phase ii committee phase 2 wg slide deck.pdf · study design international, multicentre,...

PHASE II COMMITTEE THURSDAY, MAY 31, 2018, 8:00AM – 9:00AM

• Welcome & Introductions: Kohn/Mirza

• COI declarations

• Approval of Minutes/Report: November 2017 (posted on GCIG website)

• Closed/Published Trials: Kohn/Mirza

• Ongoing Clinical Trials:

• NRG GY005 phase 2 component Lee (NCI US)

• STICs and STONEs; NEO; eVOLVE, OLALA Lheureux (PMHC)

• EN2; FANDANGO; PALEO; AVANOVA; AVANOVA-Immune1; UMB1; MaRuC Mirza (NSGO)

• GTAC updates Kohn, Mirza, All

• GEICO; PMHC; CCTG; GOTIC; GGOC; ANZGOG; NRG; NSGO

Trial name/Group name and number

Trial setting: tumour type/stage: recurrent platinum-resistant or –refractory

ovarian cancer

Study Design: Phase II/III randomized trial

Sponsor(s): CTEP/NCI U.S.

Planned No. of patients: 208 (Phase II), 236-472 (Phase III)

Current accrual: Phase II accrual complete, end of phase II analysis pending

Other important information: To re-open in 3Q 2018 for Phase III

Ongoing Trials – status updateNRG CCTGKGOGNRG-J

NRG GY005: Randomized Phase II/III study of the combination of

Cediranib and Olaparib compared to Cediranib or Olaparib alone, or

Standard of care chemotherapy in women with platinum-resistant

recurrent Ovarian Cancer

PRR OvCa patients

ECOG 0-2

Measurable disease

< 2 prior regimens in the

recurrent setting

No prior bevacizumab in

the recurrent setting

gBRCAm status is not

required at study entry

n=208*52 per arm

for Phase II

Appx. 400

for Phase III

1:1:1:1

C + O

C 30 mg daily

O 300 mg bid

PLD

wkly Paclitaxel

Topotecan

PF

S

GY005to be followed by

Ph III OS/PFS trial

NEO: Olaparib Window of Opportunity

Archival tissue

Somatic DNAprofiling

RNASequencing

ctDNAprofiling

IHC

Trial Update

5

• 12 patients enrolled – 1 patient in screening

• 3 Sites open - 5 Sites pending

• First patient enrolled 14 months ago

• Clinical: no PD – no patient off trial

• Correlatives: 1st batch to be sent for analysis

EVOLVE: A proof of concept trial of combination of Olaparib + Cediranib

Platinum SENSITIVE disease

Platinum RESISTANT disease

Prior PARPi progression, treated with further chemo

11/11 pts

8/10 pts

9/10 pts 6

Archival Baseline


RNASequencing

ctDNAprofiling

IHC

Preliminary results

7

- Median age: 57 years (range 43-76)

- BRCA mut status: 6 gBRCA1; 3 gBRCA2; 1 sBRCA1; 1WT sBRCA

- # prior chemotherapy lines: median 2 (range 2-5)

- Prior PARPi: duration - median 7 cycles (range 4-33)

3Ttt (15,21,31 mths) – 8 Maintenance (med duration 13 mths [4-33])

Platinum Sensitive Cohort

STICs and STONES: OV.25 A randomized phase II double-blind placebo-controlled

trial of Acetylsalicylic acid (ASA) in prevention of ovarian cancer in women with BRCA1/2 mutations

Co Chairs: Oza A – Lheureux S

Trial committee: Eisen A, Cormier B, McAlpine J, Weberpals J,

Philips k, Bernardini M, Fung Kee Fung M, Kim R

Pathology Chair: Patricia Shaw

Senior Investigator: Wendy Parulekar

Biostat: Dongsheng Tu

Study coordinator: WenLing Liu

Sponsor: CCTG

Support: Apotex

Study DesignInternational, multicentre, randomized, double-blind, placebo controlled phase II in women with germline BRCA1/2 mutations, scheduled to undergo risk reducing surgey within 6 months to 2 years.

• 2:1 Randomization

• Stratification• Age (<40 vs 40-50 vs >50)• Current (last dose <6 mths) combined oral contraceptive use (Yes vs No)• BRCA status (BRCA1 vs BRCA2)

ctDNA collection (LSARP application)

women with

BRCA1/2

mutations

scheduled to

undergo risk-

reducing

surgery

R

A

N

D

O

M

I

Z

E

↗

ASA

81 mg po daily

Treatment

for a

minimum of

6 months to a

maximum of

2 years

Risk-reducing

surgery

↗

Acetylsalicylic

Acid

(ASA)

↘

↘ ASA

325 mg po daily

Placebo

One tablet po daily

N=414 women

Update / Timelines

• Centrally Activated in Canada April 6 2018

• First Centre Opened in Canada May 17 2018

• Publicity efforts ongoing

• Australian activation pending: ANZGOG

• International Collaborators Identified (including UK, Israel)

– Israeli Sites 4-8: Feasibility Assessment Jun2 2018

– Planning Investigator meeting Oct 2018.

OLALA: long-term vs short-term response to Olaparib (PARPi)

11

Enrolled

19/50 pts

19/50 pts

Multicentres - Canada - International


RNASequencing

ctDNAprofiling IHC

OLALA Objectives

12

• Molecular profiling, genomic and immune profile changes between ST and LT

• Signature of PARP response vs resistance

• Pharmacokinetics and pharmacogenomics of olaparib for patients on treatment

ENGOT- N2-DGCGSponsor: DGCG

A phase II Trial of postoperative chemotherapy or no further treatment for patients with node-negative stage I-II

intermediate or high risk endometrial cancer.

Study Design:

Sponsor(s): NSGO

Planned No. of patients: 240

Current accrual: 199

Other important information: Status - recruiting

Ongoing Trials – status update

Endometrioid:Stage I - G3; II

Non-endometrioid:Stage I-II

ChemotherapyCarboplatin-Paclitaxel x 6+ Brachytherapy

Observation+ Brachytherapy

1:1 randomization

Supported by

ENGOT-EN2-DGCG


Group PI Country No. of Institutions ActivatedTotal nb of pts

randomizedMay 2018

DGCG Mirza Denmark 6 6 63

The Netherlands Netherland 4 4 2

UK United Kingdom 9 9 31

NSGO Lundgren Sweden 4 4 30

Finland 6 5 9

BGOG Kridelka Belgium 10 8 13

MITO Greggi Italy 7 1 7

C-GOG (MDACC) Soliman US 1 1 1

MaNGO Ferrero Italy 6 2 3

NOGGO Sehouli Germany 9 5 11

AGO Chr. Marth Austria 1 1 1

ISGO Levy Israel 7 3 0

GEICO Santabella Spain 14 12 21

CEEGOG Cibula Czech rep. 5 2 6

Total 89 63 199

EN1/FANDANGOSponsor: NSGO

A randomised double-blind placebo-controlled phase II trial of first line combination chemo-therapy

with nintedanib/placebo for patients with advanced or recurrent endometrial cancer

Study Design:


Current accrual: 100

Other important information: Status - recruiting

Ongoing Trials – status updateR

and

om

izat

ion

1:1

N =

14

8

Stratification:• Stage of disease (stage 3C 2 vs. stage 4 vs. recurrent disease) • Prior adjuvant chemotherapy (yes/no) • Disease status (Measurable vs. non-measurable disease according to RECIST 1.1)

ENGOT-EN1-FANDANGO - Overall Summary

16

Group NCNumber

ofSites

Number of Sites

Activated

Screened Patients

Randomized Patients

NSGO Mirza 11 11 37 34

GINECO Berton-Rigaud12 12 41 33

NOGGO Sehouli12 11 23 21

BGOG Altintas6 6 10 9

TOTAL 41 40 111 100

05

1015202530354045

Okt16

Nov16

Dec16

Jan17

Feb17

Mar17

Apr17

May17

Jun17

Jul17

Aug17

Sep17

Oct17

Nu

mb

er

of

site

s

Expected Activated sites Activated sites 41 Sites in total

40 Activated SitesScreening/Recruitment Status per group

100 Randomized patients

020406080

100120140160

No

v 1

6

De

c 1

6

Jan

17

Feb

17

Mar

17

Ap

r 1

7

May

17

Jun

17

Jul 1

7

Au

g 1

7

Sep

17

Okt

17

No

v 1

7

De

c 1

7

Jan

18

Feb

18

Mar

18

Ap

r 1

8

May

18

Nu

mb

er

of

pat

ien

tsExpected Randomized patients Randomized patients

148 Patients in total

EN3-NSGO/PALEOSponsor: NSGO

A randomized, double-blind, placebo-controlled, phase II trial of Palbociclib in combination with Letrozole versus

Placebo in combination with Letrozole for patients with Estrogen Receptor Positive advanced or recurrent Endometrial

cancer.

Study Design:


Current accrual: 42

Other important information: Slow recruitment in the PALEO study. MITO still pending regarding approvals from CA and EC


Endometrial Cancer

Primary stage 4 or relapsed disease

ER positive endometrioid

adenocarcinoma

Randomize

ARM ALetrozole, 2.5mg d 1-28 every 28 daysPlacebo 125mg d 1-21 every 28 days

Until progression

ARM BLetrozole, 2.5mg d 1-28 every 28 days

Palbociclib 125mg d 1-21 every 28 days

Until progression

Stratification:• Number of prior lines (primary adv disease vs. 1st relapse vs. ≥2 relapses)• Measurable vs. evaluable disease• Prior use of MPA/Megace

Randomization: 1:1N=78

EN3-NSGO/PALEO


Country Sites PI Submission statusPts. Randomized

Denmark Rigshospitalet Mansoor R. Mirza (NC)

CA: 13/10: ApprovedEC: 13/10: Approved 14Odense Gitte-Betina Nyvang

Aalborg Bente Lund

Roskilde Jørn Herrstedt

Norway Haukeland (Bergen) Line Bjørge (NC) CA: 02/01: Approved

EC: 03/01: Approved 4Radium Hospitalet Kristina Lindemann

Finland Tampere Annika Auranen (NC)CA: 17/03: Approved

EC: 13/03: Approved 1Kuopio Maarit Anttila

NOGGO

Jalid Sehouli (NC)

CA: 28/6-17: Approved

EC: 21/6-17: Approved 11

Charité Universitätsmedizin Berlin Dr. Jalid Sehouli

Kliniken Essen Mitte PD Dr. Beyhan Ataseven

Klinikum der Universität München PD Dr. Julia Gallwas

Universitätsklinikum Halle (Saale) Dr. Hans-Georg Strauss

Klinikum der Friedrich-Schiller-Universität Jena

Prof. Dr. Ingo Runnebaum

Universitäts-Frauenklinik Heidelberg Prof. Dr. Frederic Marmé

GEICO

HU 12 de Octubre Dr. Cesar Mendiola (NC)

CA: 27/6-17: Approved

EC: 17/5-17: Approved 12ICO Hospitalet Dra. Marta Gil

ICO Girona Dra. Pilar Barretina

HU Reina Sofía Dra. María Jesús Rubio

0

50

Jan

-…

Ap

r…

Jul-

…

Oct

…

Jan

-…

Ap

r…

Nu

mb

er

of

Site

s

Months

PALEO - Open Sites

ExpectedNumber ofopen sites

0

50

100

Jan

-…

May

…

Sep

-…

Jan

-…

May

…

Nu

mb

er

of

pat

ien

ts

Months

PALEO - Number of patients

ExpectedNubmer ofpatients

Investigator’s choice

(without niraparib)

ARM 1Niraparib

ARM 2Bevacizumab

+Niraparib

Platinum-sensitive

Ovarian Cancer

HGSOCHGEOC

orAny BRCAmut

OC

Randomize

Treat to PD/toxic

ity

Treat to PD/toxic

ity

Randomization: 1:1n=94Hypothesis: Arm 1: niraparib median PFS 8mdr

Arm2: Nir + Bev median PFS 14mdrHR 0.57Power 80%alpha 0.1 inclusion 18 months

Stratification factors:HRD positive/negative

TFI: 6-12 mo vs. >12 mo

19

ENGOT-OV24-NSGO / AVANOVA part 3Sponsor: NSGO

Investigator’s choice

(without niraparib)

ARM 1Niraparib

ARM 2Bevacizumab

+Niraparib

Platinum-sensitive

Ovarian Cancer

HGSOCHGEOC

orAny BRCAmut

OC

Randomize

Treat to PD/toxic

ity

Treat to PD/toxic

ity

Stratification factors:HRD positive/negativeTFI: 6-12 mo vs. >12 mo

20

ENGOT-OV24-NSGO/AVANOVA – Part 3

Bevacizumab +

Niraparib +

TSR042

Treat to PD/toxic

ity

Stratification factors:BRCAmut (yes/no)TFI: 6-12 mo vs. >12 mo

Same Inclusion / exclusion criteriaSame sitesNumber of BRCAmut patients capped to the same ratio as in part 2

Trial statistics:To detect a PFS hazard ratio of 0.7 between dublet and triplet treatmentPower: 80% one-sided significance level: 20%Accrual: 18 months Follow-up: 18 months The doublet arm has included 55 patients which are already in follow-up.

The aim is to have additionally 72 (65+dropouts) patients in follow-up after treatment with triplet.The below scenario is for 1:1 randomization between dublet and triplet, but since the dublet has already been included this is just a guide.

ENGOT-OV24-NSGO / AVANOVA part 3Sponsor: NSGO

ENGOT-OV42 / NSGO AVANOVA-Immune1

A randomized phase II trial of atezolizumab, niraparib and bevacizumab combination for patients with recurrent ovarian cancer.

ENGOT-OV42 / NSGO / AVANOVA-Immune1

Sponsor: NSGOStudy Chair: Mansoor Raza Mirza


Design


Objectives

Primary objective: Compare Progression-Free Survival (PFS) of niraparib-bevacizumab-atezolizumabagainst Standard of care (SoC) therapy in both cohorts (TFI 1-6months and TFI >6months).

Secondary objectives: Safety and tolerability of atezolizumab when given in combination with niraparib-bevacizumab. PFS according to trial stratification factors in both cohorts. Objective response rate according to RECIST (ORR) both in cohort 1 and cohort 2Objective response rate according to irRECIST (irORR) both in cohort 1 & cohort 2Disease control rate (DCR) (CR+PR+SD)Patient Reported Outcomes (PROs)PFS1 + PFS2

Exploratory objectives: Overall survival (OS) in each group according to trial stratification factors


Population

Study population of Cohort 1 (TFI 1-6months)

• Recurrent epithelial ovarian, fallopian tube, or peritoneal cancer within 1-6 months of last receipt of chemotherapy.

• Biopsy proven epithelial ovarian cancer.

• BRCAmut or BRCAwt or BRCA status unknown

• Prior treatment: • Patients must have received platinum-containing therapy for primary disease.• Maximum two series of prior therapies for platinum-resistant relapse.• Patients may have received bevacizumab.• Prior PARP inhibitors: patients may have participated in a placebo-controlled PARPi

trial • Patient may have participated in a placebo-controlled IO trial.


Population

Study population of Cohort 2 (TFI >6months)

• Recurrent epithelial ovarian, fallopian tube, or peritoneal cancer and no recurrence within 6 months of last receipt of chemotherapy.

• Biopsy proven epithelial ovarian cancer.

• BRCAmut or BRCAwt or BRCA status unknown

• Prior treatment: • Patients must have received platinum-containing therapy for primary disease.• Maximum two series of prior platinum-based therapies for relapse.• Patients may have received bevacizumab.• Prior PARP inhibitors: patients may have participated in a placebo-controlled PARPi

trial • Patient may have participated in a placebo-controlled IO trial


Treatment arms

Experimental arm:Arm B combination: • Niraparib 200mg PO once daily until disease progression.• Bevacizumab 15mg/kg IV q 21 days until disease progression• Atezolizumab until progression (dose to be added)

Standard armCohort 1• Arm A: chemotherapy alone (weekly paclitaxel or PLD or gemcitabin) or chemotherapy + bevacizumab.Cohort 2

• Arm A: platinum combination chemotherapy (carboplatin-PLD or carboplatin-paclitaxel or carboplatin-gemcitabine) or platinum combination chemotherapy with concomitant and maintenance bevacizumab or platinum combination chemotherapy followed by maintenance parp inhibitor.

GTAC: GCIG-wide Targeted therapy Against Cervical cancer

Gr ADrug A

Gr EDrug E

Gr BDrug B

Gr DDrug D

Gr CDrug C

GCIG

post CRTCaCx maintenance

therapyR

BSC,OBSERVATION

selected AGENT(s)

ENGOT-CX7 / NSGO / MaRuC

Arm ARucaparib 600mg BID for 24 months

Arm BPlacebo BID for 24 months

No residual disease

n = 162Randomization: 2:1Cervical cancer

Squamous, Adenosquamous, adenocarcinoma

Stage 2B, 3 & 4Or any stage withpara-aortic nodes

Patients have successfully completed definitive

treatment

Stratification factors• Histology (squamous vs adenosquamous, adenocarcinoma)• FIGO stage (2b-pos. nodes vs. 3 vs 4)

Enrolment of patients with squamous cell histology will be capped once 60% patients with this histo-type are enrolled

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• Participating groups: NOGGO, PGOG, CEEGOG, PMHC, NCRI, BGOG

• Q3 18: submissions

• Expected FPI: Q4 2018

Standard Concurrent Chemo-Radiation

R2:1

Observation for 24 months

*TSR-0428 for 24 months≤14 weeks

*TSR-042: is an anti-PD1 IgG4 humanized monoclonal antibody that binds with high affinity to PD-1. TSR-042 will be administered using a 30 minute IV

infusion (with a -5 minute and +15 minute window permitted). Patients will receive a 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.

PI: Ana Oaknin on behalf of GEICO

No Residual Disease

Stratification Factors• Histology( squamous vs adenosquamous,

adenocarcinoma)• FIGO Stage: IB2, IIA2, IIB w pos.nodes vs III/IVA vs

any Stage with positive ParaAortic Lymph nodes

N=132

A randomized double-blinded, placebo controlled , phase II trial of Anti-PD1, TSR-042, as maintenance therapy for patients with high-risk locally advanced

cervical cancer after chemo-radiation.

G-TAC: Targeted Agents in CxCa: GEICO Study design

G-TAC: GCIG - Targeted Agents in CxCaGEICO Statistical Analysis Plan

Design:Phase 2 randomized, two-arm trial (control vs. experimental treatment with TSR-042).1º End-Point: DFS@2 years:✓ We estimate 50% probability of surviving disease-free for at least 2 years in the

control arm and expect an increase to 63.7% with experimental treatment, which corresponds to a hazard ratio (HR) of 0.65.

✓ Using a 2:1 randomization a total of 138 evaluable patients are required (46 control/ 92 experimental treatment); total 10% drop-out rate is assumed.

✓ This study will be considered sufficiently mature for final analysis when there are at least 66 evaluable patients with events. This number of events provides 80% power with one-sided type I error of 0.2 for detecting significant superiority of the experimental arm using a log-rank test.

✓ The total expected study duration is 3.5 years; planned recruitment duration is 1 years with a minimum follow-up of 2.5 years.

GCIG Strategic Planning

PHASE 2 COMMITTEE

GOALS:•Advancing new opportunities through collaborative phase 2 multi-group studies

•Fostering communication regarding early phases study results to inform of new opportunities

•Collaborate with site committees in focused development

•Collaborate with Rare Tumors committee where phase 2 studies may be the target

•Moving GTAC forward

GCIG Strategic Planning – June 1, 2018, Chicago

phase ii committee phase 2 wg slide deck.pdf · study design international, multicentre,...

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