ERVIX CANCER COMMITTEE - GCIG Cervical Cancer...Centralreview of contouringand planning SURGERY RADIOTHERAPY Application for research grant to the Czech Health Research Council (2020)

CERVIX CANCER COMMITTEE

MONDAY, JUNE 1, 2020, 8:00EDT

Chair: Brad Monk Co-Chair: Antonio Casado

Harmonization Liaisons: Bette Stonebraker/Maren Keller (Ops), Alexander Reuss (Stats)

GCIG Virtual Spring Meeting 2020

Some rules for the videoconference• Please keep yourself muted• Please, do not over-run your time• Please, do not speak at the same time• Questions must be submitted via the chat function• After each new concept questions will be addressed• For all other presentations questions will be taken at

the end of each session• After the presentation of new ideas, interested

groups should send an email to the presenter

AGOG

Concept/trial design presentation

A Phase 2 Trial of Atezolizumab combined with chemoradiation for Patients with [18F]-

FDG PET/CT-defined Poor-prognostic Cervical Cancer

Chun-Chieh Wang, MD and Feng-Yuan Liu, MD/Prof. Chyong-Huey Lai, MD

4

AGO

ANZGOG

OUTBACK ANZGOG0902 / GOG0274 / RTOG1174

Prof Linda Mileshkin

Region Patients

North America 739

Australia & New Zealand 165

Asia (Singapore & China) 10

Saudi Arabia 5

TOTAL 919



221 of 234 deaths (as of 12 May 2020)

Median lag from death to reporting: 9 months!



Analysis Plan

• Initially planned for 234th event

• Revised plan: It is anticipated that at 31st Dec2020, > 90% of the expected 5yr information(i.e. if every patient been followed for up forat least 5yrs) on overall survival will beavailable.

• Planned submission to ASCO 2021

BGOG

BR-GOG

New Strategy for the Treatment

of Vulvar Cancer

Advanced VulvarCancerTrial setting:

Study Design:

OngoingTrials

Advanced Tumors□ 4 cm□ Positive lymph nodes□ Uretra or/and Anusaffected

Inguinal lymphadenectomy

Chemorradiation

Vulvectomy

PI: MD Altamiro Ribeiro DiasJr

• Radiotherapy

• 0 or 1 LN+ ( until 2 mm) :

no adjuvant treatment is recommended

→ good prognosis

• 2 ormore LN+ : inguinal and pelvic

RT (4500 cGy in 25 fractions– 5

weeks)

• Chemotherapy

• Cisplatin: 40 mg/m2 weekly - 4 to 6 weeks

Hacker NF. Vulvar cancer. In: Berek JS, Hacker NF, editors. Practical gynecologic oncology. 4th ed. Philadelphia:Williams &Wilkins; 2005. p. 585–602.

Blake P. Radiotherapy and chemoradiotherapy for carcinoma of the vulva. Best Pract Res Clin Obstet Gynaecol2003;17:649–61.

AdjuvantChemorradiation

Planned No. of patients:

- Initial Statistical sampling necessaryto continue the study : 7/21 (CPR)

- Being resized – other institutions interested

Current accrual: Under Recruitment –Actual: 29 patients

- Clinical and radiological response : 10

- Complete pathological response (CPR) :7

- Waiting vulvar time : 2 - Under chemorradiation: 2

- Recurrence: 3 Death: 9 (3 related to cancer and 6 othercauses)

Other important information:

ClinicalTrials.gov Identifier:NCT02067052

New Strategy for the Treatment

of Vulvar Cancer

OngoingTrials

Thank you!!!

MD Altamiro Ribeiro DiasJr

[email protected]

[email protected]

whats app: +55(11)99112-8281

mailto:[email protected]


Randomized phase III trial ofNeoadjuvant Treatment in stagesIB2,IIA2 and IIB of cervical cancer.

Trial setting: IB2, IIA2 and IIB cervical cancer (FIGO 2008)

++Less than 78 points in the Nomogram for predicting para-aorticlymph node metastases in patients with cervical cancer.

Archives of Gynecology and Obstetrics (2018) 298:381–388

Background:“Around 85% of the global burden occurs in the less developed regions,where it accounts for almost 12% of all female cancers.”

http://globocan.iarc.fr/old/FactSheets/cancers/cervix-new.asp

“Less developed countries face dificulties in the assessment forRadiotherapy.”

Ongoing Trials


Study Design: Randomized open controlled multicenter phase 3 study

Ongoing Trials

Cervical Cancer

FIGO stage IB2, IIA2 andIIB

- No previous treatment- <78 points in theNomogram for predicting para-aortic lymph node metastases.

RedCapRandomization

Standard arm

Radiotherapy and weekly cisplatin followed by brachytherapy

Experimental arm

Neoadjuvant Chemotherapy 3C (CDDP + Paclitaxel weekly) followed by surgery if clinical and radiological response (yIB1 yN0)+ - *Adjuvant Chemorradiation

* Risk factors in surgical specimen

Primary Objective: 5-year Overall Survival

Planned No. of patients: 220

Current accrual in Brazil: Under Recruitment

- Actual: 17 patients at 2 institutions

- Recuitment will begin at 2 other institutions after the pandemia


- Registry at the Brazilian Platform (Rebec):U1111-1238-5875

Ongoing Trials


Thank you! Obrigado!

PI MD Pedro Thomé Francisco Reis [email protected]

CCTG

Stage IB1 (2-4 cm) Cervical cancer treated with Neoadjuvant chemotherapy followed by

fertility Sparing Surgery (CONTESSA)

Dre Marie Plante

Neo-Adjuvant Chemotherapy and Conservative Surgery

in Cervical Cancer to Preserve Fertility (NEOCON-F)

Dr Frédéric Amant

• A RANDOMIZED TRIAL COMPARING RADICAL HYSTERECTOMY AND PELVIC NODE DISSECTION VS SIMPLE HYSTERECTOMY AND PELVIC NODE

DISSECTION IN PATIENTS WITH LOW-RISK, EARLY- STAGE CERVICAL CANCER (SHAPE)

• A Gynecologic Cancer Intergroup (GCIG) Trial led by the CCTG

• GCIG Trial Designation: The SHAPE Trial

• CCTG Protocol Number: CX.5

• Chair: Marie Plante

CEEGOG

Title: The role of radical surgery and adjuvant chemoradiation in the management of early-stage intermediate-risk cervical cancer patients:

A prospective multicenter international randomized trial

CERVANTES (CERVical cancer AdjuvaNt Treatment Study)

GCIG May 2020

Trial setting: Cervical cancer – early stageTrial model: AcademicStudy design: RCT Sponsor: CEEGOG Presenter: David Cibula ([email protected])

CEEGOG CX-05

Early stage cervical cancer

VLRN0; < 2 cm

SHAPE

SH

50%

LRN0; 2-4cm

No RF

RH

15%

IRN0; >4cm OR2-4 cm + RF

RH

Adj CRT

25%

HRN1, R1, T2b

Radical hysterectomy

Primary CRT

Adjuvant treatmentin IR risk cervical cancer patients

IR RISK GROUP (N0 AND RISK FACTORS)

GOG CRITERIA:

INTERMEDIATE RISK FACTORS

LIMITATIONS: Surgical part of the management was not standardizedAssessement of risk factors (tumor size assessed by palpation) Extremely poor local control in surgical arm



INCLUSION CRITERIAStage T1b-T2a

N0 on imaging

SSC or AC (usual)

IR group REG

ISTR

ATIO

N SURGERYRH C1/C2

PLND

+/- SLN

FINAL PATHOLOGYpT1b – pT2a

pN0

SC or AS usual

IR group

RA

ND

OM

IZAT

ION Adjuvant

chemoradiation

No adjuvanttherapy

FU

IR GROUP: a) ≥ 4 cm OR

b) 2 cm < 4 cm AND LVSI OR

c) TFD3 mm



N0 on imaging

SSC or AC (usual)

IR group REG

ISTR

ATIO

N SURGERYRH C1/C2

PLND

+/- SLN


pN0

SC or AS usual

IR group

RA

ND

OM

IZAT

ION Adjuvant

chemoradiation

No adjuvanttherapy

FU


SURGERY:

RH type C1 (tumor size < 4 cm) / C2 (tumor size ≥ 4 cm)

Systematic pelvic lymph node dissection (7 anatomical regions)

SLN biopsy / FS optional


N0 on imaging

SSC or AC (usual)

IR group REG

ISTR

ATIO

N SURGERYRH C1/C2

PLND

+/- SLN


pN0

SC or AS usual

IR group

RA

ND

OM

IZAT

ION Adjuvant

chemoradiation

No adjuvanttherapy

FU


STRATIFICATION CRITERIA: Tumor size (≥ 4 cm)

END-POINT: 2y PFS + QoL

N=250

QUALITY ASSURANCE PROGRAM

CRITERIA FOR SITE SELECTION✓ ≥ 12 radical parametrectomies / y✓ Anatomical landmarks of RH demonstration (photographs or video) WITHIN THE TRIAL ✓ LN in 7 anatomical regions

✓ Intraoperative photographs or video (PLND / RH)


CRITERIA FOR SITE SELECTION WITHIN THE TRIAL

✓Central review of contouring and planning

SURGERY

RADIOTHERAPY

Application for research grant to the Czech Health Research Council (2020)


DGOG

GROINSS-V II

Trial setting: Multicenter observational study - Is radiotherapy a safe alternative for lymphadenectomy in patients with a positive SN ?

Study Design: International Intergroup trial

Sponsor(s): Dutch Cancer Society, NRG (US)

Final No. of patients: 1715 registered patients; completed accrual of 150 patients with micrometastases in the SN

Timeline (first patient – trial closing): Dec 2005 – Oct 2016

Publications: (previous study) GROINSS-V I: Van der Zee AGJ et al, J Clin Oncol2008; Oonk MHM et al, Lancet Oncol 2010

Analysis: finalized

Planned publications: First results presented @ ESGO 2019 and SGO 2020, manuscript in preparation

Closed Trial – status update

0

200

400

600

800

1000

1200

1400

1600

1800

GROINSS-V III

Planned Trial – status update

• Aim: investigate the effectiveness and safety of chemoradiation in patients with a macrometastasis (>2mm) in the SN

• Observational study with stopping rules

• Inclusion criteria:– Same criteria for SN procedure as in GROINSS-V-II

– Only patients with positive SN and mets > 2mm (or > 1 micromets, and/or extranodal tumor extension) will be included

• SN macrometastasis > 2mm -> Concurrent chemoradiation

– 48.6 Gy with simultaneous boost to 56 Gy

– Chemo: Cisplatin weekly (alternative carboplatin)

• Ethics Cttee: final approval obtained June 2018

• Funding: grant from Dutch Cancer Society

• Aim to open the study 2020

EORTC

EORTC GCG 55994Randomized phase III study of neoadjuvant CT followed by surgery vs.concomitant RTX+CT in FIGO stage Ib2, IIa > 4 cm or IIb cervical cancer.

Trial setting: FIGO stage Ib2, IIa > 4 cm or IIb cervical cancer

Study Design: Randomized unblinded 2-arm randomized phase III

Sponsor(s): EORTC GCG

Final No. of patients: 626 pts (August 2002 -June 2014)


• Primary end-point: OS at 5 years → study closure 2019.

• Data base closed October 2019. Final analysis performed

• Publication expected in the coming months

•Planned sub-studies: Quality of radiotherapy, translational research, quality of life

Closed Trials – status update/GCIG June 2020

PI/Study coordinators: G. Kenter (Amsterdam), S. Greggi (Naples) [email protected] ; [email protected]



RAIDS-SPECTA

ACADEMIC TRIAL

In

Cervical cancer

Institut Curie – RAIDS SPECTA

SPONSOR

A phase I/II platform trial in recurrent/metastatic platinum resistant

cervical cancerDepartment of Drug Development and Innovation, INSTITUT CURIE

Diana BELLO ROUFAI, [email protected] SCHOLL, suzy.scholl@curie,fr

Maud KAMAL, [email protected] LE TOURNEAU, [email protected]

Gynae Cancer Group - EORTCNelleke Ottevanger, Nijmegen

Antonio Casado, Madrid

Vassilis Golfinopoulos: Specta Trial development EORTC


- Low incidence of targetable variants

- Low rate of patients finally treated with matched targeted therapy when an actionable genomic alteration is found

- Very limited activity of single targeted therapies, owing to the fact that advanced disease has multiple and heterogeneous targets

ISSUES FACED BY RECENT

BIOMARKER DRIVEN


Concept

Based on RAIDS consortium data

Molecular correlates

associated with

Population most at risk

RAIDS WEBSITE: RAIDS FP7

- Identification of complexity - main druggable genetic alterations and protein

activations

- associated with poor outcome

- from Bioraids: - a prospectively collected extensive database

from Central and Western EU countries

- Relevant pathways identified- according to occurrence and availability of

pertinent targeted therapies

- epigenetic regulator genes

- p53,

- Wnt pathway,

- PI3K pathway

Rationale


PI3K and epigenetics

pathway alterations

No alteration in PI3K and

epigenetics pathway

« Metagene » analysis of frequently altered genes

any PI3K pathway mutation AND any one of several

frequent epigenetic alteration

Thiese results led to the design of a new trial

« PEVO » Pembrolizumab and Vorinostat

in relapsed squamous cell cancers

funded in an ERAPERMED scheme 2019 -

Sequencing by A Kereszt, and B Balint: Szeged, HungaryBioinformatics: Institut Curie

www.raids-fp7.eu

http://www.raids-fp7.eu/

Data integration: submitted for publication

BioRAIDs: NCT02428842

• Recruited: n=419

• Evaluable: n=377

• Molecular evaluation: <200 so far

Funding secured : FULL EXOME, SHALLOW WHOLE

GENOME AND RNAm in all evaluable patients

www.raids-fp7.eu

baseline tumors: 3 main

c lusters

Proteins that characterize

each cluster are enriched in:

Cluster 1: EMT, ErbB signaling

Cluster 2: DNA damage

s ignalingChemoradiation (targets DNA repair): 87%

Cluster 3: p38 MAPK and PI3K

s ignaling

RPPA by Leanne de Koening

Translational platform I Curie

Venn Diagram summarizingthe sample size according to source of data. Whole Exome Sequencing and RPPA data togetherare available in 89 patients.

(Mut=mutation, Clinical=clinical data,

CNA=Copy Number Alteration, RPPA=Reverse Phase Protein Arrays

CoxBoost analysis by Aurélien Latouche and Jonas Beal: I Curie U900

GenomicProteomic


Non-zero ranked estimates from Coxboost associated with a PFS at 24 months

considering clinical data, mutational, copy number alterationsand RPPA

featuresRPPA Prot1

RPPA phospho-β-cateninSer675

HPV clade

FIGO stage III-IVRPPA Prot2

TP53 mutation

RPPA Prot3

CREBBP mutation

RPPA Prot4

RPPA Prot5MED13 mutation

RPPA Prot6

RPPA Prot7

RPPA Prot8

ATRX mutationRPPA Prot9

RPPA Prot10

RPPA Prot11

RPPA Prot12

RPPA Prot13

RPPA Prot14RPPA Prot15

RPPA phospho-β-

cateninSer552

REF: Betacatenin forms and function by Goretski et al, Nature 2018 REF: 14-3-3beta C20 and Chibby (CBY) form complex to facilitate nuclear export of Wnt signaling genes - J Cell Biol. 2008

CoxBoost analysis2 molecular forms of beta catenin emerge at extremes of outcome spectrum

ESMO : MAP (molecular analysis for persolalized therapy) London NOV 2019

Beta catenin drives proliferation, migration, invasion

www.raids-fp7.eu


Molecular markers of POOR or of GOOD

outcome

based on whole exome sequencing (WES) (tumour-blood)

• 5 - genetic markers of good outcome

• 9 - genetic markers of poor outcome (alone or in combination

– TP53, CSMD3, UBR5, PIK3CA, CREBBP, NOTCH, ARID1A, PTEN, KMT2D (MLL2)

Note the earlier appearance of progression

in case of more than one of these poor prognostic markers

www.raids-fp7.eu


Mut/CNV

Individual patients

MUT MUT and CNV

180 patients assessed out of 377Half WESHalf Panel sequencing 600 genes

CNV: difficult to assess from panel sequencing

1. Overcome issues in recentbiomarker driven trials by combined targeting of relevant genomic

alterations and epigeneticalterations (metagene)

2° Design combined therapiesbased on the patients’ owntumour caracterisitcsand additionally

validate pharmacoprofiling in the clinic

Objectives


1. Cervical carcinoma : squamous cell carcinoma, adenosquamous cell or adenocarcinoma

(Endometrial : tbd)

2. Recurrent and/or metastatic disease progressing within 6 months following a platinum based regimen (in the metastatic setting or after chemoradiation therapy)

3. Evaluable disease and mandatory fresh biopsy and imaging before treatment

Study population


1. Analysis of fresh frozen tumor biopsies and serum, using a custom theranostic test designed

to include high throughput IHC on frozen sections, NGS and copy number variants.

2. Treatment allocation to cohorts as a function of molecular alterations

3. Pilot phase I in 3 centres (Paris, Glasgow, Novisad) with 12 first patients planned to be enrolled

4. Phase II : expanding to other European centers - each cohort designed as a phase II trial with its own statistical hypothesis.

Methods


3+3 strategy - phase I

of each association

In 3 pilot centers

Followed by phase II

Primary endpoint:

PFS or ORR depending on the

investigated drug

Cohort sizes range from 32 to 76 pts

Statistics


Biomarkerdriven cohort

Hormonereceptorcohort

(activation mutations, amplifications and

protein expression using IHC)

Immunotherapycohort

(TMB high, MSI or PDL1≥1% using IHC)

PIK3CA activation (activating mutation and focal

amplifications)

P53 inactivation (truncating mutations and copy

number deletions)

Epigenetic alterations(KMT2D, KMT2A, ARID1A,

ARID2, CREBBP, KDM5C, UBR5) Immune checkpoint inhibitor+Vorinostat

Androgenreceptor

Oestrogenreceptor

Enzalutamide

letrozole

Beta catenin / Wntpathway

alpelisib

APR246

TisotumabVedotin

vorinostat

+/-im

mu

ne

che

ckpo

int in

hib

itor

1/In the absence of significant genomic targetable alteration.

2/In case of relapse or intolerance relapse on the first

line proposed drug

or

June 2020

FLIMS workshop

December 2020:

Protocol finalization

June 2021

Administrative approvals

January 2022

First inclusions

Timelines


GEICO

ATOMICC / GEICO 78-C

A randomized, open label, phase II trial of Anti-PD1, Dostarlimab (Former TSR-042), as maintenance therapy for patients with high-risk locally advanced

cervical cancer after chemo-radiation

ClinicalTrials.gov NCT03833479

Standard Concurrent Chemo-Radiation

R2:1

No Further Treatment

*TSR-0428 for 24 months≤12 weeks

*TSR-042: is an anti-PD1 IgG4 humanized monoclonal antibody that binds with high affinity to PD-1. TSR-042 will be administered at fixed 500 mg

TSR-042 dose Q3W for the first 4 doses followed by a fixed 1000 mg TSR-042 dose Q6W for the remainder of the study.

PR / CR

Stratification Factors• Histology: squamous vs adenosquamous adenocarcinoma• FIGO Stage: IB2, IIA2 or IIB wIth pelvic positive lymph nodes vs III/IVA

vs any Stage with positive ParaAorticLymph nodes• Response to Concurrent Chemo-Radiation: Partial Response vs

Complete Response by RECIST Criteria v1.1

N=132

1ºEnd-Point: PFS2ºEnd-Points: • OS• Frequency and severity of AEs• PROs

PI: Ana Oaknin, MD PhD on behalf of GEICO

ATOMICC / GEICO 78-C

ClinicalTrials.gov NCT03833479 PI: Ana Oaknin, MD PhD on behalf of GEICO

▪ Sponsor: GEICO

▪ Participant Group: GEICO

▪ Planned No. of patients: 132. Current accrual:

➢ 21 randomized patients (out of 32 screened)

➢ 5 in screening

➢ 8 screening Failures

▪ Recruitment Period: 18 months*

➢ Last Patient First Visit (LPFV): planned for January 2021

*This enrollment period is expected to be extended

▪ Duration of the Study: 24 months treatment + 6 months follow up

▪ Status: Recruiting

▪ Other important information: Currently working on the addition of at least two other EU countries

BEATcc Trial: ENGOT-Cx10/GEICO 68-C / JGOG1084 / GOG-3030

Sponsor: GEICO (Spain)

Planned No. of patients: 404

Current accrual: 154 patients (Recruiting)

A Randomized Phase III Trial of Platinum Chemotherapy plus Paclitaxelwith Bevacizumab and Atezolizumab versus Platinum Chemotherapy plus

Paclitaxel and Bevacizumab in Metastatic (stage IVB), Persistent, orRecurrent Carcinoma of the Cervix

GEICO 19 sites 19 sites activated

AGO 15 sites 1 site activated

GINECO 17 sites 15 sites activated

GOG-F 7 sites 0 sites activates

JGOG 8 sites 8 sites activated

MaNGO 7 sites 3 sites activated

MITO 10 sites 5 sites activated

NSGO 7 sites 7 sites activated

BEATcc Trial: ENGOT-Cx10/GEICO 68-C / JGOG1084 / GOG-3030


▪ Patients Randomized: 154 patients

▪ Patients in Screening: 8 patients (27 Screening Failures)

▪ Carboplatin has been added as an alternativeto Cisplatin

Groups Patients in Screening Patients Randomized

GEICO 3 75

GINECO 3 45

JGOG 0 26

NSGO 1 6

MITO 0 2

AGO 1 0

Total 8 154

GINECO

SENTICOL III : International prospective validation trial of sentinel node biopsy in cervical cancer. (GINECO-CE106 / ENGOT-Cx24)

Trial setting: tumour type/stage: cervical cancer; stage Ia1 – IIa1

Study Design: randomized, single blind phase III trial

Sponsor(s): Hospital Besançon for GINECO

•Squamous or adenocarcinoma of the cervix,•Stage Ia1 with lympho vascular emboli , Ib1, Ib2, IIa1 (FIGO 2018)

•Maximum diameter ≤ 40mm.

Frozen section

(bilateral detection, safety algorithm)

Patients with bilateral detection without macroscopic suspicious node and negative frozen section on SLN

(pN0)

DFS, RFS, QOL, OS

Arm A (experimental) :SLN biopsy only

+ hysterectomy or trachelectomy

Arm B (reference) :SLN biopsy

+ Pelvic Lymphadenectomy+ hysterectomy or trachelectomy

Patients with nodal involvement(pN1)

Followed in a separate cohort to record treatment and outcomes

Randomisation

1 : 1

- Planned number of patients : 950- Current accrual : 141 registered patients, 110 randomized patients and 11 patients in the pn1 cohort

Other information :

- Japan (GOTIC) and China (CCRN site) are open (7 randomized patients in China)- Pending opening : Italy (MANGO), Canada (CCTG), Brazil (BrGOG and CCRN sites) India (KolGOTrg), Switzerland, Netherland (DGOG), Norway (NSGO), UK isolated sites

Regulatory process/ contracts

Activated country

Enrolment ongoing

The SENTICOLIII map

BrGOG

GOG-PARTNERS

GOG Foundation (GOG-F)

GOG-Foundation (F)

Larry Copeland (President)

GOG-Partners (P)

Directors

Robert Coleman

Bradley Monk

Associate Directors

Thomas Herzog

Kathleen Moore

Clinical Trial Advisors

David O’Malley (Ovary)

Leslie Randall (Cervix)

Brian Slomovitz(Uterine)

Bhavana Porthuri

Ramez Eskander

NRG Oncology

Robert Mannel

Gynecology Cancer Committee Chair

Carol Aghajanian

Funded by Industry

Government funded

- Recurrent, persistent, and/or metastatic cervical cancer

- Progressed within 6 months of the last dose of platinum

R

A

N

D

O

M

I

Z

E

REGN2810 350 mg Q3W,

for up to 96 weeks

Physicians choice chemotherapy

PI = Krishnansu S. Tewari, MD

N = 534

Primary Endpoint = OS

Enrollment = 559

Pemetrexed 500 mg/m2 Q3WTopotecan 1 mg/m2 daily for 5 days, Q21 daysIrinotecan 100 mg/m2 days 1, 8, 15, & 22,

followed by 2 weeks rest (6-week cycle)Vinorelbine 30 mg/m2 days 1 & 8, Q21 daysGemcitabine 1000 mg/m2 on days 1 & 8, Q21 days

REGN2810, a fully human monoclonal antibody against programmed death-1 (PD-1)

Empower Cervical 1: R2810-ONC-1676/GOG-3016/ENGOT CX9/GEICO 72-C

ClinicalTrials.gov Identifier: NCT03257267

KGOG

GOG 263PI; Sang Young Ryu, MD

Randomized Phase III Clinical Trial of Adjuvant Radiation vs Chemoradiation In

Intermediate Risk, Stage I/IIA Cervical Cancer Treated With Initial Radical Hysterectomy

and Pelvic Lymphadenectomy

Cervical cancer

Stage I-IIA

Radical hysterectomy+BPLND

>2 of intermediate risk factors

Control Arm; Radiation therapy

CRT Arm; Weekly CDDP

40mg/m2 concurrent to radiation

Ran

dom

izatio

n

TACO(Tri-weekly Administration of Cisplatin in LOcally Advanced

Cervical Cancer)

Cervical cancer

Locally advanced cervical

cancer

Stage IB2, IIB-IVA

Control Arm; Weekly Cisplatin

40mg/m2 6 cycles

Study Arm; Tri-weekly Cisplatin

75mg/m2 3 cycles

Ran

dom

izatio

n

MITO

ENGOT CX 11 – A Randomized, Phase 3, Double-Blind Study of Chemoradiotherapy With or

Without Pembrolizumab for the Treatment of High-risk, Locally Advanced Cervical Cancer

ENGOT Model: C Sponsor: Merck Sharp & Dohme Corp.Lead Group: MITO

Phase III - Study design

Stratification Factors:

• IMRT or VMAT (yes/no)

• Total radiotherapy dose (>70 vs < 70 Gy)

• Early stage versus late stage (IB2-II versus III-IVA)

Participants

High Risk Locally Advanced

Cervical Cancer:

FIGO stage IB2-IIB2 with

positive nodes

FIGO stage III-IVA with any

nodes

Randomization

1:1

N=980

Treatment with cisplatin (40 mg/m2

x 5 cycles [1 cycle weekly]) and

radiotherapy (EBRT followed by

brachytherapy) in combination with

Placebo (Q3W, 5 cycles)

Treatment with cisplatin (40 mg/m2

x 5 cycles [1 cycle weekly]) and

radiotherapy (EBRT followed by

brachytherapy) in combination with

Pembrolizumab (200 mg Q3W,

5 cycles)

Placebo

(Q 6W, 15 cycles)

Pembrolizumab

(400 mg Q 6W, 15 cycles)

PRIMARY ENDPOINTS✓ OS rate at 3 years

✓ PFS rate at 2 years

SECONDARY ENDPOINTS✓ CR at 12 weeks, DOR and ORR (as assessed by BICR per RECIST 1.1 criteria)

✓ AEs/SAEs and changes in vital signs and laboratory values (as defined by CTCAE,Version 4.0)

✓ QoL evaluated with the EORTC QLQ-C30 and EORTC QLQ-CX24 questionnaires andEuroQoL EQ-5D-5L questionnaires

EXPLORATORY ENDPOINTScellular components (eg, protein, DNA, RNA, metabolites) and other circulatingmolecules, to identify novel predictive/PD biomarkers and generate information that maybetter guide single-agent and combination therapy with immuno-oncology drugs.

Endpoints

Translational Studies

✓ Germline (blood) genetic analyses (eg, SNP analyses, wholeexome sequencing, whole genome sequencing)

✓ Genetic (DNA) analyses from tumor

✓ Tumor and blood RNA analyses

✓ Proteomics and IHC using blood or tumor

✓ Other blood-derived biomarkers

Statistical Hypothesis

• Randomized phase 3 trial

• PFS rate at 2 years in the standard arm is 57% versus 69% for the treatment arm (hazardratio = 0.660)

• OS rate at 3 years in the standard arm is 54% versus 66% for the treatment arm (hazardratio = 0.674)

• The planned sample size is approximately 980 participants with 490 participants in eacharm

• The PFS hypothesis testing is designed for one-sided α = 0.0125 and power of 91% todetect an HR of 0.660 with approximately 237 and 304 events between the two arms atthe planned PFS interim and final analyses.

• The OS hypothesis testing is designed for one-sided α = 0.0125 and power of 90% todetect an HR of 0.674 with approximately 193, 251 and 322 events between the two armsat the planned OS interim and final analyses.

• Enrollment duration of 28 months with an average accrual rate of 35 participants permonth

Participating ENGOT groups and sites

GROUPS N° of sites

MITO 8 MANGO 2

BGOG 6

Cancer trials Ireland 4

GINECO 6

HeCOG 4CEEGOG 8 GEICO 6ISGO 5NCRI 4

AGO+ NOGGO 9

NSGO 3A-AGO 4

TRSGO 4

Total 73

Other participating groups

NCRI

Randomise

Carboplatin AUC2 & Paclitaxel 80mg/m2

Weeks 1-6

Weeks 7 – 13Standard CRT

Standard CRT

Follow-up3 monthly for 2 years; 6 monthly for 3 years. Survival data will then be collected for all patients on a six monthly basis until the end of the trial; which is defined as 3 years after the last patient has completed

treatment

Standard CRT : 40—50.4Gy in 20-28 fractions plus Intracavitary brachytherapy to give total EQD2 dose of 78-86Gy to point A/volume.Weekly cisplatin 40mg/m2 x 5 weeks

INTERLACE

INTERLACE – induction chemotherapy followed by standard chemoradiation vs standard chemoradiation alone in patients with locally advanced cervical cancer

Current Status

Target Recruitment: 500

Accrual to Date (UK, Mexico, Italy & India) – 415

Number of Sites Open – 30

• UK: 27 sites open

• GICOM (Mexico): 1 site open - 96 patients recruited

• MaNGO (Italy): 1 site open – 7 patients recruited

• India: 1 site open; 2 sites in set-up – 4 patients recruited

• Brazil: 1 site in set-up

Sponsor: University College London

INTERLACE

NOGGO

Planned Global survey on the surgical approach in cervical cancer

and the impact of the LACC trial

Sehouli J, Keller M, Armbrust R on behalf of NOGGO

83

NRG

NRG GY006Newly diagnosed uterine cervix cancer

•Squamous•Adenosquamous•Adenocarcinoma

Clinical stage bulky (> 5 cm) IB2, or Clinical stage II, IIIB, or IVA followed by

Negative para-aortic nodal staging by PET/CT

Stratify para-aortic node-negative patients by: a. Age (≤ 45 years or > 45 years)b. Performance status (0, 1, or 2)c. Intensity Modulated Radiation Therapy (yes or no)

d. Stage (≤ clinical stage II, or ≥ clinical stage III)

RANDOMIZE

Arm 1:• Radiation• Cisplatin

Arm 2:• Radiation• Cisplatin•Triapine

Radiation: 45 Gy / 25 fractions of 1.8 Gy + 5.4 Gy / 3 fraction parametrium boost + 40 Gy LDR or 30 Gy HDR brachytherapy

Cisplatin: X1 weekly cisplatin 40 mg/m2 (maximum 70 mg) days 2, 9, 16, 23, 30 of radiation (5 total infusions;

a sixth administration on day 36 is permissible at the treating physician’s discretion.)

Triapine: X3 weekly 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (Triapine) 25 mg/m2 (maximum 50 mg) days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26, 29, 31, 33 of radiation (15 total infusions)

PI = TREY LEATH MD

N = 450

Enrollment to date = 277

Primary Endpoint = RFS

NTO-1151- Triapine:Small moleculechelator – inhibitsribonucleasereductase

ClinicalTrials.gov Identifier:NCT02466971

NSGO

ENGOT-Cx7 / NSGO / MaRuC

Sponsor: NSGO

A randomized double-blind placebo-controlled phase II trial of Rucaparib maintenance therapy for patients with locally advanced

cervical cancerENGOT-CX7 / NSGO / MaRuC

Study Status• Submissions ongoing• Expected FPI: Q3 2019

Participating groups:• BGOG, Belgium• CEEGOG, Czech Rep, Hungary, Ukraine• NOGGO, Germany• PGOG, Poland• PMHC, Canada

Study DesignENGOT-Cx7-NSGO/MaRuC

Arm ARucaparib 600mg BID for 24 months

Arm BPlacebo BID for 24 months

No residual disease

n = 162Randomization: 2:1

Cervical cancer

Squamous, Adenosquamous,

Adenocarcinoma

Stage III, IVA

Patients have successfully completed

definitive chemoradiation

According to FIGO

classification 2018

Stratification factors• Histology - squamous vs adenosquamous, adenocarcinoma

• FIGO stage - FIGO stage IIIA vs. IIIB IIIC vs. IVA

Enrolment will be observed regarding histology. Once 95 patients with squamous cell histology are enrolled a decision will be taken whether to cap further enrolment of this histo type

Primary endpoint: Progression Free Survival

Documents

ERVIX CANCER COMMITTEE - GCIG Cervical Cancer...Centralreview of contouringand planning SURGERY RADIOTHERAPY Application for research grant to the Czech Health Research Council (2020)