrations of cabozantinib and should be avoided. Strong CYP3A4 inhibitors should be avoided and other drugs that inhibit CYP3A4 should be used with caution because these drugs have the potential to increase exposure (AUC) to cabozantinib. Selection of alternate concomitant medications with no or minimal CYP3A4 enzyme inhibition potential is recommended.

In addition, cimetidine should be avoided because of its potential to interfere with CYP3A4 mediated metabolism of cabozantinib. Please refer to the drug interaction tables at the following websites for lists of substrates, inducers, and inhibitors of selected CYP450 isozyme pathways:

♦ Http://medicine.iupui.edu/clinpharm/ddis/table.aspx

♦ http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm

5.5.3.2 Protein Binding Cabozantinib is highly bound (≥ 99.7%) to human plasma proteins. Therefore, highly protein bound drugs (eg, diazepam, furosemide, dicloxacillin, and propranolol) should be used with caution with cabozantinib because there is a potential displacement interaction that could increase free concentrations of cabozantinib and/or a co-administered highly protein-bound drug (and a corresponding increase in pharmacologic effect).

A case of a drug-drug interaction between cabozantinib and warfarin has been reported in the literature (Ref. 37), which likely resulted from a protein-displacement interaction. Because warfarin is a highly protein bound drug with a low therapeutic index, administration of oral anticoagulants at therapeutic doses is not allowed in subjects receiving cabozantinib due to the potential for a protein binding displacement interaction.

5.5.3.3 Other Interactions Food may increase exposure levels of cabozantinib by 57%, fasting recommendations should be followed. Patients should fast (with the exception of water) for at least 2 hours after eating the evening meal before taking their dose of cabozantinib. After the 2-hour fast and before going to bed, patients are to take cabozantinib with a full glass of water (minimum of 8 oz or 240 mL) with no more food intake for one hour post-dose.

In vitro data suggest that cabozantinib is unlikely to be a substrate for P-glycoprotein, but it does appear to have the potential to inhibit the P-glycoprotein transport activity. Therefore, cabozantinib may have the potential to increase plasma concentrations of co-administered substrates of P-glycoprotein. Patients should be cautioned regarding taking a P-gp substrate (eg, fexofenadine, aliskiren, ambrisentan, dabigatran etexilate, digoxin, colchicine, maraviroc, posaconazole, ranolazine, saxagliptin, sitagliptin, talinolol, tolvaptan) while receiving cabozantinib.

Cabozantinib was shown to be a substrate of drug transporter MRP2 in an in vitro assay. Administration of MRP2 inhibitors to patients may result in increases in cabozantinib plasma concentrations. See Appendix E.

Concomitant administration of PPI esomeprazole resulted in no clinically-relevant effect on cabozantinib plasma PK in healthy subjects. Therefore, concomitant use of gastric pH modifying agents (ie, PPIs, H2 receptor antagonists, and antacids) is not contraindicated in subjects administered cabozantinib.

http://medicine.iupui.edu/clinpharm/ddis/table.aspx

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm


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6 Clinical evaluation, laboratory tests and follow-up 6.1 Before treatment start

6.1.1 Investigations performed within 28 days prior to start of treatment Tumor evaluation (by RECIST 1.1) will be performed with CT of the chest, abdomen and pelvis with intravenous and oral contrast, or MRI. The same method should be used for repeated measurements throughout the study.

6.1.2 Investigations performed within 14 days prior to start of treatment ♦ Past and ongoing medical history and demographics (age, gender).

♦ Physical examination (ECOG performance status, blood pressure, weight, height (only at baseline), pulse rate).

♦ Cancer signs and symptoms.

♦ Assessment of adverse events.

Record concomitant medications

♦ Cardiac function: 12-lead ECG (complete, standardized 12-lead recording with calculation of QTc according to Fridericia's formula) and ejection fraction (by cardiac ultrasound or multi-gated acquisition scan). The same method should be used throughout the study.

♦ Dipstick urinalysis

♦ Any level of proteinuria diagnosed by dipstick should be quantified by a urine protein-to-creatinine ratio (UPCR; mg/dL protein/ mg/dL creatinine). When a UPCR exceeds 1, a repeat UPCR or a 24-hour urine protein and creatinine should be performed to confirm the result.

♦ Central pathology review: ♦ Archival formalin fixed paraffin-embedded (FFPE) tumor tissue (5 unstained slides of 4

micrometer thickness) from the primary tumor or a metastatic site of GIST will be collected for pathology review.

♦ Translational research :

♦ Archival tumor tissue available from primary tumor or metastatic site (10 unstained slides with archived tumor tissue of 10 micrometer thickness and two hematoxylin and eosin (H&E) stained slides)

♦ Blood sample (10 ml) for circulating cell-free DNA.

6.1.3 Investigations performed within 7 days prior to start of treatment ♦ Complete blood counts will be performed, to include at least red blood cell count, hematocrit,

hemoglobin, white blood cell count (neutrophils, basophils, eosinophils, lymphocytes, monocytes) and platelets.

♦ A chemistry panel will be performed to include at least potassium, sodium, ionized calcium, magnesium, phosphorus, chloride, bicarbonate, creatinine, total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), γ-glutamyltransferase (GGT), lactate dehydrogenase, total protein, albumin, lipase, amylase, blood urea nitrogen, glucose.

♦ Creatinine clearance to be calculated as per local standard.


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♦ Thyroid function: TSH. In case of elevated TSH, to test free T3 and T4.

♦ Coagulation test (to include at least PT/INR, PTT).

6.1.4 Investigations performed within 72 hours prior to start of treatment Pregnancy test: serum beta HCG in fertile female study participants. The pregnancy test is to be renewed/repeated during protocol treatment according to national regulations/institution guidelines.

6.2 During treatment

6.2.1 Every cycle (3 weeks, day 1 +/- 3 days of each cycle) The following examinations and tests will be performed prior to each cycle:

♦ Ongoing medical history.

♦ Physical examination (ECOG performance status, blood pressure, weight, pulse rate).

♦ As per recommendation in chapter 5.4, more frequent BP monitoring will be performed in case of elevated blood pressure.

♦ Assessment of all adverse events that have occurred since the previous visit and ongoing events from previous cycles should be followed.

Concomitant medications

♦ Complete blood counts (see chapter 6.1.2).

♦ Serum chemistry panel (see chapter 6.1.2).

♦ Routine monitoring of thyroid function (TSH; in case of elevated TSH, T3 and T4 to be added). Assessments for signs and symptoms associated with thyroid dysfunction are recommended.

♦ Coagulation tests (to include at least PT/INR, PTT).

♦ Dipstick urinalysis.

♦ Any level of proteinuria diagnosed by dipstick should be quantified by a urine protein-to-creatinine ratio (UPCR; mg/dL protein/ mg/dL creatinine). When a UPCR exceeds 1, a repeat UPCR or a 24-hour urine protein and creatinine should be performed to confirm the result.

Patients requiring dose modifications as per chapter 5.4 may benefit from more frequent assessment of relevant tests, as indicated in the instructions for handling AEs.

6.2.2 Every 6 weeks (+/- 3 days) The following examinations and tests will be performed every 6 weeks during the first 48 weeks and every 12 weeks thereafter, regardless of interruptions and delays in therapy unless otherwise indicated.

Cardiac function: 12-lead ECG (complete, standardized 12-lead recording).

♦ If clinically indicated, ejection fraction (by cardiac ultrasound or multi-gated acquisition scan) will be assessed again. The same method should be used throughout the study.

♦ In case of QTc prolongation, additional tests will be performed as per chapter 5.4.4.10.

Tumor evaluation (by RECIST 1.1) with CT of the chest, abdomen and pelvis with intravenous and oral contrast, or MRI.

♦ All sites of GIST that were found to be involved at the initial assessment will be re-investigated by the same method.


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♦ All lesions chosen as target during the initial assessment will be measured by the same method.

♦ All investigations will be consistent with baseline in order that the development of new lesions in previously normal areas can also be determined.

The evaluation at 12 weeks is mandatory for all patients unless disease progression has been documented earlier. A central review of all anonymized digital CT and MRI images will be organized (see chapter 15.4). For this central review, the sites must provide radiological material: anonymized CD-ROMs with CT/MRI images up to week 12 (including baseline and week 6 scans) must be shipped by week 14 to the EORTC HQ.

Anonymized CD-ROMS including all CT/MRI images after week 12 will have to be shipped to EORTC HQ as well. Shipment has to be performed within 4-2 weeks after progression AND after the definitive end of treatment.

6.2.3 Translational research Blood samples (10 ml at each time point) for cfDNA will be collected at week 6, week 12 and at time of RECIST progression (according to local assessment). Samples will be kept on site at -80°C and shipped in bulk (see chapter 10.3.1).

6.3 Upon permanent discontinuation of treatment The following examination should be performed 30 days (+/- 7 days) after the last administration of study treatment:

♦ Ongoing medical history.

♦ Physical examination (ECOG performance status, blood pressure, weight, pulse rate).

♦ Assessment of all adverse events that have occurred since the previous visit and ongoing events from previous cycles should be followed.


♦ Cardiac function: 12-lead ECG (complete, standardized 12-lead recording) and ejection fraction (by cardiac ultrasound or multi-gated acquisition scan). The same method should be used throughout the study.

♦ Complete blood counts (see chapter 6.1.2).

♦ Serum chemistry panel (see chapter 6.1.2).

♦ Thyroid function (see chapter 6.2.1)

♦ Coagulation test (to include at least PT/INR, PTT).

♦ Dipstick urinalysis (see chapter 6.2.1).

6.4 After end of treatment (Follow-up) Follow up for AEs or response assessment will stop when a patient starts a consecutive line of treatment for GIST after stopping cabozantinib.


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6.4.1 For patients who discontinued protocol treatment due to disease progression

After the end of treatment visit (see chapter 6.3), follow up for survival will be provided every 12 weeks until death. Information regarding the type and duration of subsequent anti-tumoral therapies received by the patients will also be collected. Patient visits are preferred but a telephone call to the patient is acceptable.

If at the time of treatment discontinuation, the patient suffers from a related Grade 3 or 4 adverse event, the event must be followed until resolution or determination by the investigator that the event has become stable or irreversible. Any treatment related death occurring beyond this time frame must be reported to EORTC.

6.4.2 For patients who discontinued treatment in the absence of per protocol progression

In case a patient withdraws for reasons other than clinical disease progression, follow up must still be provided for the study endpoints (PFS and OS) until disease progression as per protocol, or start of a new anti-tumoral treatment. Therefore disease evaluations will be continued every 6 weeks during the first 48 weeks of treatment and every 12 weeks thereafter, as described in chapter 6.2.2. After progression or start of new anti-tumoral treatment, the follow-up will be as described for patients discontinuing due to disease progression (see chapter 6.4.1).

If a patient is discontinued from study treatment because of an AE considered to be related to study treatment and the event is ongoing 30-days after the last dose of study treatment, the event must be followed until resolution or determination by the investigator that the event has become stable or irreversible. Any treatment related death occurring beyond this time frame must be reported to EORTC.


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6.5 Summary table

Before start Treatment period Permanent

discontinuation treatment

After end of treatment

Within

14 days

Within 7 days

Every cycle (3 weeks)

Every 6 weeks17

Weeks 6 & 12

After PD

Every 12

weeks

Discontinued treatment in absence of

PD

Refer chapters

6.1 6.2.1 6.2.2 6.2.3 6.3 6.4.1 6.4.2

Past and ongoing medical history

Pregnancy test1

(within

72 hours)

# # #

Physical examination2

♣14 ♣15

Cancer signs & symptoms

Adverse events3

♣14 ♣15


Hematology 4 ♣14 ♣15

Serum chemistry panel 5

♣14 ♣15

PT/INR, PTT ♣14 ♣15

Thyroid function6

♣14 ♣15


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Before start Treatment period Permanent

discontinuation treatment

After end of treatment

Within

14 days

Within 7 days

Every cycle (3 weeks)

Every 6 weeks17

Weeks 6 & 12

After PD

Every 12

weeks

Discontinued treatment in absence of

PD

Dipstick 9 urinalysis and urine protein/ creatinine ratio

♣14 ♣15

ECG with 12-lead recording7

♣14 ♣15

LVEF 8 ♣ ♣ ♣14 ♣15

Tumor evaluation10

Within

28 days

16, 17

(Every 6 weeks)

Tissue sample11

Translational research blood sample12

Survival13 in all cases ♣ if clinically indicated # as per national regulations/institutions guidelines

1. Pregnancy test: serum beta HCG in fertile female study participants. The pregnancy test is to be renewed/repeated during protocol treatment according to National regulations/institution guidelines.

2. Physical examination includes ECOG performance status, blood pressure, weight, height (only at baseline), pulse rate.

3. In case of specific AEs more frequent assessments of specific tests must be done according to chapter of management of AEs (see 5.4)

4. Complete blood counts will be performed, to include at least red blood cell count, hematocrit, hemoglobin, white blood cell count (neutrophils, basophils, easinophils, lymphocytes, monocytes) and platelets.

5. Serum chemistry includes at least: potassium, sodium, ionized calcium, magnesium, phosphorus, chloride, bicarbonate, creatinine, total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), γ-glutamyltransferase (GGT), lactate dehydrogenase, total protein, albumin, lipase, amylase, blood urea nitrogen, glucose. Creatinine clearance to be calculated as per local standard. Serum chemistry tests may be repeated more frequently based on management of AEs as per chapter 5.4.

6. During treatment, TSH will be monitored every 3 weeks and if elevated T3 and T4 will be checked.

7. 12-lead ECG (complete, standardized 12-lead recording) will be performed at baseline, every 6 weeks and upon permanent discontinuation of study treatment. In case of QTc prolongation, additional tests will be performed as per chapter 5.4.4.10.

8. To be performed at baseline and upon permanent discontinuation of study treatment. During treatment this test will be done if clinically indicated. Assessment by cardiac ultrasound or multi-gated acquisition scan, the same method should be used throughout the study.


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9. During treatment any level of proteinuria by dipstick should be quantified by UPCR. When UPCR exceeds 1, a repeat UPCR or a 24-hour urine protein and creatinine should be performed to confirm result.

10. Tumor evaluation (by RECIST 1.1) with CT of the chest, abdomen and pelvis with intravenous and oral contrast, or MRI. The evaluation at 12 weeks is mandatory for all patients unless disease progression has been documented earlier. A central review will be organized and for this review the sites will need to provide radiological material.

11. At baseline archival formalin fixed, paraffin-embedded (FFPE) tumor tissue from the primary tumor or a metastatic site of GIST will be collected for reference pathology (5 unstained slides of 4 micrometer thickness) and translational research (10 unstained slides with archived tumor tissue of 10 micrometer thickness and two hematoxylin and eosin (H&E) stained slides).

12. Blood sampling/processing of circulating cell-free DNA will be collected at baseline, week 6, week 12 and at progression. Samples will be kept on site -80°C and shipped in bulk.

13. Follow up until death

14. For patients suffering from a severe adverse event Grade 3 or 4, the event must be followed until resolution or determination by the investigator that the event has become stable or irreversible

15. If a patient is discontinued from study treatment because of an AE related to cabozantinib and the event is ongoing 30 days after the last dose of study treatment: follow up until resolution or determination by the investigator that the event has become stable or irreversible. Any treatment related death occurring beyond this time frame must be reported to EORTC.

16. Disease evaluation until progression or start of new treatment for GIST after stopping cabozantinib.

17. Every 6 weeks during the first 48 weeks and every 12 weeks thereafter.

7 Criteria of evaluation 7.1 Progression free survival at 12 weeks (binary) The primary end-point of the study is PFS at 12 weeks after start of treatment, measured as a binary variable. This will be based on the disease evaluation by the local investigator of the radiological images performed 12 weeks after start of treatment. Patients will be considered as a "success" if this radiological evaluation indicates either CR, PR or SD as defined by RECIST v1.1 (see hereunder); all other cases will be considered as failures (including patients who have progressed or died before the week 12 assessment, patients with unknown progression status at week 12, or patients who started new anti-tumor therapy in the absence of progressive disease).

7.2 Progression free survival PFS will be computed from the date of start of treatment to the first documented date of progression (by central review of the radiological images based on RECIST v1.1 - see hereunder) or death, whatever the cause, whichever occurs first. Patients alive and free from progression at the time of the analysis will be censored at the date of last disease assessment.

7.3 Overall survival OS will be computed from the date of start of treatment to the date of death (due to any cause). Patients alive at the time of analysis will be censored at the date of last follow-up.

7.4 Objective response rate ORR (CR + PR) will be based on the best response recorded from the start of treatment until treatment discontinuation based on RECIST v1.1 (see hereunder).

Response criteria are essentially based on a set of measurable lesions identified at baseline as target lesions, and – together with other lesions that are denoted as non-target lesions – followed until disease progression.


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The following paragraphs are a quick reference to RECIST (version 1.1). The complete criteria are included in the published RECIST document (Ref. 17) also available at http://www.eortc.org/recist /

7.4.1 Measurability of tumor lesions at baseline

7.4.1.1 Definitions ♦ Measurable disease - the presence of at least one measurable lesion. If the measurable disease is

restricted to a solitary lesion, its neoplastic nature should be confirmed by cytology/histology.

♦ Measurable lesions - tumor lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm with chest x-ray, and as ≥ 10 mm with CT scan or clinical examination [using calipers]. Bone lesions are considered measurable only if assessed by CT scan and have an identifiable soft tissue component that meets these requirements (soft tissue component > 10 mm by CT scan). Malignant lymph nodes must be ≥ 15 mm in the short axis to be considered measurable; only the short axis will be measured and followed. All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters) by use of a ruler or calipers. Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, are usually not considered measurable unless there has been demonstrated progression in the lesion.

♦ Non-measurable lesions - All other lesions (or sites of disease), including small lesions are considered non-measurable disease. Bone lesions without a measurable soft tissue component, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, lymphangitic involvement of lung or skin and abdominal masses followed by clinical examination are all non-measurable. Nodes that have a short axis <10 mm at baseline are considered non-pathological and should not be recorded or followed.

♦ Target lesions. When more than one measurable tumor lesion or malignant lymph node is present at baseline all lesions up to a maximum of 5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs should be identified as target lesions and will be recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements. Note that pathological nodes must meet the criterion of a short axis of ≥ 15 mm by CT scan and only the short axis of these nodes will contribute to the baseline sum. At baseline, the sum of the target lesions (longest diameter of tumor lesions plus short axis of lymph nodes: overall maximum of 5) is to be calculated and recorded.

♦ Non-target lesions. All non-measurable lesions (or sites of disease) including pathological nodes (those with short axis ≥ 10 mm but < 15 mm), plus any measurable lesions over and above those listed as target lesions are considered non-target lesions. Measurements are not required but these lesions should be noted at baseline and should be followed as “present” or “absent”.

All baseline evaluations should be performed as closely as possible to the beginning of the treatment and never more than 28 days before the beginning of the treatment.

7.4.1.2 Methods of measurements The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow-up. Assessments should be identified on a calendar schedule and should not be affected by delays in therapy. While on study, all target lesions recorded at baseline should have their actual measurements recorded on the CRF at each subsequent evaluation, even when very small (e.g. 2 mm). If it is the opinion of the radiologist that the lesion has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned. For lesions which fragment/split add

http://www.eortc.org/recist%20/


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together the longest diameters of the fragmented portions; for lesions which coalesce, measure the maximal longest diameter for the “merged lesion”.

♦ Clinical lesions. Clinical lesions will only be considered measurable when they are superficial and ≥ 10 mm as assessed using calipers (e.g. skin nodules). For the case of skin lesions, documentation by color photography including a ruler to estimate the size of the lesion is recommended. If feasible, imaging is preferred.

♦ Chest X-ray. Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. However, lesions > 20 mm on chest X-ray may be considered measurable if they are clearly defined and surrounded by aerated lung. The use of chest X-ray for response assessment in this trial is discouraged.

♦ CT, MRI. CT is the best currently available and reproducible method to measure lesions selected for response assessment in various malignancies. In GIST the interpretation of conventional CT or MRI scans can be difficult, as the therapeutic effects of tyrosine kinase inhibitors cannot be assessed by tumor shrinkage only. This guideline has defined measurability of lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans). While PET scans are not considered adequate to measure lesions, PET-CT scans may be used providing that the measures are obtained from the CT scan and the CT scan is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast). The use of PET for response assessment in this trial is discouraged.

♦ Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used as a method of measurement. If new lesions are identified by ultrasound in the course of the study, confirmation by CT should be obtained. The use of ultrasound for response assessment in this trial is discouraged.

♦ Endoscopy, laparoscopy. The utilization of these techniques for objective tumor evaluation is not advised. However, they can be useful to confirm complete pathological response when biopsies are obtained or to determine relapse in trials where recurrence following complete response or surgical resection is an endpoint. The use of endoscopy for response assessment in this trial is discouraged.

♦ Tumor markers. Tumor markers alone cannot be used to assess objective tumor response. If markers are initially above the upper normal limit, however, they must normalize for a patient to be considered in complete response. There are no established tumor markers for GIST.

♦ Cytology, histology. These techniques can be used to differentiate between PR and CR in rare cases if required by protocol (for example, residual lesions in tumor types such as germ cell tumors, where known residual benign tumors can remain). When effusions are known to be a potential adverse effect of treatment (e.g. with certain taxane compounds or angiogenesis inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment when the measurable tumor has met criteria for response or stable disease is advised to differentiate between response or stable disease and progressive disease. The use of cytology/histology for response assessment in this trial is discouraged.

7.4.2 Tumor response evaluation All patients will have their BEST RESPONSE from the start of study treatment until the end of treatment classified as outlined below:

Complete Response (CR): disappearance of all target and non-target lesions and normalization of tumor markers. Pathological lymph nodes must have short axis measures < 10mm (Note: continue to record the measurement even if < 10 mm and considered CR). Tumor markers must have normalized. Residual


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lesions (other than nodes < 10 mm) thought to be non-malignant should be further investigated (by cytology or PET scans) before CR can be accepted.

Partial Response (PR): at least a 30% decrease in the sum of measures (longest diameter for tumor lesions and short axis measure for nodes) of target lesions, taking as reference the baseline sum of diameters. Non target lesions must be non-PD.

Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum of diameters on study.

Progressive Disease (PD): at least a 20% increase in the sum of diameters of measured lesions taking as references the smallest sum of diameters recorded on study (including baseline) AND an absolute increase of ≥ 5 mm. Appearance of new lesions will also constitute PD (including lesions in previously unassessed areas). In exceptional circumstances, unequivocal progression of non-target disease may be accepted as evidence of disease progression, where the overall tumor burden has increased sufficiently to merit discontinuation of treatment, for example where the tumor burden appears to have increased by at least 73% in volume (which is the increase in volume when all dimensions of a single lesion increase by 20%). Modest increases in the size of one or more non-target lesions are NOT considered unequivocal progression. If the evidence of PD is equivocal (target or non-target), treatment may continue until the next assessment, but on further documentation, the earlier date must be used.

Table 1: Integration of Target, non-Target and New lesions into response assessment:

Target Lesions Non-Target Lesions New

Lesions Overall

Response Best Response for this category also requires

Patients with Target lesions ± non target lesions

CR CR No CR

Normalization of tumor markers, tumor nodes < 10 mm

CR Non-CR/Non-PD No PR

CR Not all evaluated No PR

PR Non-PD/ not all

evaluated No PR

SD Non-PD/ not all evaluated No SD documented at least once ≥

6 wks from baseline

Not all evaluated Non-PD No NE

PD Any Any PD

Any PD Any PD

Any Any Yes PD

Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression [or evidence of unequivocal disease progression] at that time should be reported as “symptomatic deterioration”. This is a reason for stopping therapy, but is NOT objective PD. Every effort should be made to document the objective progression even after discontinuation of treatment.


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7.4.2.1 Frequency of tumor re-evaluation Tumor assessments will be performed at baseline and every 6 weeks during the first 48 weeks of treatment and every 12 weeks thereafter, until progression.

Patients who remained on treatment after documented progression, but are deriving clinical benefit, will still be evaluated every 6 weeks during the first 48 weeks of treatment and every 12 weeks thereafter, until permanent discontinuation of treatment.

After discontinuation of protocol treatment, patients who have not progressed will still be evaluated every 6 weeks during the first 48 weeks and every 12 weeks thereafter, until progression or start of new treatment (see chapter 6.4.2).

7.4.2.2 Date of progression This is defined as the first day when the RECIST (version 1.1) criteria for PD are met.

7.4.3 Reporting of tumor response All patients included in the study must be assessed for response to treatment, even if there is a major protocol treatment deviation or if they are ineligible, or not followed/re-evaluated. Each patient will be assigned one of the following categories: complete response, partial response, stable disease, progressive disease, early death or not evaluable.

Early death is defined as any death occurring before the first per protocol time point of tumor re-evaluation.

Patients’ response will be classified as "not evaluable" if insufficient data were collected to allow evaluation per these criteria.

7.5 Clinical benefit rate CBR (CR + PR + SD) will be based on the best response recorded from the start of treatment until treatment discontinuation based on RECIST v1.1 (see chapters 7.4.1 to 7.4.3).

7.6 Total duration of treatment This end-point is of interest as treatment with cabozantinib beyond radiological progression is allowed by protocol. Total duration of treatment will be computed from the date of start of treatment to the date of discontinuation of treatment for any reason, including disease progression, treatment toxicity, and death. Patients alive and still on protocol treatment at the time of the analysis will be censored at the date of last known treatment administration.

7.7 Evaluation of safety

7.7.1 Adverse events All AEs will be recorded; the investigator will assess whether those events are drug related (reasonable possibility, no reasonable possibility) and this assessment will be recorded in the database for all adverse events.

Only the worst grade per CTCAE 4.0 category will be recorded per cycle. The collection period will start from day -14 prior to the first administration of the investigational agent until total resolution of all adverse events and discontinuation of treatment with cabozantinib. Persistent adverse events will be followed for at least 30 days (+/- 3 days).


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7.7.2 General evaluation of adverse events This study will use the International Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, for adverse event reporting. A copy of the CTCAE can be accessed from the EORTC home page www.eortc.org\investigators-area\ctc.

Hematological and biochemistry adverse events will be assessed on the basis of at least three-weekly blood counts. The highest CTCAE grading per cycle and per patient will be computed at the EORTC HQ for analysis.

Planned safety analysis and tabulations are described in the statistics section.

7.7.3 Serious adverse events Serious adverse events are defined by the Good Clinical Practice Guideline.

SERIOUS ADVERSE EVENTS SHOULD BE IMMEDIATELY REPORTED ACCORDING TO THE PROCEDURE DETAILED IN THIS PROTOCOL (see chapter on Reporting

Serious Adverse Events)

7.7.4 Toxic death Toxic death is defined as death due to toxicity (defined as adverse events that are not confirmed as unrelated). The cause of death must be reported as "toxicity".

The evaluation of toxic deaths is independent of the evaluation of response (patients can die from toxicity after a complete assessment of the response to therapy).

7.7.5 Evaluability for safety All patients who have started the treatment will be included in overall safety analyses.

For hematological events, the medical review team may decide that blood counts have not been performed and/or reported according to the protocol and are therefore inadequate for the evaluation of one/several hematological parameters in some patients.

Patients who have discontinued treatment because of toxicity will always be included in the safety analyses.

7.8 Evaluation of exploratory endpoints The relative efficacy of cabozantinib in different mutational subtypes of GIST and the use of circulating plasma DNA for centralized mutational analysis in GIST, will be assessed/explored by using blood samples and tissue samples collected from patients. Details are provided in chapter 10.

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8 Statistical considerations 8.1 Statistical design

8.1.1 Sample size Progression free survival at 12 weeks (taken as a binary indicator; see chapter 7.1) has been chosen as primary endpoint of the trial and was used to derive the sample size calculations described below.

The A'Hern one stage (Ref. 21) design will be used to test the null hypothesis H0: P ≤ P0 versus HA: P > P0. The power and sample size is computed under the alternative hypothesis that P = P1. The following design characteristics and decision rules apply

P0 will be taken as 40% - success in ≤ 40% of the cases will be considered as unacceptable, and would not warrant further investigation. This reference value was obtained as follows: the observed rate should be substantially better than the one observed for placebo (11%) in the GRID study (Ref. 9) and should allow a sufficiently large sample size to support further investigation. P1 will be taken as 60%. This value is based on the estimate of PFS at 3 months (centrally reviewed) which was obtained with regorafenib in the GRID study (Ref. 9). Type I and type II errors are fixed at 10% (alpha = beta = 0.10).

Under those hypotheses, the study requires 41 eligible and evaluable* patients. If at least 21 out of 41 eligible and evaluable patients are progression-free at the week 12 assessment (see Section 7.1), the activity of cabozantinib in this trial will be deemed sufficient to warrant further exploration of the drug in metastatic GIST.

To allow for a sufficient number of patients to be assessable for the decision rule, screening can continue beyond 41 patients, but will be capped at 50. It is anticipated that these 50 patients will enter the study at the average rate of 1.3 patients / month during the first 3 months, 2 patients / month during months 4 to 6, 2.9 patients / month during months 7 to 9, 3.8 during months 10 to 12, and 5 patients per month thereafter. The duration of accrual is expected to last 18 months from first patient in (FPI).

The final analysis of the primary endpoint will be performed when all patients have been treated for at least 12 weeks and an evaluation of the disease has been performed and reported. * A patient will be considered as "evaluable" for the primary endpoint if he/she started the study treatment (at least one dose) and he/she had an imaging assessment at baseline.

8.2 Statistical analysis plan

8.2.1 Primary and secondary endpoints Primary and secondary end-points are defined in chapter 7.

8.2.2 Analysis populations A patient will be considered to be eligible if he/she did not have any deviation from the patient entry criteria listed in chapter 3 of the protocol. Potential eligibility problems will be assessed by the Clinical Research Physician and Study Coordinator at time of medical review.

Analyses of all efficacy end-points will be based on all patients who have started therapy, with the exception of the decision rule that will only take into account the first 41 eligible and evaluable patients, according to the order in which they were registered in the study. Analyses of safety end-points will be based on all patients who have started therapy, whether they were eligible or not.


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8.2.3 Statistical methods The decision rules described in Section 8.1.1 will be applied.

PFS at 12 weeks after start of therapy, ORR and CBR are binary indicators (see Chapter 7) and will be reported as proportions with their 95% confidence interval (from the exact binomial distribution).

PFS, OS, and total duration of treatment will be estimated by the Kaplan-Meier (KM) method. The full curves will be included in the report. KM estimates at 3 months intervals will be tabulated with their standard error; median will be provided with its 95% confidence interval.

For adverse events, the worst grade of each event will be tabulated.

8.2.4 Pre-planned sensitivity or exploratory analyses Patients are not encouraged to, but can start a new anticancer treatment in the absence of documented progression. In this case, study specific disease evaluations will be stopped at the time of starting a new treatment (see chapter 6.4.2). Therefore, following the definition of PFS in Section 7.2, these patients will be censored at the date of last disease assessment. If this happens in more than 10% of the patients (at any time), two sensitivity analyses of PFS will be carried out, a) considering the start of a new therapy as failure, and b) considering the start of a new therapy as a competing risk.

8.2.5 Follow-up analyses A follow-up analysis will be performed one year after the last patient entered the study to provide a more mature estimate of the time to event endpoints (PFS, OS and total duration of treatment).

8.2.6 Data recoding and display Frequencies will be tabulated for all categorical variables by the levels of the variables as they appear on the Case Report Forms (with %). Categories with a text field specification will be tabulated as categories and then supplemented by a listing with the following information for the patients fulfilling the condition for the specification (patient id, institution, value of the item and text field contents).

Dates relating to events prior to entry will be presented as the delay in days (or weeks, months, or years) between the past event and the date of entry (date of registration – date of past event + 1) and presented using the median and range. For example, the date of last administration of prior treatment (or the date of first diagnosis of the cancer) will be presented as the time elapsed (in days, weeks, months or years, as appropriate) since the day of the last administration and the date of entry on study (date of registration – last administration/diagnosis +1).

Other delays (eg. pre-treatment delays) are presented as continuous variables using the median and range.

Continuous variables for which a coding system exists (such as for laboratory data) will be recoded into categories (for adverse events, the grading scale specified in the protocol will be used). Whenever no specific scale exists, lab data will be categorized based on the normal range: for example, below the lower normal limit (when appropriate), within the normal range, above the upper normal limit (ULN) and the degree to which it is above the ULN (for example > 2.5 x ULN, > 5 x ULN, > 10 x ULN). For laboratory data, the nadir is generally displayed. The nadir in a given cycle is the lowest laboratory value in that cycle; the overall nadir for a patient is the lowest laboratory value among all cycles.

Other continuous variables (for example age, dose …) are presented using the median and range (minimum, maximum).

The dose intensity of the treatments will be calculated on actual treatment dose of cabozantinib received and actual treatment duration (in weeks). The relative dose intensity will be calculated as the ratio of the


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actual dose intensity and the theoretical dose intensity indicated by the protocol, expressed in %. The dose intensity parameters will be presented using median and ranges.

If appropriate, continuous data may also be presented in categories (for example, age may also be grouped in decades).

8.3 End of study End of study occurs when all of the following criteria have been satisfied:

1. Thirty days after all patients have stopped protocol treatment.

2. The trial is mature for the analysis of the primary endpoint as defined in the protocol

3. The database has been fully cleaned and frozen for this analysis

9 Data Monitoring Safety data are reviewed within the EORTC Headquarters on a regular basis as part of the Medical Review process. Problems which are identified will be discussed with the Study Coordinators who will take appropriate measures. Safety information will also be included in trial status reports which serve as a basis of discussion during EORTC Group meetings. These reports will be made available to investigators participating in the study.

The EORTC Independent Data Monitoring Committee (IDMC) will review all safety problems identified by the EORTC Headquarters for which an advice is sought. Experts on the IDMC performing this review will be selected to have the relevant early trials/drug development expertise and will provide a review process independent of that of the Medical Review. In principle, no access to outcome data is necessary for safety reviews. However, the IDMC will also provide recommendations as an initial step in phase III trials to advise if a full review of all study data and endpoints is needed.

The EORTC IDMC is charged with the interim review (planned in the protocol or ad hoc) of randomized phase II and phase III studies. When interim analyses are carried out, the interim monitoring of efficacy and safety data is performed according to the Statistical Considerations chapter in this protocol and EORTC Policy 004 on “Independent Data Monitoring Committees and Interim Analyses”.

The results of the interim analyses are confidential and are discussed by the EORTC IDMC. The IDMC will subsequently recommend to the EORTC Group whether any changes should be made to the study.

No efficacy results will be presented at EORTC Group meetings or elsewhere before the trial is closed to recruitment and the data are mature for the analysis of the primary endpoint, unless recommended otherwise by the EORTC IDMC.

10 Translational research Translational research is mandatory and exploratory

10.1 Introduction The following exploratory research projects will be performed in this trial.

♦ Efficacy of cabozantinib in different molecular subtypes of GIST, based on KIT/PDGFRA mutations.

This project will assess the relative efficacy of cabozantinib in different mutational subtypes of GIST, evaluated centrally, based on archived tumor material derived from the primary tumor or a metastatic site.

♦ Exploration of cell-free DNA (cfDNA) in plasma originating from the tumor


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This project will explore the use of tumor DNA circulating in plasma (“liquid biopsy”) for mutational analysis in GIST, based on the targeted next generation sequencing (tNGS).

For these projects the collection of samples must be performed. If patient refuses to consent for these samples the patient will not be eligible.

10.2 Efficacy of cabozantinib in different molecular subtypes of GIST

Activating mutations in KIT and PDGFRA have been identified as driving oncogenic events in GIST and are present in the majority of these tumors (Ref. 18). Mutational status and types of KIT and PDGFRA mutations have prognostic importance and also allow predicting the response to TKI treatment (Ref. 19, Ref. 20). The goal of the biomarker analysis is to provide supportive data for the clinical study, and to assess the prognostic value of the primary KIT/PDGFRA mutation for the response to cabozantinib in GIST patients.

Utmost care will be taken to protect the patient’s identity during the biomarker analyses. Collection, handling, and shipment of biomarker samples will be performed as described in a laboratory manual (provided separately).

10.2.1 Archival fixed tissue collection for tumor characterization Archival tumor tissue available from primary tumor or metastatic site (10 unstained slides with archived tumor tissue of 10 μm thickness and two hematoxylin and eosin (H&E) stained slides) will be collected from all patients, ideally originating from the time of the initial diagnosis, prior to exposure to TKIs. For procedures and contact details please refer to Study Procedures Manual.

Fresh-frozen, paraffin-embedded tissue (FFPE) will be shipped to the Central Laboratory. Samples will be subject to centralized mutational assessment of KIT and PDGFRA genes, performed at the Department of Human Genetics, University Hospitals Leuven.

DNA will be isolated from unstained slides, which will be evaluated for the presence of tumor tissue. If necessary (<75% tumor cells in the specimen, as assessed by H&E staining) tumor tissue will be macro-dissected prior to DNA extraction. The analysis will be done using Sanger direct sequencing of exons 9, 11, 13 and 17 of KIT, and exons 12, 14 and 18 of PDGFRA. The mutational status of the tumor will be correlated with the response to cabozantinib in this clinical trial.

In addition the FFPE-isolated DNA will be evaluated using the same tNGS platform, established for cfDNA analysis (see chapter 10.3), to detect potential additional changes in selected genes.

10.2.2 Instructions for preparing slides from FFPE blocks (mandatory) ♦ Ten 10µm unstained sections from a block will be cut after decontamination of the cutting surfaces.

Sections should contain predominately tumor tissue.

♦ Sections should be prepared on Superfrost plus (or similar) charged slides to ensure maximal tissue adhesion.

♦ Tissue sections should be air-dried overnight and stored at -20°C (preferred) or at ambient temperature in slide boxes for shipment to the Central Laboratory.

♦ Unstained slides (n=10) should be accompanied by two H&E stained slides from the same block, one cut before and one after the last unstained slides, to ensure the tumor content in histological sections, to be used for DNA isolation.

♦ If tissue is more limited, as many slides as possible should be prepared.


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♦ Every slide should be clearly labeled (for detailed instructions see the laboratory manual)

♦ Collection, handling, and shipping of biomarker samples will be performed as described in the laboratory manual (provided separately).

Left-over material will be bio banked for future, yet to be defined research purposes. Any future proposals of translational research (TR) will be evaluated for scientific merit and feasibility by the steering committee (composed of the study coordinators and EORTC headquarters representatives) of the trial and will be submitted for approval to the relevant ethical committees (see chapter 10.5).

10.2.3 Statistical analysis The primary KIT/PDGFRA mutations will be tabulated.

The association of the primary KIT/PDGFRA mutation with PFS, OS and total treatment duration will be analyzed using Cox proportional hazard models. The relation of the primary KIT/PDGFRA mutation with response and clinical benefit rate will be investigated through a logistic regression model, possibly adjusted for important prognostic factors depending on the available number of events.

These analyses are exploratory in nature; no adjustment for multiple testing will be implemented.

10.3 Exploration of plasma cell-free DNA (cfDNA), originating from the tumor

cfDNA is believed to be a promising surrogate marker for assessment of the sensitivity or resistance to a given anti-tumor treatment. It has been shown that tumor-specific oncogenes, suppressor genes, point mutations of genes, microsatellite instability and loss of heterozygosity can be detected in cfDNA from cancer patients (Ref. 25, Ref. 26). Recent studies showed that cfDNA can be found in >75% of advanced tumors (e.g. pancreatic, ovarian, colorectal) and in >50% of patients with primary brain, renal, prostate or thyroid cancers (Ref. 27).

As characterization of the tumor mutational profile is required for informed choice of therapy especially in the context of the use of TKIs such as in the clinical setting of GIST, it is postulated that cfDNA could be useful for multiple clinical purposes. In theory, such potential applications include early detection, screening, prognosis, monitoring of tumor dynamics over time or detection of minimal residual disease (Ref. 27).

Multiple methods for detection and analysis of cfDNA have been developed and are currently under validation, such as BEAMing (beads, emulsion, amplification and magnetics) technology (Ref. 28, Ref. 29).

The latter approach was used in the pivotal Phase III study comparing regorafenib versus placebo in GIST resistant to imatinib and sunitinib, where it was shown that KIT mutations associated with TKI resistance were more frequently detected in plasma (47%) than in tumor tissue (12%). In addition they were able to detect multiple resistant mutations in the plasma of GIST patients, while only single mutations were present in the conventional, archived tumor biopsy.

Techniques such as BEAMing are very sensitive (able to detect mutations present in only 1 out of 10.000 DNA molecules), however this technology can be used only to detect predefined mutations.

A potential methodological alternative could be targeted (tagged-amplicon) deep sequencing, which has already been successfully used to identify mutations in selected genes with an allele frequency (AF) as low as 5% (Ref. 30, Ref. 31, Ref. 32, Ref. 33).

Blood samples will be collected at baseline (prior to starting treatment with cabozantinib) and at 6 and 12 weeks, with the intention to detect and evaluate cfDNA levels in plasma. Blood will be collected in participating institutions using special tubes (Streck) to stabilize cfDNA. Plasma will be prepared at the


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investigational sites by centrifugation, stored at -80° C and later be shipped in bulk to the Central Laboratory for analysis.

cfDNA will be isolated using a validated QIAamp Circulating Nucleic Acid Kit (QIAGEN). The low level mutations in DNA will be detected using sequencing targeted Next Generation Sequencing (tNGS) (Ref. 30, Ref. 33). Using this approach the multiple preselected amplicons of the entire genes, e.g. KIT, PDGFRA, encoding proteins from PI3K/AKT and RAS/RAF/MAPK signaling pathways, selected tumor suppressor genes (PTEN, TP53, RB…) all implicated in GIST tumorigenesis and/or TKI resistance will be analyzed.

In this trial the feasibility of using the tNGS to analyze cfDNA in GIST patients will be evaluated with the aim to detect activating and resistance mutations as well as to monitor the response to cabozantinib by longitudinal plasma sampling. Moreover the concordance of primary KIT/PDGFRA mutations results using two different types of samples will be studied.

The work will be performed in the close collaboration between Department of General Medical Oncology, UZ Leuven (Patrick Schöffski), responsible for EORTC1317 on behalf of EORTC, the Laboratory of Experimental Oncology, KU Leuven (Agnieszka Wozniak), responsible for central handling, processing and preparation of the biological material, and the Genomics Core at UZ Leuven (Joris Vermeesch), a facility with extensive expertise in deep sequencing, equipped with multiple high-throughput platforms (i.e. HighSeq), experience with handling cfDNA (as the Belgian accredited reference center for non-invasive prenatal diagnosis) and with access to the required bioinformatics support.

10.3.1 Blood sample collection for characterization of circulating cell-free DNA (mandatory)

cfDNA will be isolated from plasma samples from all patients. Blood samples (10 ml each) will be obtained at cycle 1/day 1 (prior to start of study drugs), week 6, week 12 and at time of RECIST progression (according to local assessment).

The blood samples will be collected using special tubes (Streck) to stabilize cfDNA, and pre-processed within one hour (two centrifugation steps) on site. Collected plasma will be aliquoted and stored at -80°C prior shipment to the central laboratory, where cfDNA extraction and further evaluations will be performed.

Collection, handling, and shipping of blood samples will be performed as described in the laboratory manual (provided separately).

10.3.2 Statistical analyses Differences of cfDNA mutation distributions over the different assessment times will be tabulated. The relationship between baseline cfDNA assessments and response rate will be analyzed using logistic regression models. The association between baseline cfDNA assessmentsand PFS and other time-related measures of efficacy in the clinical trial will be analyzed using Cox proportional hazard models, possibly adjusted for important prognostic factors depending on the available number of events.

The concordance of the results obtained from the two different types of samples in the presence of primary KIT/PDGFRA mutations will be tabulated.

These analyses are exploratory in nature; no adjustment for multiple testing will be implemented.


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10.4 Data storage, transfer and development of technical appendices

The translational projects will be the result of the work of collaborating institutions and EORTC HQ. Statistical analysis plan will be jointly developed for each project. These documents will be developed and approved before starting any analysis. They will specify the analytical and methodological details. Clinical data will be stored in the EORTC clinical database and biological investigational data will be stored in respective collaborating institutions. Transfer of data will be performed according to applicable policies in each organization (e.g. EORTC POL008) or according to jointly approved data transfer charters.

10.5 General principles for human biological material (HBM) collection

Biobanking for future research is optional and patient will be offered to participate. Human biological material (HBM) collection involves the collection and storage of biological material, residual biological material or derivatives in compliance with ethical and technical requirements.

In this study, biological material will be centralized and stored at the University Hospitals Leuven, Belgium. From here, the biological material will be used or distributed to the other research laboratories involved in the translational research (TR) projects defined in the future.

The following principles apply to storage of HBM:

The collected HBM should be documented, i.e. the amount remaining and its location.

The Study Steering Committee* (SSC) will be responsible for TR project review and prioritization, including the consideration of newly proposed TR projects not specified in the protocol. In the absence of a SSC, responsibilities of the SSC are transferred to the Group and/ or EORTC HQ as applicable.

* Study Steering Committee will be further detailed by a charter.

Final decisions on the use of HBM will be determined by a majority vote of the SSC. Additional expertise may be sought through advisory non-SSC/Group committee members.

Access to HBM (see EORTC Biobanking Policy POL020): HBM may be used for another purpose for which it was originally collected, subject to meeting ethical principles/and is covered by informed consent/ethics approval. In the case of secondary use of HBM, (i.e. for new TR projects that are not specified in the clinical study protocol and that were not foreseen at the time of protocol writing) interested parties may apply for the use of HBM and will follow the next steps:

♦ A short description of the new TR projects will be written and submitted to EORTC HQ for coordination with the appropriate SSC.

♦ The SSC will prioritize the TR projects. Access procedures defined by the SSC will build on the following key points:

♦ Project prioritization:

♦ Should be strongly based on scientific merit.

♦ Should consider the contribution of the different investigators to the trial and TR project.

♦ Will take into consideration if the applicant is an EORTC member or not (whilst maintaining the principle of access to the wider scientific community and commitments owed to study participants and ethical committees).

♦ Protection of confidentiality must be respected.


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♦ An EORTC HQ feasibility check, including recommendations for regulatory and ethical matters and other restrictions on the use of the HBM, will take place. If in the event the HBM collections are still retained at individual clinical sites, the TR project leader and the involved EORTC Group are responsible for collecting and providing information on availability of HBM for the feasibility assessment.

♦ Prioritized TR projects will then be reviewed by the Translational Research Advisory Committee (TRAC).

♦ Once SSC prioritization, the EORTC HQ feasibility assessment, and TRAC review are complete and when all applicable competent Ethics Committees approvals are in place and ethical principles are met, the TR project can be activated and HBM release and analysis can commence.

♦ The EORTC Board will mediate any disagreements of opinion between TRAC, the EORTC HQ feasibility assessment, the SSC and the TR project leader(s), as needed.

11 Investigator authorization procedure Investigators will be authorized to register patients in this trial only once they have returned the following documents to the EORTC Headquarters:

♦ The updated signed and dated curriculum vitae of the Principal Investigator in English with a GCP training proof.

♦ The (updated) list of normal ranges for the investigator’s institution signed and dated by the head of the laboratory. Please make sure normal ranges are provided also for those tests required by the protocol but not routinely done at the investigator’s institution.

♦ The Confirmation of interest by Principal Investigator Form (CIF), stating that the investigator will fully comply with the protocol. This must include an estimate of yearly accrual and a statement on any conflict of interest that may arise due to trial participation.

NB: A signed conflict of interest disclosure form will be required only if a possible conflict is declared on the CIF.

♦ The Study Agreement between EORTC and investigator's institution.

♦ A copy of the favorable opinion of the local or national (whichever is applicable) ethics committee mentioning the documents that were reviewed (including the version numbers and version dates of all documents). A list of all members of the ethics committee is also requested.

♦ A copy of the translated and adapted (according to all national requirements) Patient Information / Informed Consent sheet. Version numbers and dates must be clearly stated on each page.

♦ The signature log-list of the staff members with a sample of each authorized signature and the indication of the level of delegations. In case patients receive treatment at a satellite institution, i.e. outside the authorized institution, details on the satellite institution, including the CV of the local investigator, normal lab ranges and the approval of an ethics committee will have to be transmitted to the EORTC Headquarters. Please keep in mind that all communication is done ONLY between the primary institution and the EORTC Headquarters.

♦ The full name, address, phone numbers and e-mail address of the local pharmacist who will be responsible for the trial medication (for any trial where the drug will be provided).

♦ An accreditation, a certification, an established quality control / external quality assessment or another validation should be provided for the own laboratory.


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The center specific list of required documents will be included in the protocol activation package, with proper instructions as required by this protocol, your group and / or the applicable national law.

The new investigator will be added to the “authorization list”, and will be allowed to register patients in the trial as soon as

♦ All the above mentioned documents are available at the EORTC Headquarters.

♦ All applicable national legal and regulatory requirements are fulfilled.

Patient registration from centers not (yet) included on the authorization list will not be accepted.

12 Patient registration procedure Patient registration will only be accepted from authorized investigators (see chapter on “investigator authorization procedure").

Patients should be registered directly on the EORTC online randomization system (ORTA = online randomized trials access), accessible 24 hours a day, 7 days a week, through the internet. To access the interactive registration/randomization program, the investigator needs a username and a password (which can be requested at http://orta.eortc.be/).

In case of problems investigators can phone the EORTC Headquarters from 9.00 am to 5.00 pm (Belgian local time) from Monday through Friday in order to register patients via the EORTC call center. Registration via the phone is not available on Belgian holidays. A list of these holidays is available on the EORTC web site (http://orta.eortc.be/) and it is updated annually.

Through Internet: http://orta.eortc.be/

In case of problems by phone: +32 2 774 16 00

A patient can only be registered after verification of eligibility. Both the eligibility check and registration must be done before the start of the protocol treatment. STANDARD INFORMATION REQUESTED:

♦ institution number

♦ protocol number

♦ step number: 1

♦ name of the responsible investigator

♦ patient's code (maximum 4 alphanumerics)

♦ patient's birth date (day/month/year) or year of birth (as allowed per applicable legislation)

PROTOCOL SPECIFIC QUESTIONS:

♦ all eligibility criteria will be checked one by one

♦ actual values for the eligibility parameters will be requested when applicable

♦ date of written informed consent (day/month/year)

♦ date foreseen for protocol treatment start

Once eligibility has been verified, a sequential patient identification number (“seqID”) will be allocated to the patient. This number will allow the identification of the patients in the VISTA/Remote Data Capture system (VISTA/RDC) that will be used to complete the Case Report Forms.

http://orta.eortc.be/




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13 Forms and procedures for collecting data 13.1 Case report forms and schedule for completion Data will be reported on the forms specifically designed by the EORTC Headquarters for this study. Forms should be electronically sent to the EORTC Headquarters through the VISTA/RDC (Remote Data Capture) system, with the exception of the SAE/Pregnancy notification forms which are paper CRF's.

SERIOUS ADVERSE EVENTS SHOULD BE IMMEDIATELY REPORTED ACCORDING TO THE PROCEDURE DETAILED IN THIS PROTOCOL (see chapter on Reporting Serious Adverse Events).

A. Before the treatment starts: ♦ The patient must be registered in the trial by INTERNET or in case of problems by phone.

The electronic CRFs to be completed for a patient are available on the VISTA/RDC website one day after the registration on http://rdc.eortc.be/ or on http://www.eortc.org in the section for investigators.

B. During/after treatment The list of forms to be completed for this study and their submission schedule are available on the VISTA/RDC website and are also described in the "guidelines for completion of case report forms" that are provided to each participating investigator.

ALL Forms must be electronically approved and sent by the responsible investigator or one of his/her authorized staff members with the exception of the SAE/Pregnancy notification forms which need to be signed and dated individually by the responsible investigator or one of his/her authorized

staff members.

13.2 Data flow The forms must be completed electronically, with the exception of the SAE and pregnancy forms, according to the schedule defined in the guidelines for completion of Case Report Forms.

The list of staff members authorized to enter data (with a sample of their signature) must be identified on the signature log and sent to the EORTC Headquarters by the responsible investigator before the start of the study. To enter the RDC system, the investigator or authorized staff member needs to use the same username and password that are used to access the interactive registration program (ORTA).

In all cases, it remains the responsibility of the principal investigator to check that data are entered in the database as soon as possible and that the electronic forms are filled out completely and correctly.

The EORTC Headquarters will perform extensive consistency checks on the received data and will issue queries in case of inconsistent data. The queries for the electronic forms will appear in the VISTA/RDC system and must be answered there directly.

The EORTC data manager will subsequently apply the corrections into the database.

When satellite institutions are involved, all contact is made exclusively with the primary institution, for purposes of data collection and all other study related issues.

If an investigator (or an authorized staff member) needs to modify a CRF after the form has been electronically sent to the EORTC Headquarters, he/she should create a request for data correction in the VISTA/RDC system.

The data corrections will appear in the VISTA/RDC system and the EORTC data manager will subsequently apply the corrections into the database.

http://rdc.eortc.be/

http://www.eortc.org/


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More details on the data flow can be found in the Guidelines for completion of Case Report Forms.

14 Reporting of Serious Adverse Events ICH GCP and the EU Directive 2001/20/EC require that both investigators and sponsors follow specific procedures when notifying and reporting adverse events/reactions in clinical trials. These procedures are described in this section of the protocol.

14.1 Definitions These definitions reflect the minimal regulatory obligations; specific protocol requirements might apply in addition.

AE: An Adverse Event is defined as “any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment”. An adverse event can therefore be any unfavorable and unintended signs (such as rash or enlarged liver), symptoms (such as nausea or chest pain), an abnormal laboratory finding (including results of blood tests, x-rays or scans) or a disease temporarily associated with the use of the protocol treatment, whether or not considered related to the investigational medicinal product.

AR: An Adverse reaction of an investigational medicinal product is defined as “any noxious and unintended response to a medicinal product related to any dose administered”.

All adverse events judged by either the reporting investigator or the sponsor as having a reasonable causal relationship to a medicinal product qualify as adverse reactions. The expression reasonable causal relationship means to convey in general that there is evidence or argument to suggest a causal relationship.

UAR: An Unexpected Adverse Reaction is “any adverse reaction, the nature, or severity of which is not consistent with the applicable product information" (e.g. investigator's brochure for an unapproved investigational product or summary of product characteristics (SmPC) for a marketed product).

When the outcome of the adverse reaction is not consistent with the applicable product information this adverse reaction should be considered as unexpected.

Severity: The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, moderate or severe, or as described in CTC grades); the event itself, however, may be of relative minor medical significance (such as severe headache). This is not the same as “serious,” which is based on patient/event outcome or action criteria usually associated with events that pose a threat to patient’s life or functioning. Seriousness (not severity) serves as a guide for defining regulatory reporting obligations.

SAE: A Serious Adverse Event is defined as any untoward medical occurrence or effect in a patient, whether or not considered related to the protocol treatment, that at any dose:

♦ results in death

♦ is life-threatening (i.e. an event in which the subject was at risk of death at the time of event; it does not refer to an event which hypothetically might have caused death if it was more severe)

♦ requires inpatient hospitalization or prolongation of existing patient hospitalization

♦ results in persistent or significant disability or incapacity

♦ is a congenital anomaly or birth defect

♦ is a medically important event or reaction.

♦ Medical and scientific judgment should be exercised in deciding whether other situations should be considered serious such as important medical events that might not be immediately life-threatening or result in death or hospitalization but might jeopardize the patient or might require intervention to


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prevent one of the other outcomes listed in the definition above. Examples of such events are intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or development of drug dependency or drug abuse.

AESI: The following Adverse Event of Special Interest should be reported as a SAE in an expedited way:

♦ Arterial thrombotic events

♦ Any QTc prolongation event

♦ Fistulas

♦ Gastrointestinal perforations

♦ Hemorrhage

♦ Osteonecrosis

SAR: A Serious Adverse Reaction is defined as any SAE which is considered related to the protocol treatment.

SUSAR: Suspected Unexpected Serious Adverse Reaction.

SUSARs occurring in clinical investigations qualify for expedited reporting to the appropriate Regulatory Authorities within the following timeframes:

♦ Fatal or life-threatening SUSARs within 7 calendar days

♦ Non-fatal or non-life-threatening SUSARs within 15 calendar days

Note: all Grade 5 adverse reactions (ARs) will be reported as suspected unexpected serious adverse reactions (SUSARs)

Inpatient hospitalization: a hospital stay equal to, or greater than, 24 hours.

Second primary malignancy is one unrelated to the treatment of a previous malignancy (and is NOT a metastasis from the previous malignancy).

Secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment with investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not considered a metastasis of the previous malignancy.

14.2 Exceptions The following situations do not need to be reported as SAEs:

♦ Elective hospitalization for pre-existing conditions that have not been exacerbated by trial treatment.

♦ A hospitalization which was planned before the patient consented for study participation and where admission did not take longer than anticipated.

♦ A hospitalization planned for protocol related treatment or protocol related procedure as per institutional standard timelines.

♦ Social and/or convenience admission to a hospital

♦ Medical or surgical procedure (e.g. endoscopy, appendectomy); the condition that leads to the procedure is an (S)AE.

♦ Situations where an untoward medical occurrence did not occur (palliative care, rehabilitation, overdose without occurrence of an adverse event).


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♦ Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen.

By EORTC convention, clinical events related to the primary cancer being studied or to the primary cancer progression are not to be reported as SAEs, even if they meet any of the seriousness criteria from the standard SAE definition, unless the event is more severe than expected and therefore the investigator considers that their clinical significance deserves reporting.

14.3 Severity assessment The severity of all AEs (serious and non-serious) in this trial should be graded using CTCAE v4.0 www.eortc.org\investigators-area\ctc

14.4 Causality assessment The investigator is obligated to assess the relationship between protocol treatment and the occurrence of each SAE following the definitions in this table:

Relationship to the protocol treatment

Description

Reasonable possibility There is a reasonable possibility that the protocol treatment caused the event

No reasonable possibility

There is no reasonable possibility that the protocol treatment caused the event

The investigator will use clinical judgment to determine the relationship. Alternative causes, such as natural history of the underlying diseases, medical history, concurrent conditions, concomitant therapy, other risk factors, and the temporal relationship of the event to the protocol treatment will be considered and investigated.

The decision will be recorded on the SAE form and if necessary the reason for the decision will also be recorded.

14.5 Expectedness assessment The expectedness assessment is the responsibility of the sponsor of the study. The expectedness assessment will be performed against the following reference document:

♦ For cabozantinib: Investigator's Brochure.

14.6 Reporting procedure for investigators This procedure applies to all Serious Adverse Events (SAEs) occurring from the time a subject is registered until 30 days after last protocol treatment administration and to any SAE that occurs outside of the SAE detection period (after the 30-days period), if it is considered to have a reasonable possibility to be related to the protocol treatment or study participation.

Registration till 30 days after last protocol treatment administration:

All SAEs

From day 31 after last protocol treatment administration: Only related SAEs

http://www.eortc.org/investigators-area/ctc


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Any secondary malignancy should also be reported in expedited way on a SAE form with the appropriate seriousness criteria! All reporting must be done by the principal investigator or authorized staff member (i.e. on the signature list) to confirm the accuracy of the report.

All SAE data must be collected on the study-specific SAE form.

All SAEs must be reported immediately and no later than 24 hours from the time the investigator or staff became aware of the event.

All SAE-related information needs to be provided in English.

All additional documents in local language must be accompanied by a translation in English, or the relevant information must be summarized in a follow-up SAE report form.

All SAE-related information must be faxed or e-mailed to:

EORTC Pharmacovigilance Unit:

Fax No. +32 2 772 8027

E-mail: [email protected]

To enable the Sponsor to comply with regulatory reporting requirements, all initial SAE reports should always include the following minimal information: an identifiable patient (SeqID), a suspect medicinal product if applicable, an identifiable reporting source, the description of the medical event and seriousness criteria, as well as the causality assessment by the investigator. Complete information requested on the SAE form of any reported serious adverse event must be returned within 7 calendar days of the initial report. If the completed form is not received within this deadline, the Pharmacovigilance Unit will make a written request to the investigator.

Queries sent out by the EORTC Pharmacovigilance Unit need to be answered within 7 calendar days.

All forms need to be dated and signed by the principal investigator or any authorized staff member (i.e. on the signature list).

14.7 Reporting responsibilities for EORTC The EORTC Pharmacovigilance Unit will forward all SAE reports to the appropriate persons within the EORTC Headquarters and to the pharmacovigilance contact at Exelixis as per Pharmacovigilance Agreement.

The EORTC Pharmacovigilance Unit will provide a six-monthly summary which will be added in the Trial Status Report and which will be accessible to all participating investigators.

The EORTC Pharmacovigilance Unit will take in charge the reporting of SUSARs to the Competent Authorities, central Ethics committees, EudraVigilance Clinical Trial Module (EVCTM) and all participating investigators, whenever applicable.

14.8 Pregnancy reporting Pregnancy occurring during a patient’s participation in this trial, although not considered an SAE, must be notified to the EORTC Pharmacovigilance Unit within the same timelines as an SAE (within 24 hours) on a Pregnancy Notification Form. The outcome of a pregnancy should be followed up carefully and any adverse outcome to the mother or the child should be reported for at least 6 months after birth. This also applies to pregnancies in female partners of a male patient participating in this trial.



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♦ Any pregnancy in a female subject or in a female partner of a male subject diagnosed during the treatment period or within 30 days after last protocol treatment administration must be reported to the EORTC Pharmacovigilance Unit

♦ This must be reported within 24 hours of first becoming aware of the event by fax or e-mail, to the Pharmacovigilance Unit on a Pregnancy Notification Form

♦ If an SAE occurs in conjunction with the pregnancy, please also complete an SAE form as explained in the SAE reporting chapter.

15 Quality assurance 15.1 Control of data consistency Data forms will be entered in the EORTC Headquarters database by using the VISTA/RDC (Remote Data Capture) system. Computerized and manual consistency checks will be performed on newly entered forms; queries will be issued in case of inconsistencies. Consistent forms will be validated by the Data Manager. Inconsistent forms will be kept "pending" until resolution of the inconsistencies.

15.2 On-site quality control The EORTC Headquarters will perform on-site quality control visits.

The first visit in a participating site will be performed within 6 months after the first patient's registration at this site. Frequency and number of subsequent visits will depend on site's accrual and quality observed during the first visit.

Overall, the frequency of site visits will be around one visit a year per recruiting site.

The aim of these site visits will be:

♦ to verify that the site facilities remain adequate for performing the trial

♦ to verify that the principal investigator and site staff involved in the trial are working in compliance with GCP and protocol requirements

♦ to assess the consistency of data reported on the case report forms with the source data

♦ to check that Serious Adverse Events have been properly reported and that follow-up information or queries are correctly fulfilled

♦ to assist the site in resolving any outstanding queries

♦ to control the drug accountability process

15.3 Audits The EORTC Quality Assurance and Control Unit (QA&C) regularly conducts audits of institutions participating in EORTC protocols. These audits are performed to provide assurance that the rights, safety and wellbeing of subjects are properly protected, to assess compliance with the protocol, processes and agreements, ICH GCP standards and applicable regulatory requirements, and to assess the quality of data.

The investigator, by accepting to participate in this protocol, agrees that EORTC, any third party (e.g. a CRO) acting on behalf of the EORTC, or any domestic or foreign regulatory agency, may come at any time to audit or inspect their site and all subsites, if applicable.

This audit consists of interviews with the principal investigator and study team, review of documentation and practices, review of facilities, equipment and source data verification.


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The investigator will grant direct access to paper and/or electronic documentation pertaining to the clinical study (e.g. CRFs, source documents such as hospital patient charts and investigator study files) to these authorized individuals. All site facilities related to the study conduct could be visited during an audit (e.g. pharmacy, laboratory, archives …). The investigator agrees to co-operate and provide assistance at reasonable times and places with respect to any auditing activity.

If applicable, the company(ies) supplying the study drug(s) may have access to anonymized data but will not have access to source documents.

If a regulatory authority inspection is announced, the investigator must inform the EORTC Headquarters QA&C Unit immediately (contact at: [email protected]).

In this way EORTC can provide support in preparing and/or facilitating the inspection. EORTC representatives/delegates may also attend the inspection.

15.4 External review of histology

15.4.1 Forms Two electronic "Pathology Forms" will be used for this review and will be available on the VISTA/RDC website (http://rdc.eortc.be or http://www.eortc.be)

Local Pathology Form will be completed by the site

Pathology Review Form will be completed by the reference pathologist

15.4.2 Material to be shipped to reference pathologists The local pathologist will send to the reference pathologist (see overview in Section 15.3.4):

♦ Tumor material: 5 slides of 4μm thickness.

♦ His/her pathology report to reference pathologist

♦ Results of local mutational analysis should be provided if available.

For procedures and contact details please refer to Study Procedures Manual

Personal data of the patient must be anonymized and replaced by the EORTC sequential identification number allocated to this patient at the time of registration.

Copies of informed consent cannot be provided

15.4.3 Reference pathologist The reference pathologist will complete the Pathology Review Form.


http://rdc.eortc.be/

http://www.eortc.be/


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15.4.4 The list of reference pathologists List of pathologists for the EORTC investigators is given in the table hereunder

United Kingdom

C. Fisher

Dept of Histopathology Royal Marsden Hospital - Chelsea, London Fulham Road 203 London SW3 6JJ Great Britain (United Kingdom) E-mail: [email protected] Phone: +44 2078082631 Fax: +44 2078082578

France F. Collin

Dept of Pathology Centre Georges-Francois-Leclerc 1, Rue du Professeur Marion 21079 Dijon CEDEX France E-mail: [email protected] Phone: +33 380737514 Fax: +33 380671915

Germany

Hungary

Czech Republic

Belgium

Eva Wardelmann

Gerhard-Domagk-Institute of Pathology University Hospital Muenster Albert-Schweitzer-Campus 1, Building D17 48149 Muenster Germany Phone: +49251/83-55441 Sekr.: +49251/83-55440 Fax: +49251/83-57559 E-mail: [email protected]

15.5 External review of responses In accordance with the recommendations of RECIST 1.1 all scans will be assessed centrally.

For this central review, the sites will need to provide radiological material.

Please refer to Imaging guidelines for technical guidance and material to be provided.

15.5.1 Storage The radiological material will be stored at EORTC.





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16 Ethical considerations 16.1 Patient protection The responsible investigator will ensure that this study is conducted in agreement with either the Declaration of Helsinki (available on the World Medical Association web site (http://www.wma.net)) and/or the laws and regulations of the country, whichever provides the greatest protection of the patient.

The protocol has been written, and the study will be conducted according to the ICH Harmonized Tripartite Guideline on Good Clinical Practice (ICH-GCP, available online at http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002874.pdf).

The protocol must be approved by the competent ethics committee(s) as required by the applicable national legislation.

16.2 Subject identification The name of the patient will neither be asked for nor recorded at the EORTC Headquarters. A sequential identification number will be automatically allocated to each patient registered in the trial. This number will identify the patient and will be included on all case report forms. In order to avoid identification errors, the patient’s code (maximum of 4 alphanumerics) and date of birth or year of birth (as allowed per applicable legislation) will also be reported on the case report forms.

16.3 Informed consent All patients will be informed about

♦ the aims of the study

♦ the possible adverse events

♦ the procedures and possible hazards to which the patient will be exposed

♦ the mechanism of treatment allocation

♦ strict confidentiality of any patient data

♦ medical records possibly being reviewed for trial purposes by authorized individuals other than their treating physician

The template of the patient’s informed consent statement is given as a separate document dated and version controlled to this protocol.

An adapted translation of the PIS/PIC will be provided by EORTC Headquarters and it is the responsibility of the Coordinating investigators for this trial (sometimes called National Coordinators) to adapt it to national/local requirements where necessary.

The translated informed consent documents are to be submitted to ethics committees for approval. The competent ethics committee for each institution must approve the informed consent documents before the center can join the study. It is the responsibility of the competent ethics committee to ensure that the translated informed documents comply with ICH-GCP guidelines and all applicable national legislation.

It is emphasized in the patient information sheet that participation is voluntary and that the patient is free to refuse further participation in the protocol whenever he/she wants to. This will not have any impact on the patient’s subsequent care. Documented informed consent must be obtained for all patients included in the study before they are registered and/or randomized at the EORTC Headquarters. The written informed

http://www.wma.net/

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002874.pdf

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002874.pdf


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consent form must be signed and personally dated by the patient or by the patient’s legally acceptable representative.

All of the above must be done in accordance with the applicable national legislation and local regulatory requirements.

17 Administrative responsibilities 17.1 The study coordinator The Study Coordinator works closely with the study team to develop the outline and full protocol and discusses the contents of the reports with the study team. The Study coordinator is responsible for publishing the study results. He/she will assist the Clinical Research Physician for answering some clinical questions concerning eligibility, treatment, and contributes to the medical review of the patients.

Study coordinator: Patrick Schöffski University Hospitals Leuven Department of General Medical Oncology Herestraat 49 3000 Leuven Belgium Phone: +32 16 346900 Fax: +32 16 346901 e-mail: [email protected]

17.2 The EORTC Headquarters The EORTC Headquarters will be responsible for writing the protocol and PIS/IC, reviewing the protocol, setting up the trial, collecting case report forms, controlling the quality of the reported data, organizing the medical review and generating reports and analyses in cooperation with the Study Coordinator. All methodological questions should be addressed to the EORTC Headquarters.

EORTC HEADQUARTERS Avenue E. Mounierlaan 83/11 Brussel 1200 Bruxelles België - Belgique Fax: +32 2 7723545

17.3 The EORTC group All questions concerning ongoing membership in the group should be addressed to the chairman and/or secretary of the group.

For new membership contact Membership Committee at [email protected]




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EORTC Soft Tissue and Bone Sarcoma group Chairperson: Alessandro Gronchi Fondazione IRCCS Istituto Nazionale dei Tumori Menanoma and Sarcoma Unit, Department of Surgery Via Venezian, 1 20133 Milano Italy Phone: +39 02 23903234 Fax: +39 02 23902404 E-mail: [email protected]

Secretary: Hans Gelderblom Leiden University Medical Center Albinusdreef 2 - Postbus 9600 2300 RC Leiden Netherlands Phone: +31 715260000 Fax: +31 715266760 E-mail: [email protected]

18 Trial sponsorship and financing EORTC is the legal Sponsor for all EORTC participants.

The contact details of the EORTC are:

EORTC Headquarters Avenue E. Mounierlaan 83/11 Brussel 1200 Bruxelles België - Belgique Phone: +32 2 7741611 Fax: +32 2 7723545 e-mail: [email protected]

Financial support is provided by Exelixis.

19 Trial insurance A clinical trial insurance has been taken out according to the laws of the countries where the study will be conducted. An insurance certificate will be made available to the participating sites at the time of study initiation.

Clinical trial insurance is only valid in centers authorized by the EORTC Headquarters. For details please refer to the chapter on investigator authorization.




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20 Publication policy All publications must comply with the terms specified in the EORTC Policy 009 “Release of Results and Publication Policy” version 4.2 dated 03/03/2015. The final publication of the main clinical trial results will be written by the EORTC Study Coordinator on the basis of the final analysis performed at the EORTC Headquarters and published in a major scientific journal.

The final publication of associated translational research studies will be written by the EORTC Study Coordinator, the Coordinator of the corresponding translational research study and researchers who made substantial contribution to the research.

Authors of the final manuscript(s) describing the primary endpoint of the trial will include the Study Coordinator, the investigators who have included more than 5% of the eligible patients in the trial (by order of inclusion), and the statistician and clinical research physician in charge of the trial at the EORTC Headquarters. When > 15% patients have been entered by one institution, then that institution qualifies for 2 authors, of whom the first listed author must be a full member of the Group. One of the pathologists of the pathology review panel will be included in authorship. For studies in which a member of the pathology review panel has reviewed > 25% of cases, that pathologist will qualify for authorship, in other cases the pathology review panel, in consultation with the board of the STBSG, will decide which pathologist will be author on behalf of the pathology review panel.

The title of all manuscripts will include “EORTC”, and all manuscripts will include an appropriate acknowledgment section, mentioning all investigators who have contributed to the trial, the EORTC Headquarters staff involved in the study, as well as supporting bodies (NCI, cancer leagues, supporting company …).

Prior to submission, all publications (papers, abstracts, presentations…) including data pertaining to patients from the present trial will be submitted for review to the EORTC Headquarters and to all co-authors. The publications will also be circulated to representatives of the manufacturer of cabozantinib for review (allowing 7 days for review of abstracts and 60 days for manuscripts).

The above rules are applicable to publications involving any individual patient registered in the trial.

Publications related to the outcome of individual patients registered in this trial can only be submitted after the outcome of the primary endpoint of the Phase 2 trial has been reported and results are in the public domain.


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Appendix A: References Ref. 1 Corless CL et al. Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev

Cancer. 2011 Nov;11(12):865–78

Ref. 2 Wozniak A et al. Tumor genotype is an independent prognostic factor in primary gastrointestinal stromal tumors of gastric origin: A European multicenter analysis based on ConticaGIST. Clin Cancer Res. 2014 Dec;20(23): 6105-16

Ref. 3 DeMatteo RP et al. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg. 2000 Jan; 231 (1):51-8.

Ref. 4 Zalcberg JR et al. EORTC Soft Tissue and Bone Sarcoma Group, the Italian Sarcoma Group; Australasian Gastrointestinal Trials Group. Outcome of patients with advanced gastro-intestinal stromal tumours crossing over to a daily imatinib dose of 800 mg after progression on 400 mg. Eur J Cancer. 2005 Aug; 41(12):1751-7.

Ref. 5 Blanke CD et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008 Feb; 26(4):626-32.

Ref. 6 Joensuu et al. Twelve versus 36 months of adjuvant imatinib (IM) as treatment of operable GIST with a high risk of recurrence: Final results of a randomized trial (SSGXVIII/AIO). J Clin Oncol. Vol 29, 2011 (Abstr: LBA1)

Ref. 7 Demetri GD et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006 Oct; 368 (9544):1329-38.

Ref. 8 Goodman VL et al. Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res. 2007 Mar; 13(5):1367-73.

Ref. 9 Demetri GD et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet.2013 Jan;381(9863):295-302.

Ref. 10 Schöffski P et al. An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantinib (XL184) in medullary thyroid carcinoma (MTC) patients (pts) with documented RECIST progression at baseline. J Clin Oncol, Vol 30, 2012 (Abstr: 5508)

Ref. 11 Gebreyohannes YK et al. The multitarget tyrosine kinase inhibitor cabozantinib (CABO) shows anti-tumor efficacy in xenograft models of gastrointestinal stromal tumor (GIST). Connective Tissue Oncology Society 20th Annual Meeting, 2015 Nov (Abstr: P031)

Ref. 12 Cohen NA et al. Pharmacological inhibition of KIT activates MET signaling in gastrointestinal stromal tumors. Cancer Res. 2015 May 15; 75(10):2061-70

Ref. 13 Nokihara H et al. Molecular profile and anti-tumor activity in non-small cell lung cancer (NSCLC) patients (pts) in a phase 1 study of cabozantinib (XL184) in Japan. Conference ESMO 2012 (Abstr: #1708PD)

Ref. 14 Investigator’s brochure for Cabozantinib edition 11, 13-July-2015

Ref. 15 Roy S et al. A novel multiple tyrosine-kinase targeted agent to explore the future perspectives of anti-angiogenic therapy for the treatment of multiple solid tumors: cabozantinib: Anticancer Agents Med Chem. 2015;15 (1):37-47.


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Ref. 16 Choueiri TK et al. Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med 2015 Nov; 373:1814-1823

Ref. 17 Smith MR et al. Final analysis of COMET-1: Cabozantinib (Cabo) versus prednisone (Pred) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) previously treated with docetaxel (D) and abiraterone (A) and/or enzalutamide (E). J Clin Oncol, Vol 33, 2015 (Abstr: 139)

Ref. 18 Basch EM et al. Final analysis of COMET-2: Cabozantinib (Cabo) versus mitoxantrone/prednisone (MP) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) with moderate to severe pain who were previously treated with docetaxel (D) and abiraterone (A) and/or enzalutamide (E). J Clin Oncol, Vol 33, 2015 (Abstr: 141)

Ref. 19 Italiano A et al. Patterns of care, prognosis, and survival in patients with metastatic gastrointestinal stromal tumors (GIST) refractory to first-line imatinib and second-line sunitinib. Ann Surg Oncol. 2012 May; 19(5):1551-9.

Ref. 20 Kang YK et al. Randomized phase III trial of imatinib (IM) rechallenge versus placebo (PL) in patients (pts) with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) after failure of at least both IM and sunitinib (SU): RIGHT study. J Clin Oncol, Vol 31, 2013 (Abstr: LBA10502)

Ref. 21 A’Hern. Sample size tables for exact single-stage phase II designs. Statistics in Medicine 2001, 20, 859- 866

Ref. 22 Simon R. Optimal two-stage designs for phase II clinical trials. Controlled Clinical Trials 1989, 10, 1-10.

Ref. 23 Torino F et al. Is hypothyroidism a clinically relevant toxicity of tyrosine kinase inhibitors? Thyroid. 2009 May; 19(5):539-40.

Ref. 24 Wright, J.R. et al. Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. J Clin Oncol 2007, 25, 1027–1032.

Ref. 25 Anker P. et al. Circulating nucleic acids in plasma and serum as a noninvasive investigation for cancer: Time for large-scale clinical studies? Cancer Metastasis Rev. 1999; 18: 65-73.

Ref. 26 Shaw JA, et al. Microsatellite Alterations in Plasma DNA of Primary Breast Cancer Patients. Clin Cancer Res. 2000; 6: 1119-24.

Ref. 27 Bettegowda et al. Detection of Circulating Tumor DNA in Early- and Late-Stage Human Malignancies. Sci Transl Med 2014; 6: 224ra24.

Ref. 28 Diehl et al. Detection and quantification of mutations in the plasma of patients with colorectal tumors.Proc Natl Acad Sci USA 2005; 102: 16368-73.

Ref. 29 Li M, et al. BEAMing up for detection and quantification of rare sequence variants. Nat Methods. 2006 Feb; 3(2):95-7.

Ref. 30 Wagle N. et al. High-Throughput Detection of Actionable Genomic Alterations in Clinical Tumor Samples by Targeted, Massively Parallel Sequencing. Cancer Discov. 2012; 2: 82-93.

Ref. 31 Wu et al. Recurrent GNAS Mutations Define an Unexpected Pathway for Pancreatic Cyst Development. Sci Transl Med 2011; 3: 92ra66.

Ref. 32 Harismendy O et al. Detection of low prevalence somatic mutations in solid tumors with ultra-deep targeted sequencing. Genome Biol 2011; 12: R124.

Ref. 33 Forshew T et al .Noninvasive Identification and Monitoring of Cancer Mutations by Targeted Deep Sequencing of Plasma DNA. Sci Transl Med. 2012; 4: 136ra68.


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Ref. 34 Kaplowitz N, DeLeve LD. Drug-Induced Hepatic Disease, Marcel Decker Inc. New York, 2003.

Ref. 35 Zimmerman HJ. Hepatotoxicity: The Adverse Effects of Drug and Other Chemicals on the Hepatic, 2nd edition, Philadelphia, Lippincott Williams and Wilkins, Chapters 4, 5 and 16, 1999.

Ref. 36 Choueiri TK, Escudier B. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. ,Lancet Oncol 2016 Jul;17(7):917-27.

Ref. 37 Foxx-Lupo WT, Sing S, Alwan L, Tykodi SS. A Drug Interaction between Cabozantinib and Warfarin in a Patient with Renal Cell Carcinoma. Clin Genitourin Cancer. 2016;14(1):e119-e121.


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Appendix B: Abbreviations AE Adverse event

ALP Alkaline phosphatase

ALT Alanine aminotransferase

ANC Absolute neutrophil count

AR Adverse reaction

AST Aspartate aminotransferase

AUC Area under the curve

BP Blood pressure

CBR Clinical benefit rate

CR Complete response

CRF Case report form

CTCAE Common terminology criteria for adverse events

CYP Cytochrome P450

DBP Diastolic blood pressure

DCR Disease control/patient benefit rates DVT Deep vein thrombosis

ECG ElectroCardioGram

EMA European Medicines Agency

FBE Free-Base Equivalent

FDA US Food and Drug Administration

ICH/GCP International conference on harmonisation/Good clinical practice

GABA γ-aminobutyric acid

GFR Glomerular filtration rate

GI Gastro-intestinal

GIST Gastrointestinal stromal tumor

H&E Hematoxylin and eosin

HLM Human liver microsomal

HR Hazard ratio

INR International normalized ratio

IUD Intrauterine device

IUS Intrauterine hormone-releasing system

LDH Lactate dehydrogenase

LEO Laboratory of Experimental Oncology

http://www.google.be/url?sa=t&rct=j&q=&esrc=s&source=web&cd=4&cad=rja&uact=8&sqi=2&ved=0CDQQFjADahUKEwjOnK2_6b_IAhWIxRQKHUkUDao&url=http%3A%2F%2Fwww.niddk.nih.gov%2Fhealth-information%2Fhealth-communication-programs%2Fnkdep%2Flab-evaluation%2Fgfr-calculators%2FPages%2Fgfr-calculators.aspx&usg=AFQjCNFlmGztMgombqq7Ov5J-51Zjw1eTw&bvm=bv.104819420,d.bGQ


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LMWH Low-Molecular-Weight Heparin

NSAID Nonsteroidal anti-inflammatory drugs

NYHA New York Heart Association

ORR Objective response rate

OS Overall survival

ONJ Osteonecrosis of the jaw

PD Progressive disease

PDGFRA Platelet-derived growth factor receptor alpha

PE Pulmonary embolism

PEG Percutaneous endoscopic gastrostomy

PFS Progression-free-survival

P-gp P glycoprotein

PK Pharmacokinetic

p.o. Per os

PPE Palmar-plantar erythrodysesthesia

PR Partial response

PS Performance status

PT Prothrombin time

PTT Partial thromboplastin time

QTcF Fridericia’s correction of QT

RFS Recurrence-free survival

SAE Serious adverse event

SAR Serious adverse reaction

SBP Systolic blood pressure

SC Study Coordinator

SD Stable disease

SUSAR Suspected unexpected serious adverse reaction

TFT Thyroid function test

TKI Tyrosine kinase inhibitor

TSH Thyroid stimulating hormone

TTP Time to progression

UAR Unexpected adverse reaction

ULN Upper limit of normal

UPCR Urine protein/creatinine ratio

WOCBP Women of child bearing potential


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WBC White blood cells


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Appendix C: ECOG performance status scale ECOG PERFORMANCE STATUS

Grade ECOG

0 Fully active, able to carry on all pre-disease performance without restriction

1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work

2 Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours

3 Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours

4 Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair

5 Dead

The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair


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Appendix D: Hy's Law criteria Hy's Law or rule can be used to estimate severity and the likelihood that a health product will cause increased incidence of severe hepatotoxicity. Hy's Law is based on the combined evidence of hepatic injury, decreased hepatic function, and the absence of disease-induced damage (Ref. 34, Ref. 35). It requires that the following 3 criteria be met:

injury: elevation of >3 × ULN ALT or AST activity; and

function: >2 × ULN Total Bilirubin (another clinical marker for function, such as > 1.5 × ULN INR may be acceptable if the change is clinically significant in the absence of obstruction) without >2 × ULN ALP; and

clinical verification to ensure effect is health product-induced and not induced by disease or another cause of injury.


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Appendix E: MRP2 inhibitors Administration of MRP2 inhibitors may result in increases in cabozantinib plasma concentrations. Therefore, concomitant use of MRP2 inhibitors (eg, cyclosporine, delaviridine, efavirenz, emtricitabine) should be approached with caution.

Drug Class Indications Source

probenecid uricosuric

gout hyperuricemia [1]

furosemide loop diuretic

heart failure edema [1]

ritonavir protease inhibitor antiretroviral [2]

saquinavir protease inhibitor antiretroviral [3]

lamivudine Nucleoside analog antiviral [4]

abacavir Nucleoside analog antiretroviral [4]

emtricitabine Nucleoside analog antiviral [4]

efavirenz NNRTI antiretroviral [4]

delavirdine NNRTI antiretroviral [4]

nevirapine NNRTI antiretroviral [4]

cidofovir nucleoside phosphonate antiviral

adefovir nucleoside phosphonate antiviral [3]

tenofovir nucleoside phosphonate antiviral [4]

References

1.Bakos E, Evers R, Sinkó E, Váradi A, Borst P, Sarkadi B (April 2000). "Interactions of the human multidrug resistance proteins MRP1 and MRP2 with organic anions". Mol. Pharmacol. 57 (4): 760–8.

2. Peyrière H, Reynes J, Rouanet I, et al. (March 2004). "Renal tubular dysfunction associated with tenofovir therapy: report of 7 cases". J. Acquir. Immune Defic. Syndr. 35 (3): 269–73.

3. Gimenez F, Fernandez C, Mabondzo A (June 2004). "Transport of HIV protease inhibitors through the blood–brain barrier and interactions with the efflux proteins, P-glycoprotein and multidrug resistance proteins". J. Acquir. Immune Defic. Syndr. 36 (2): 649–58.

4 Weiss J, Theile D, Ketabi-Kiyanvash N, Lindenmaier H, Haefeli WE (March 2007). "Inhibition of MRP1/ABCC1, MRP2/ABCC2, and MRP3/ABCC3 by nucleoside, nucleotide, and non-nucleoside reverse transcriptase inhibitors". Drug Metab. Dispos. 35 (3): 340–4.

https://en.wikipedia.org/wiki/Probenecid

https://en.wikipedia.org/wiki/Uricosuric

https://en.wikipedia.org/wiki/Gout

https://en.wikipedia.org/wiki/Hyperuricemia

https://en.wikipedia.org/wiki/Multidrug_resistance-associated_protein_2#cite_note-pmid10727523-5

https://en.wikipedia.org/wiki/Furosemide

https://en.wikipedia.org/wiki/Loop_diuretic

https://en.wikipedia.org/wiki/Heart_failure

https://en.wikipedia.org/wiki/Edema


https://en.wikipedia.org/wiki/Ritonavir

https://en.wikipedia.org/wiki/Protease_inhibitor_%28pharmacology%29

https://en.wikipedia.org/wiki/Antiretroviral


https://en.wikipedia.org/wiki/Saquinavir

https://en.wikipedia.org/wiki/Protease_inhibitor_%28pharmacology%29



https://en.wikipedia.org/wiki/Lamivudine

https://en.wikipedia.org/wiki/Reverse_transcriptase_inhibitor#INucleoside_analog_reverse_transcriptase_inhibitors_.28NARTIs_or_NRTIs.29

https://en.wikipedia.org/wiki/Antiviral_drug


https://en.wikipedia.org/wiki/Abacavir




https://en.wikipedia.org/wiki/Emtricitabine




https://en.wikipedia.org/wiki/Efavirenz

https://en.wikipedia.org/wiki/Reverse_transcriptase_inhibitor#Non-nucleoside_reverse_transcriptase_inhibitors_.28NNRTIs.29



https://en.wikipedia.org/wiki/Delavirdine




https://en.wikipedia.org/wiki/Nevirapine




https://en.wikipedia.org/wiki/Cidofovir


https://en.wikipedia.org/wiki/Adefovir



https://en.wikipedia.org/wiki/Tenofovir



Documents

EORTC Soft Tissue and Bone Sarcoma Group Phase II study of ...€¦ · EORTC-1317-STBSG Ph II CABOGIST in GIST Version 3.2 7 / 97 March 29, 2017 8.2 Statistical analysis plan 68 8.2.1