ACRIN EISC

VIRGINIA COMMONWEALTH UNIVERSITYAMERICAN COLLEGE OF RADIOLOGY

IMAGING NETWORK

ACRIN 6688

PHASE II STUDY OF 3'-DEOXY-3'-18F FLUOROTHYMIDINE (FLT) IN INVASIVE

BREAST CANCER

Agent Name: 3'-deoxy-3'-[F-18] fluorothymidine

Agent NSC Number: 750184IND Number: 71,260

ACRIN EISC

Protocol Investigators

VCU Study Chair VCU Study Co-Chair VCU Study Co-ChairPaul R Jolles, MD Harry D Bear, MD, PhD Michael O Idowu,MD,MPHDept Radiology Dept of Surgery Dept of Pathology

Richmond, VA Richmond, VA Richmond, VA prjolles@vcu.edu hdbear@vcu.edu midowu@mcvh-vcu.edu

ACRIN Study Co-Chair ACRIN Study Co-ChairDavid Mankoff, MD, PhD Lale Kostakoglu, MD, MPHProfessor of Radiology Professor of Radiology Seattle Cancer Care Alliance Mount Sinai School of Medicine Seattle, WA New York, NY 10029dam@u.washington.edu lale.kostakoglu@mssm.edu

VCU Study Statistician ACRIN Study Statistician Donna K McClish, PhD Fenghai Duan, PhDDepartment of Biostatistics Ctr for Statistical SciencesRichmond, VA 23298 Brown Universitymcclish@mail2.vcu.edu fduan@stat.brown.edu

ACRIN EISC

FLT is a structural analog of thymidine

Although FLT is not incorporated into DNA, it is trapped in the cell due to phosphorylation by TK

Recently developed disease specific molecular agents induce cell cycle arrest (cytostatic effect) rather than tumor cell death (cytotoxic effect)

Evaluating alterations in DNA metabolism may reflect response to treatment better than alterations in glucose utilization

FLT PET can be used as an imaging probe to assess in vivo cellular proliferation in malignant tumors

Buck AK, Methods 2009: 48:205

[F-18] FLT Background

ACRIN EISC

Buck AK, Methods 2009: 48:205

Preliminary Studies

ACRIN EISC

aggressive

lymphoma

Low grade

lymphoma

Ki-67 labeling index: >90%

Ki-67 labeling index: <

5%

Buck AK, Methods 2009: 48:205

Non-Invasive detection and grading of malignant lymphomausing FLT PET as surrogate marker of tumor proliferation

ACRIN EISC

BloodThe box plot shows the mean percent error (horizontal line within the box), the 25th and 75th percentiles (bottom and top of box, respectively), and the range (bottom and top horizontal bars on vertical whiskers).

Shields, AF, Clin Cancer Res. 2008;14:4463 Kenny, EJNMMI 34:1339, 2007

Reproducibility of [18F]FLT Parameters

ACRIN EISC Kenny, EJNMMI 34:1339, 2007

Pre Therapy Post Therapy

RESPONSE in a patient with

grade II lobular ca

NO RESPONSE in a patient with grade II IDC

7 dys post- therapy

7 dys post- therapy

ACRIN EISC

Primary Objective:

To correlate the percentage change in SUVs between baseline (FLT-1) and mid-therapy (FLT-3) with pathologic complete response (pCR) to neoadjuvant chemotherapy of the primary tumor in patients with locally advanced breast cancer (LABC)

Study Objectives

ACRIN EISC

Obtain pre-treatment Proliferative Indices

Establish Eligibility

Baseline Imaging

Mid-therapy Imaging

Chemotherapy

Surgical Resection

Chemotherapy

• Baseline organ function• Pathologically confirmed disease• Determine primary systemic Rx

•Ki-67 and mitotic index on bx sample or re-biopsy (if available)

•18FLT PET/CT(FLT-1)

•18FLT PET/CT(FLT-3)

•18FLT PET/CT(FLT-2)

Obtain post-treatment Proliferative Indices

• Pathologic response, • Ki-67 and mitotic index, surgical specimens

Early therapy Imaging

Chemotherapy

[F-18] FLT Study Outline

ACRIN EISC

Three imaging sessions • pre-treatment (FLT-1), • after one cycle (FLT-2), • at mid-treatment (FLT-3)

FLT-1 PET must be completed within 3 wks prior to beginning chemo

FLT-2 PET must be performed 5-10 dys after initiation of first chemo cycle

FLT-3 must be performed halfway through the therapy protocol and at least 5 dys after completion of the last chemo prior to the mid-point, and prior to the first chemo cycle after the midpoint

For example, in a protocol consisting of 4 cycles of therapy this will be after cycle 2 and before cycle 3 and in a protocol consisting of 6 cycles, this would be after 3 cycles therapy and before cycle 4. In a regimen where a change of chemotherapy is planned, for example a change from doxorubicin-based therapy to taxane-based therapy, the midpoint would occur after the completion of the first type of chemotherapy and before the administration of the second type of chemotherapy.

Imaging ProtocolTiming of FLT PET Studies

ACRIN EISC

Secondary Objectives:

evaluate the relationship between FLT-1, FLT-2 and FLT-3 uptake parameters and pCR and residual cancer burden (RCB)

evaluate the relationship between FLT-1, FLT-2 and FLT-3 uptake parameters and non-response (SD or Prog disease)

demonstrate correlation between FLT-1, FLT-2 and FLT-3 uptake parameters and tumor proliferation markers

continue to monitor for potential safety issues and define any physiologic effects associated with [18F] FLT

Study Objectives

ACRIN EISC

Secondary Objectives (cont’d):

evaluate the relationship between FLT-1, and FLT-3 uptake parameters and pCR to neoadjuvant chemotherapy in patients with regional disease in the LNs

compare the changes of FLT-2 and FLT-3 uptake parameters to changes in tm sizes from other serial imaging modalities such as mammograms, MRI, and US, as available

compare changes of FLT-2 and FLT-3 uptake parameters to metabolic changes from FDG-PET, as available

Study Objectives

ACRIN EISC

Pathologically confirmed breast cancer, determined to be a candidate for neoadjuvant therapy and for surgical resection of residual primary tm after neoadjuvant therapy.

This includes all patients with locally advanced breast cancer (Stage IIIB and some IIIA), all patients with Stage IIIC disease (supraclavicular node involvement), and patients for whom neoadjuvant therapy is indicated to make breast conservation surgery feasible. The last group would be expected to have a median tumor diameter of approximately 4 cm

Tumor size >2cm, measured on imaging or estimated by PE

No obvious contraindications for primary Residual tumor planned to be removed surgically

following completion of neoadjuvant therapy Age >18

Inclusion Criteria

ACRIN EISC

ECOG Performance Status ≤ 2 (Karnofsky ≥ 60%) Normal organ and marrow function, pre-

chemotherapy:-leukocytes ≥ 3,000/μl;

-absolute neutrophil count ≥ 1,500/μl;

-platelets ≥ 100,000/μl;

-total bilirubin within N institutional limits;-AST(SGOT)/ALT(SGPT) ≤2.5 times institutional upper limit

of N

-creatinine within normal institutional limits; -creatinine clearance ≥ 60 mL/min/1.73 m2 for patients

with creatinine levels above institutional normal;

Able to lie still for 1.5 hours If female, postmenopausal for a min of one year, OR

surgically sterile, OR not pregnant, confirmed by ß-HCG blood test, and willing to use adequate contraception

Able to understand and willing to sign a written informed consent document and a HIPAA authorization in accordance with institutional guidelines

Inclusion Criteria, con’t

ACRIN EISC

Prior treatment (chemo, RT or surgery) to involved breast Uncontrolled intercurrent illness.

Ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

Medically unstable Condition requiring anesthesia for PET scanning; History of allergic reactions attributed to compounds of similar

chemical or biologic composition to F-18 FLT Pregnant or nursing. Pregnant women are excluded from this

study because the effects of [18F]FLT in pregnancy are not known. Breastfeeding should be discontinued if the mother receives [18F]FLT.

Previous malignancy, other than basal cell or squamous cell carcinoma of the skin or in situ ca of the cervix, from which the patient has been disease free for < 5 years

No hormonal therapy is allowed

Inclusion Criteria

ACRIN EISC

The participant will undergo [18F]FLT injection,

• immediately after injection a dynamic regional PET/CT imaging will be done for 60 minutes

• dynamic imaging will be followed by a static whole

body image from top of head to upper thigh; 5-7 bed positions

AnalysesSUV30 ∆SUV60-120

SUV60 Patlak slope SUV120 FluxFLT

∆SUV30-60 k3

Imaging ProtocolImaging Sessions

ACRIN EISC

[18F] FLT Parameters Compared To Pre-Rx (FLT-1) parameters Ki-67/mit index, biopsy

Clinical ResponseCT ResponsePathological Response

(pCR and RCB)

After one cycle (FLT-2) parameters Clinical Response (absolute values and % change from FLT-1) CT Response

Mid-therapy (FLT-3) parameters Ki-67/mit index, surgical (absolute values and % change from FLT-1) Clinical

ResponseCT Response

Pathological Response (pCR and

RCB)

Imaging ProtocolImaging Sessions

ACRIN EISC

Participant Accrual

Enrollment Target 54 cases in 18 months

Initial Sites: MSSM, UPENN, UW, VCU

Site Target: total # of sites ~10

Site enrollment expectations: 60 - 70 percent of what site reported on application

Trial enrollment expectations: min 3 patients per month

The ACRIN Biostatistics and Data Management Center (BDMC) will monitor participant accrual

ACRIN EISC

The presence of any invasive tumor cells will be considered negative for pathologic complete response

Following will be performed at the Core Lab at VCU/Dept of Pathology Ki-67 (MIB-1 antibody) Immunohistochemical staining Mitotic index Routine Clinical Histopathology Calculation of Residual Cancer Burden

pCR is a dichotomous, but tm response is a continuous variable with non-response ranging from very small residual tm to resistant tms with progressing disease

• size of the tumor bed• cellularity of residual primary tumor• percentage of DCIS component• number of positive nodes• size of macrometastasis

This tool is available at http://www3.mdanderson.org/app/medcalc/index.cfm?pagename=jsconvert3

Therefore, continuous measures of residual cancer burden (RCB) would be expected to be more predictive of clinical outcome than simple dichotomous classification as currently practiced. RCB determined from routine pathologic materials may be a significant predictor of distant relapse-free survival (98). Different parameters will be collected and submitted to the data collection center for calculation of RCB and will include:

• The Residual Cancer Burden calculation will use clinical information obtained from participating institutions and pathological analysis at VCU. As the calculation of RCB is dependent on the parameters provided by participating institutions, the Core Laboratory at Virginia Commonwealth University will calculate the RCB as long as the parameters needed for the calculation are present in the reports.

Tissue Specimen Analysis

ACRIN EISC

Participants who, are unable to complete chemotherapy and undego

primary tumor surgery will be excluded from the primary analysis. Those who are able to complete the study to midpoint can be included in secondary analysis regardless of outcome

are unable to complete study to midpoint because of therapy toxicity or disease progression will be removed

experience any serious adverse event from the FLT PET imaging procedure as listed in Section 9.0 will be removed from the study

deviate from planned therapy for lack of response or tumor progression will be excluded from primary cohort analysis

Criteria for Removal from the Study