ICON 9 An international phase III randomised study to evaluate the efficacy of maintenance therapy with olaparib and cediranib or olaparib alone in patients.

Presentazione sul tema: "ICON 9 An international phase III randomised study to evaluate the efficacy of maintenance therapy with olaparib and cediranib or olaparib alone in patients."— Transcript della presentazione:

1 ICON 9 An international phase III randomised study to evaluate the efficacy of maintenance therapy with olaparib and cediranib or olaparib alone in patients with relapsed platinum-sensitive ovarian cancer following a response to platinum-based chemotherapy

2 Trial Schema – Design changes
Relapsed platinum sensitive ovarian, fallopian tube, primary peritoneal cancer Following completion of 6 cycles (min 4 cycles) of chemotherapy, if CT/MRI show ‘CR’ or ‘PR’ and patients are eligible they will be randomised Arm 1 Olaparib + Cediranib Arm 2 Olaparib Stratified by 6-12 vs >12 month progression free interval; surgery vs no surgery at relapse prior to chemotherapy; prior bevacizumab therapy; BRCA status Olaparib: 300 mg BD Cediranib: 20 mg OD

3 ICON9 Trial Schema Eligibility & Registration
Arm 1 Oral olaparib 300mg BD + Oral cediranib 20mg OD until disease progression or beyond if deriving clinical benefit Mid-Treatment Chemotherapy Response Patients who have received 3 to 4 cycles of combination platinum based chemotherapy are assessed for treatment response according to local practice Eligibility & Registration Patients with evidence of response to 3 or 4 cycles of chemotherapy (GCIG CA125 response or PR on CT) and meet the inclusion criteria will be consented and registered Randomisation Following completion of 6 cycles (min 4 cycles) of chemotherapy, if CT/MRI show ‘CR’ or ‘PR’ and patient remains eligible they will be randomised 1:1 to receive: Olaparib + Cediranib or Olaparib Trial treatment Follow up 2 weekly for 8 weeks, then 4 weekly for year 1 and 8 weekly for year 2 CT scan at  16, 32 and 48 weeks after randomisation 1st relapse platinum sensitive ovarian, fallopian tube, primary peritoneal cancer N=618 Arm 2 Oral olaparib 300mg BD until disease progression or beyond if deriving clinical benefit Archival tissue sample collected for BRCA mutation analysis Stratified by: 6-12 vs >12 month progression free interval; surgery vs no surgery at relapse prior to chemotherapy; prior bevacizumab therapy, BRCA status Long term Follow up  Patients who have discontinued use of all trial drugs due to progression will have follow-up data collected every 12 weeks in the first two years then every 26 weeks in the third year (clinic attendance not required); patients who discontinue due to toxicity will continue to have follow-up assessments every 8 weeks until progression. QOL instruments will continue to be completed after relapse Endpoints Primary – PFS Secondary – OS No. of BRCAMut patients will be capped at 260

4 BRCA Estimate 50% will have BRCA germline testing at site already
Stratification by BRCA (local testing results will need to be received within 3-4 weeks) If somatic BRCA status is unevaluable, patients will be stratified using germline BRCA Funding for remaining 50% in place Trial capped for BRCA mutant (260 patients)

5 Study Endpoints End points Primary Objective PFS (RECIST v1.1) OS
Secondary objectives Toxicity Adherence PFS in BRCAm and BRCAwt subgroups PFS and OS measured from the time of starting second-line chemotherapy TSST (Time to start of subsequent therapy) Quality of Life and Patient Reported Outcomes and EQ-5D-5L (health economic analysis) Progression free survival by CA125 – GCIG criteria Response rates by RECIST/CA125 at 16 weeks of treatment in patients with measureable disease or elevated CA125 at randomisation TR to identify predictors of response and prognostic markers

6 Clinician/datamanager
ICON 9 : MITO sites Centre Clinician/datamanager 1 Candiolo (TO) Oncologia Medica IRCC Università degli Studi di Torino Giorgio Valabrega/Celeste Cagnazzo 2 Roma Ginecologia Oncologica Policlinico A Gemelli Giovanni Scambia, Vanda Salutari/Michela Panella 3 Napoli Oncologia Medica Istituto Nazionale Tumori Fondazione G. Pascale Sandro Pignata/Jane Brice 4 Milano Ginecologia Istituto Nazionale Tumori Domenica Lorusso/Iolanda Pulice 5 Brindisi Oncologia Medica A.O. “A. Perrino” di Brindisi Saverio Cinieri/Pasqualinda Ferrara 6 Bologna Oncologia Ospedale S.Orsola Malpighi Università di Bologna Claudio Zamagni

7 Details Trial approved with changes in design in UK: May 2017
Quintiles will contact centers for submission and will manage on site monitoring (Semptember 2017)

8 BRCA mutations IN OVARIAN CANCER TUMOUR TISSUE
‘BACO’ study BRCA mutations IN OVARIAN CANCER TUMOUR TISSUE A MITO-15 retrospective evaluation Primary objective To assess BRCA somatic mutations as independent predictors of treatment response to trabectidin in Advanced Ovarian Cancer (AOC) Secondary objectives To assess BRCA mutations as independent predictor of survival Prevalence of BRCA somatic mutations in BRCA germline negative and patients with unknown BRCA status

9 In MITO 15 study: planned to study BRCA 1 and 2 gene in formalin-fixed paraffin embedded tumor tissues obtained from OC patients. A specific informed consent for translational studies has been collected at time of enrollment Due to financial and operational constraints, this sub-study were not carried on as planned. Given the availability of Tumor BRACAnalysis CDx, a full somatic BRCA 1 and 2 sequencing by Myriad Genetics GmBH using Next Generation Sequencing (NGS), MITO 15 study committee agreed to ask Myriad Genetics to support analysis of sporadic BRCA1 or BRCA2 mutations in archived tumor tissues. This study is aimed to retrospectively estimate to what extent BRCA mutations found in paraffin embedded tumor samples are associated with trabectidin response in patients enrolled into MITO 15 study

10 CENTRO 002 RASPAGLESI - MILANO
CENTRI Blocchetti tissutali disponibili status CENTRO 001 SCAMBIA - ROMA 12 Inviati campioni CENTRO 002 RASPAGLESI - MILANO 17 ……. CENTRO 011 MOSCONI - PERUGIA 7 Ok CE, campioni in corso di invio CENTRO 013 SABBATINI - MODENA 5 Attesa CE CENTRO 021 ARTIOLI - MIRANO 3 Campioni pronti ma no approvazione CE CENTRO 030 PIGNATA - NAPOLI 16 CENTRO 039 SORIO - AVIANO 8 Approvato CE, in corso recupero campioni

11 MITO 21: STUDIO OSSERVAZIONALE SUL TRATTAMENTO DEI TUMORI A PICCOLE CELLULE DELL’APPARATO GENITALE

12 Criteri di inclusione sesso femminile, senza limiti di età
diagnosi di tumore a piccole cellule del tratto genitale femminile (carcinoma a piccole cellule della cervice, dell’utero, dell’ovaio, della vagina e della vulva, tumori dell’utero PNET, tumore desmoplastico a piccole cellule dell’utero) disponibilità (ove applicabile) a fornire il consenso informato al trattamento dei dati personali disponibilità (ove applicabile) a fornire i preparati allestiti dell’esame istologico per la revisione centralizzata

13 Procedure di raccolta dati
Da inserire i nuovi casi, pubblicazione entro la prossima riunione mito . Arruolamento per centro (Dicembre 2017) Centro Principal Investigator Codice centro Pazienti inserite Policlinico A. Gemelli Roma Giovanni Scambia 1 28 INT MILANO Raspagliesi 2 25 San Raffaele Milano Giorgia Mangili 14 10 Dipartimento di Oncologia Medica B, Istituto Nazionale Tumori Regina Elena Roma Patrizia Vici 49 4 Di. Ginecologia, Ostetricia, Neonatologia Policlinico Bari Gennaro Cormio 20 8 III U.O. Ginecologia e Ostetricia, Policlinico di Bari Marco Marinaccio 27 Istituto Nazionale Tumori Napoli Sandro Pignata 30 7 Dip. Di Ostetricia e Ginecologia IRCCS Policlinico San Matteo Pavia Stefano Bogliolo 50 IRST- Istituto Scientifico Romagnolo per lo studio e la cura dei tumori -ONCOLOGIA MEDICA Ugo De Giorgi 19 Ginecologia Oncologica Università La Sapienza Roma Benedetti Panici/F Tomao totale 100/100

14 ENGOT-EN3 - NSGO / PALEO Study Design
Randomization: 1:1 N=80 (0) Endometrial Cancer Primary stage 4 or relapsed incurable disease ER positive endometrioid adenocarcinoma ARM A Letrozole, 2.5mg d 1-28 every 28 days Until progression Randomize ARM B Letrozole, 2.5mg d 1-28 every 28 days Palbociclib 125mg d 1-21 every 28 days Until progression Stratification: Number of prior lines of therapy (0 vs. 1 vs. more than one) Disease status RECIST 1.1 (measurable disease vs. evaluable disease only) Prior MPA/Megace

15 ENGOT-ENxx - NSGO / PALEO
Study Population Histological confirmed endometrial cancer of endometrioid type. Mixed tumor histology is allowed if the non-endometrioid component is less than 5%. Tumour must be oestrogen receptor positive. Prior therapy Patients may have received chemotherapy for primary advanced (stage 3-4) or relapsed disease, though maximum one-line of therapy. Patients may have received adjuvant chemotherapy for stage 1 or 2. Patients may have received external beam radiotherapy, brachytherapy, surgery. Max one line of prior endocrine therapy with MPA/Megace is permitted. Disease status 7. Patients must have measureable disease or non measurable disease on CT scan according to RECIST 1.1 outside irradiated field. ENGOT-ENxx - NSGO / PALEO

16 ENGOT-ENxx - NSGO / PALEO
Study Endpoints Primary: Investigator-assessed progression-free survival (PFS) Secondary: Investigator-assessed PFS in the sub-populations as in stratification factors. Overall Survival (OS) Objective response rate according to RECIST (ORR) Disease Control Rate (CR+PR+SD) Progression-Free Survival 2 (PFS2): Time to second subsequent therapy (TSST) Patient Reported Outcomes (PROs) (e.g. QoL) Safety and tolerability in the two treatment arms Compliance in the two treatment arms. Time to subsequent therapy ENGOT-ENxx - NSGO / PALEO

17 Statistical Assumptions ENGOT-ENxx - NSGO / PALEO
Design Parameters:  Type 1 error (1-sided) % Statistical power 80% Randomization 1:1 Interim analysis none Hazard Ratio No. of PFS events required 64 Accrual 80 ENGOT-ENxx - NSGO / PALEO

18 ENGOT-EN3 - NSGO / PALEO: MITO centers Clinician/datamanager
Centre Clinician/datamanager 1 Candiolo (TO) Oncologia Medica IRCC Università degli Studi di Torino Giorgio Valabrega/Celeste Cagnazzo 2 Roma Ginecologia Oncologica Policlinico A Gemelli Giovanni Scambia, Vanda Salutari/Michela Panella 3 Napoli Oncologia Medica Istituto Nazionale Tumori Fondazione G. Pascale Sandro Pignata/Jane Brice 4 Milano Ginecologia Istituto Nazionale Tumori Domenica Lorusso/Iolanda Pulice 5 Lecce Oncologia Medica Ospedale “Vito Fazzi” Graziana Ronzino 6 Bologna Oncologia Ospedale S.Orsola Malpighi Università di Bologna Claudio Zamagni 7 Meldola Oncologia Medica I.R.S.T  Ugo De Giorgi

19 A randomized phase II trial of Palbociclib in combination with letrozole versus letrozole for patients with oestrogen receptor positive recurrent endometrial cancer. ENGOT-EN3-NSGO/PALEO Study Status MITO coordinator centre Policlinico Gemelli (CE approval planned for 25/7/2017 ) Adjuvant Endometrial Cancer Trial - Mirza

20 The OREO study design PFS, TFST, TSST, FACT-O,SAFETY, AESI, OS BRCA+
2 cohorts independently powered for PFS: BRCA +, BRCA -ve Population All epithelial OC (not just HGSOC), 1 prior PARPi maintenance therapy Known BRCA status PFS, TFST, TSST, FACT-O,SAFETY, AESI, OS Olaparib 300mg tablets bd BRCA+ Known gBRCA+ or sBRCA+ 136 Placebo 300mg tablets bd Enrollment period: 2 ys BRCA+ 3 ys BRCA-ve Primary Analysis: BRCA+ approx. 42 months after (FSI) BRCA -ve approx. 48 months after (FSI) 2:1 Randomization Olaparib 300mg tablets bd BRCA-ve all-comers HRR+, HRD+ and wt (may include some undetected sBRCA) 280 Placebo 300mg tablets bd Powered 80% for PFS primary endpoint. BRCA+ HR=0.5, 74 events. BRCA- HR=0.65, 191 events. Patients followed to OS for long term safety

21 Investigator meeting - 18/05/2017
ENGOT:- European Network of Gynaecological Oncological Trial Groups (10 groups working on OReO) ISGO Israely Society of Gynecologic Oncology GINECO Group d’Investigateurs Nationaux pour l’Etude des Cancers Ovarians, France AGO Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe. Germany NSGO Nordic Society of Gynaecological Oncology BGOG Belgium and Luxembourg Gynaecological Oncology Group L’ENGOT est constitué d’une 20 aine de groupes coopérateurs impliqués dans les cancers gynécologiques dans un 15 aine de pays et sa mission est de permettre à aux patientes de tous les pays européens de rentrer dans un essai clinique. 10 groupes participent à OReO …. MITO Multicenter Italian Trials in Ovarian Cancer, Italy NCRI National Cancer Research Institute. UK MaNGO Mario Negri Gynecologic Oncology group; Italy GEICO Group Espanol de Investigacion en Cancer de Ovario, Spain Investigator meeting - 18/05/2017

22 TRIAL OVERVIEW AND TIMELINES
Approximately 416 patients to be enrolled: 136 BRCA +ve; 280 BRCA –ve 100 sites in 10 Participating countries : France (21 sites) - Italy (10 sites) - Poland (6 sites) - Israel (8 sites) Belgium (4 sites) - Spain (9 sites) - UK (8 sites) - Germany (22 sites) Denmark (4 sites) - Norway(3 sites) Overall study timelines: 1st site initiated in France on 24-April-2017 ( Dr Selle)

23 TRIAL STATUS Sites Selection: ongoing 117 sites identified
78 sites qualified 2 site initiated Countries with CEC & MoH approval : France – 2 sites initiated Countries with CEC approval : Poland -SIV planned in June Countries with MoH approval : Belgium -SIV planned in July Countries with CEC & MOH submission completed : Germany, Italy, Spain Countries with CEC submission completed : Israel Countries with pending CEC & MOH submission: UK- Denmark - Norway

24 Site initiation status
Investigator meeting - 18/05/2017

25 RA/EC submission plans

26 Clinician/datamanager
OREO : CENTRI MITO PROPOSTI Centre Clinician/datamanager 1 Candiolo (TO) Oncologia Medica IRCC Università degli Studi di Torino Giorgio Valabrega/Celeste Cagnazzo 2 Roma Ginecologia Oncologica Policlinico A Gemelli Giovanni Scambia, Vanda Salutari/Michela Panella 3 Istituto Regina Elena Roma Cognetti/Savarese 4 Napoli Oncologia Medica Istituto Nazionale Tumori Fondazione G. Pascale Sandro Pignata/Jane Brice 5 Milano Ginecologia Istituto Nazionale Tumori Domenica Lorusso/Iolanda Pulice 6 Oncologia Guido Fazi Lecce Graziana Ronzino 7 Bologna Oncologia Ospedale S.Orsola Malpighi Università di Bologna Claudio Zamagni 8 Ospedale Cannizzaro Giuseppina Scandurra/Paolo Scollo 9 Meldola Ugo De Giorgi