AGGIORNAMENTO STUDI CLINICI IN CORSO

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1 AGGIORNAMENTO STUDI CLINICI IN CORSO
RIUNIONE MITO MILANO 21/06/2017 AGGIORNAMENTO STUDI CLINICI IN CORSO Domenica Lorusso

2 OVAIO PRIMA LINEA DI TRATTAMENTO
- PAOLA 1 Chiuso (INT-Napoli) EWOC TRIAL (INT-Milano) Chiuso PRIMA TRIAL (INT-Milano): Ongoing MITO 28 Pembrolizumab (INT Napoli), MITO 25 Rucaparib (INT Milano), ENGOT OV 39 Atezo-Beva (INT Napoli), Trust trial: coming soon

3 PAOLA -1 Study design

4 Study status 30/05/2017 Expected end of randomizations: July 2017
Currently: 1191 screened patients in Europe + 26 in Japan → screened patients 682 randomized patients in Europe + 24 in Japan → 706 randomized patients / 786 expected 361 screening failures in Europe + 2 in Japan → 34,5% SF in Europe Sylvie: j’ai mis à jour les données au 30/05 Expected end of randomizations: July 2017

5 Study Status 30/05/2017 Sylvie: j’ai mis à jour les données au 30/05

6 Sylvie: j’ai mis à jour les données au 30/05

7 Sylvie: j’ai mis à jour les données au 30/05

8 Elderly Women Ovarian Cancer
EWOC Elderly Women Ovarian Cancer Multicenter, randomized trial of carboplatin +/- paclitaxel in vulnerable elderly patients with stage III-IV advanced ovarian cancer  Participating Groups GINECO, AGO, MITO, ANZGOG, Canada, JGOG, GOTIC, NSGO

9 Arm A : carboplatin AUC 5 + paclitaxel 175mg/m² q21 X 6 cycles
Arm B : carboplatin AUC 5-6 q21 X 6 cycles Arm C : carboplatin AUC 2 + paclitaxel 60 mg/m² weekly q28 (d1, d8, d15) x 6 cycles Patient >70 years old GVS* > 3 Rando EWOC DESIGN of Chemotherapy in Advanced OC (stage III-IV - Elderly Vulnerable Pts in an adjuvant or neoadjuvant setting ) *GVS = Geriatric Vunerability Score : - score ADL < 6 - score IADL < 25 - score HADS > 14 - albuminemia < 35g/L - Lymphopenia < 1G/L GVS =  factors with vulnerable score

10 Procedures of registration and randomization

11 +/- Interval debulking (stratified)
PRIMARY ENDPOINT To compare the rate of success to deliver 6 courses of chemotherapy without progression at 6 months or unacceptable toxicity* of 3 different regimens in vulnerable elderly patients Screening Chemotherapy 6 cycles 6 month visit Follow-up every 3 mo. (up to 2 years) GVS>3 Imagery QOL Imagery QOL +/- Interval debulking (stratified) * Unacceptable Toxicity = is defined as a major adverse event related to chemotherapy or treatment procedures leading either to early treatment stopping, to an unplanned hospital  admission or to death. 

12 IMPORTANT UPDATED EWOC-1 STUDY
First interim analysis 30 November 2015 : The IDMC concluded that there was no need to close the trial or stop one of the treatment arms but asked to review the safety data when 30 patients will be included in each arm and had received at least 6 cycles of treatment or stopped their treatment prematurely. In response to this IDMC request, the tolerance and efficacy results of the first 92 patients in the trial were submitted to the IDMC on Taking into account that, the data presented did not correspond to planned analysis in the protocol and the risk of concluding on immature data, the Independent Committee recommended to suspend the randomizations and reassess the data on efficacy and tolerance after the first 120 patients have received at least 6 cycles of treatment or prematurely discontinued their treatment. Given the opinion of the Independent Committee, the EWOC-1 Trial Management Group requests the suspension of the RANDOMIZATIONS in the EWOC-1 trial from today until further notice. However, the REGISTRY remains open and we hope that you will continue to include all vulnerable and non-vulnerable elderly patients in the registry. This registry is indeed a tremendous opportunity to validate prospectively the geriatric vulnerability score defined in the EWOC-1 trial.

13 – UPDATE

14 – UPDATE

15 OVAIO RECIDIVA PLATINO RESISTENTE
Attualmente non protocolli attivi nelle platino resistenti In arrivo: MITO 27 Pembro MITO 29 Decitabina - Studio retrospettivo sul rechallenge della PLD nel carcinoma ovarico

16 1° PLD: response CR PR SD PD PLD 0 (0%) 4 (100%) 4 Carboplatino-PLD 1 (4.55%) 10 (45.45%) 22 Trabectidina-PLD 1 (100%) 1 total 1 (3.7%) 11 (40.74%) 14 (51.85%) 27 Rechallenge: response CR PR SD PD PLD 3 (23.08%) 3 (23.1%) 4 (30.7%) 13 Carboplatino-PLD 1 (20%) 0 (0%) 3 (60.0%) 5 Trabectidina-PLD 2 (22.2%) 1 (11.1%) 6 (66.67%) 9 total 4 (14.81%) 5 (18.5%) 8 (29.6%) 10 (37.04%) 27

17 1° PLD USE Toxicity Grade 1 Grade 2 Grade 3 Anemia 7 (25.93) 8 (29.63) Trombocytopenia 5 (18.52) Neutropenia 11 (40.74) 6 (22.22) Nausea 13 (48.15) vomiting diarrhea 2 (7.41) 3 (11.11) Constipation Neuro 1 (3.7) Cardiac Toxicy

18 Rechallenge Toxicity Grade 1 Grade 2 Grade 3 Grade 4 Anemia 11 (40.74)
8 (29.63) 1 (3.7) Trombocytopenia 6 (22.22) 2 (7.41) Neutropenia 9 (33.33) 4 (14.81) Nausea 15 (55.56) vomiting 7 (25.93) diarrhea 3 (11.11) Constipation Neuro Cardiac Toxicy

19 OVAIO RECIDIVA PLATINO SENSIBILE
ENGOT –OV 27 (INT Napoli) Farletuzumab in platinum sensitive ovarian cancer with low (<105 u/mL) CA125 MITO 18 (Policlinico Gemelli Roma) ICON 9 (Policlinico Gemelli Roma) BACO study (Policlinico Gemelli Roma) Coming soon: OREO

20 BGOG-ov18 Randomized Phase II of chemo +/- Farletuzumab
Carbo PLD x6 + Farletuzumab : Concomittant + maintenance till PD loading dose for the first 2 weeks of 10 mg/kg farletuzumab (double blind), followed by 5 mg/kg weekly First recurrent platin sensitive high grade serous ovarian carcinoma CA125 < 3UNL Evaluable or measurable according to RECIST N = 210 Carbo PLD 2:1 Carbo PLD x6 + Placebo : Concomittant + maintenance Investigator Choice 1:1 Carbo Pacli + Farletuzumab : Concomittant + maintenance till PD loading dose for the first 2 weeks of 10 mg/kg farletuzumab (double blind), followed by 5 mg/kg weekly Carbo Pacli 2:1 Carbo Pacli x6 + Placebo : Concomittant + maintenance FPI: Mar 2015 (US); Aug 2015 (EU) ENGOT Model: C Primary endpoint: PFS * (Assumed HR = 0.667, investigator read) Secondary endpoints: OS, Pt free interval, OR, TTR, DR, safety, PK and exposure-response

21 ENGOT ov-27/MORAb-003-011 Site Activation & Enrollment

22 ENGOT ov-27/MORAb-003-011 Enrollment Summary

23 MITO sites

24 Surgery plus Hyperthermic Intra-PEritoneal Chemotherapy (HIPEC) versus surgery alone in patients with platinum-sensitive first recurrence of ovarian cancer: a prospective randomized multicenter trial. PROTOCOL ID: HORSE Hyperthermic intra-peritoneal chemotherapy (HIPEC) in platinum-sensitive Ovarian cancer recurrence: Randomized trial on Survival Evaluation.

25 Surgery plus Hyperthermic Intra-PEritoneal Chemotherapy (HIPEC) versus surgery alone in patients with platinum-sensitive first recurrence of ovarian cancer: a prospective randomized multicenter trial. PROTOCOL ID: HORSE Hyperthermic intra-peritoneal chemotherapy (HIPEC) in platinum-sensitive Ovarian cancer recurrence: Randomized trial on Survival Evaluation.

26 Patients included (inclusion/exclusion criteria)
LPT: Maximal Surgical Effort Patients eligible (CC-0; CC-1) Patients not eligible (CC>1) Randomization CDDP 75 mg/m2 in 2L/m2 SF temperature 41.5C for 60 min 79 HIPEC NO 79 HIPEC YES Pl based CHT Pl based CHT Drop-out FU FU Drop-out

27 Status: On going Enrollement 126 patients 63 ARM A 63 ARM B

28 Principal Investigator
Arruolamento per centro CODICE CENTRO ISTITUTO Principal Investigator Pazienti Arruolate Braccio A Braccio B 001 Policlinico Gemelli-UCSC UO di Ginecologia Oncologica Giovanni Scambia 94 47 003 Casa di cura Fondazione Giovanni Paolo II Campobasso Vito Chiantera 6 2 4 005 A.O. per l'emergenza Cannizzaro SC di Ginecologia ed Ostetricia Paolo Scollo / 006 IEO di Milano Angelo Maggioni 1 007 IRCCS Arcispedale S. Maria Nuova, Oncologia Medica, Martino Abrate 3 029 Centro di Chirurgia Oncologica avanzata c/o Clinica Chirurgica Enricomaria Pasqual 030 Istituto Nazionale Tumori Napoli Stefano Greggi 032 Ospedale Sant'Orsola Malpighi -Bologna- Pierandrea De Iaco 13 8 5 038 IRCCS Centro di Riferimento Oncologico CRO Aviano (PN) Giorgio Giorda 046 AUSLL 11 di Empoli Ospedale San Giuseppe Empoli (FI) PI Marco Filippeschi - SOMMA 126 63

29 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

30 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

31 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

32 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, Francesco Raspagliesi/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

33 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)

34 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

35 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

36 CENTRO 002 RASPAGLESI - MILANO
CENTRI Blocchetti tissutali disponibili status CENTRO 001 SCAMBIA - ROMA 12 Inviati campioni CENTRO 002 RASPAGLESI - MILANO 17 Attesa CE CENTRO 011 MOSCONI - PERUGIA 7 Ok CE, campioni in corso di invio CENTRO 013 SABBATINI - MODENA 5 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

37 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

38 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)

39 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

40 OVAIO TUMORI RARI Mito 9 (Ospedale San Raffaele) Studio retrospettivo e registro prospettico sui tumori germinali e stromali ovarici MITO 14 (Dott Breda): chiuso, elaborazione dati in corso MITO 21 (Policlinico Gemelli Roma)piccole cellule MITO 19 (INT Napoli): Studio retrospettivo sui tumori sierosi di basso grado MITO 21 (Dr Artioli) : Studio retrospettivo tumori BRCA mutati - Studio Alienor (INT-Milano; ENGOT, chiuso)

41 MITO 9 retrospettivo e prospettico: trattamento dei tumori stromali e germinali ovarici maligni
Raccogliere e analizzare i dati relativi a tutti gli istotipi e tutti gli stadi Modalità Fase 1 retrospettivo Fase 2 prospettico Fino a dicembre 2014 Dal 2014 Scelta terapeutica a carico del singolo centro in base ai propri standard STOP

42 MITO9 STROMALI – RETROSPETTIVO
TIPO TUMORE TOT Tumori a cellule della granulosa - Adulto 214 Tumori a cellule della granulosa- Giovanile 19 Tumore Sertoli Leydig 34 Tumori dei cordoni sessuali – tubuli anulari 10 Esclusi 14 Totale complessivo 296

43 MITO 9-GERMINALI RETROSPETTIVO
TIPO TUMORE Totale Disgerminoma 92 Teratomi Immaturi 87 Tumori del seno endodermico 48 Misti 26 Carcinoma embrionario 1 Carcinoide 7 Esclusi Totale complessivo 268

44 MITO 9-TUMORI del TROFOBLASTO RETROSPETTIVO
Ospedale San Raffaele- Milano 74 INT PASCALE – Napoli 3 Bergamo 6 Bari 7 Federico II – Napoli Campus Biomedico- Roma 2 Pisa 13 Pavia 1 Torino 27 Totale complessivo 123

45 Criteri di inclusione Disegno dello studio
Studio multicentrico, nazionale,osservazionale prospettico (dal 2014) che prevede la raccolta dati relativa a pazienti affette da neoplasie ginecologiche rare nei Centri partecipanti Attualmente sono in corso 2 sottostudi osservazionali 1- Tumori non epiteliali dell’ovaio : paziente affette da neoplasie non epiteliali dell’ovaio: Tumori germinali Tumori stromali Trattate o inviate per il follow up in un Centro MITO 2- Tumori del trofoblasto di origine gestazionale Pazienti affette da tumori del trofoblasto di origine gestazionale insorti dopo una gravidanza molare, abortiva o a termine e che necessitano di trattamento chemioterapico o chirurgico

46 MITO9 STROMALI – PROSPETTICO
TIPO TUMORE TOT Tumori a cellule della granulosa - Adulto 56 Tumori a cellule della granulosa- Giovanile Tumore Sertoli Leydig 9 Tumori dei cordoni sessuali – tubuli anulari 2 Esclusi Totale complessivo 67

47 MITO-9 GERMINALI PROSPETTICO
CENTRO Totale Oncologia medica CRO Aviano 3 Università Cattolica Sacro Cuore Roma 11 Ospedale San Raffaele Milano 6 I.F.O 1 Istituti Clinici di Perferzionamento Mangiagalli Milano Ospedale Sant’Anna Torino Pavia Università Cattolica Sacro Cuore Campobasso 2 Istituto Nazionale dei Tumori Milano Bari 4 Totale complessivo 37

48 MITO 14 AGGIORNAMENTO Dott. Enrico Breda

49 Ospedale N° Fatebenefratelli Tiberina (RM) 45
Dipartimento Oncologia Ospedale Mirano (VE) 15 Università Bari Policlinico II (BA) 62 Santa Maria della Misericordia (PG) 8 San Raffaele (MI) 68 Centro Riferimento Oncologico Aviano (UD) 35 Istituto Tumori (MI) 47 Policlinico Gemelli (RM) 201 Azienda Ospedaliera Univ Integrata (VR) 51 Istituto Nazionale Tumori (NA) 67 Campus Biomedico (RM) 18 Mater Salutis ULSS21 Legnago (VR) 20 II Università Napoli (NA) IRCCS Casa sollievo della sofferenza (FG) 13 Ospedale Guastalla (RE) 5 Ospedale Santa Maria Goretti (LT) 27 Ospedali Riuniti (BG) 92 Ospedale di Trento (TN) 39 Ospedale Canizzaro (CT) 40 Ospedale Civile (CZ) 19 Policlinico S. Orsola (BO) 152 INT Regina Elena (RM) Cattedra Oncologica Medica Federico II (NA) 24 III Clinica di Ginecologia e Ostretricia (BA) 1 Arcispedale Santa Maria Nuova (RE) Ospedale S. Giuseppe USL 11 Toscana Ospedale Faenza 6 Vici INT Regina Elena B (RM) Ospedale Civile Boldrini Thiene (VI) 34 SCDU Ginecologia e Ostetricia Ospedale Mauriziano (TO) 81 Università La Sapienza (RM) 44 1359

50 Caratteristiche pazienti MITO 14
N° % PAZIENTI  1311 Età (mediana, range) 46 Mediana osservazione < 55 anni (premenopausa) 820 > 55 anni (postmenopausa) 491 CHIRURGIA 1311 LPS (laparoscopia) 41.1 LPT (laparotomia) 54.5 Chirurgia completa 12,3 Chirurgia incompleta 87,7 STADIAZIONE FIGO FIGO I 86,8 FIGO II 5,4 FIGO III - IV 7,8 ISTOLOGIA Sierosi 54,3 Mucinosi 35 Sieromucinosi 4,1 altri 4,6 Microinvasione 3,1 Micropapillarità 0.9 IMPIANTI 202 15,4 invasivi Impianti non invasivi CHEMIOTERAPIA ADIUVANTE 65 4,95 8,2 14,08 FIGO III 30,4 Platino 23 Platino doppietta 40 Altro 2 METASTASI 138 10,2 Chirurgia conservativa 97 Chirurgia radicale 3 1 ricaduta 117 2 ricaduta 15 3 ricaduta 5 4 ricaduta 1 ISTOLOGIA METASTASI Borderline 110 Carcinoma invasivo 28 10.5 Stadio I Stadio II 19,7 Stadio III 29,4 DECESSI 26 1,9

51 Mito 19 criteri di inclusione LGSOC/Recidiva Invasiva di SBLT operato
Diagnosi posta tra e il Preparato istologico per revisione centralizzata Età > 18 aa INT Napoli Ist Regina Elena CRO Aviano Pol Univ A. Gemelli Roma

52 Mito 19: obiettivi endpoint primari endpoint secondari
Rischio di recidiva in pazienti operate RR a CHT, OT e terapia combinata in I linea e in linee successive endpoint secondari PFS, OS Profilo di tossicità KRAS, BRAF, p53 correlazione tra mutazione di BRAF e outcome favorevole??? Grisham, BRAF mutation is associated with early stage disease and improved outcome in patients with low-grade serous ovarian cancer, Cancer 2013; 1;119(3): Wong, BRAF mutation is rare in advanced-stage low-grade ovarian serous carcinomas, Am J Pathol, 2010; 177(4):1611-7

53 Informazioni operative (1)
E’ stato attivato il Gemelli (ATTESA DATI UMBERTO I e GEMELLI per raggiungere target)

54 MITO 22: STUDIO OSSERVAZIONALE SUL TRATTAMENTO DEI TUMORI A PICCOLE CELLULE DELL’APPARATO GENITALE

55 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

56 Procedure di raccolta dati
Da inserire i nuovi casi, pubblicazione entro la prossima riunione mito . Arruolamento per centro (Dicembre 2016) 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

57 Avastin and weekly pacLItaxel use in sEx cord-stromal ovariaN tumORs
ALIENOR ENGOT- OV7 Avastin and weekly pacLItaxel use in sEx cord-stromal ovariaN tumORs A randomized, open label, phase II trial of bevacizumab plus weekly paclitaxel followed by maintenance with bevacizumab monotherapy versus weekly paclitaxel followed by observation in patients with relapsed ovarian sex-cord stromal tumors

58 Standard surveillance
STUDY DESIGN Bevacizumab 15mg/Kg every 3 weeks Paclitaxel alone 80mg/m², IV, at D1, D8 and D15 every 4 weeks Paclitaxel 80mg/m², IV, D1, D8 and D15 every 4 weeks + 10mg/kg, IV, D1 and D15 RANDOMISATION Maximum of 6 cycles Up to 1 year or until PD / intolerance Arm A Arm B Standard surveillance Standard of care PD or Toxicity At the investigator discretion Population : Patients with an histologically confirmed diagnosis of ovarian sex-cord stromal tumor in relapse after a platinum-based chemotherapy. Stratification Anterior chemotherapy lines : 1 or 2 vs 3 and more Platinum Free Interval Interval (PFI) <12 months vs >12 months Primary objective : Clinical benefit rate (non-progression rate after 6 months of treatment) GCIG Meeting-Melbourne 2014

59 GCIG Meeting-Melbourne 2014
PRIMARY OBJECTIVE To evaluate the clinical benefit of combining bevacizumab long-term treatment to weekly paclitaxel measured by the non progression rate after 6 months of treatment SECONDARY OBJECTIVES To evaluate in the 2 study arms: The Progression-Free survival The Overall Survival The duration of response The Quality of Life (FACTO); To describe the safety profile of the association Paclitaxel plus Bevacizumab using the NCI- CTC AE scale version 4.0; To evaluate the benefit of Bevacizumab alone after re progression in the arm A GCIG Meeting-Melbourne 2014

60 ALIENOR STUDY Enrollment period : 36 months First Patient In : February 2013 Treatment + maintenance : 18 months Last Patient Out of Maintenance : August 2017 Follow-up : 36 months Last Patient Out : August 2020

61 Enrollment closed on

62 MITO 21 Centro Coordinatore : Oncologia - Mirano VE
Studio Retrospettivo Multicentrico: Correlazione tra Genotipo, Fenotipo e Outcome Clinico nei Tumori Ovarici Ereditari BRCA1 e BRCA2 mutati Centro Coordinatore : Oncologia - Mirano VE Grazia Artioli e Lucia Borgato

63 Obiettivo Primario Obiettivi Secondari
Creazione di un database per raccogliere i singoli tipi di mutazione germinale a carico di BRCA1 e BRCA2 e la correlazione con la risposta al trattamento nelle pazienti affette da EOC Obiettivi Secondari correlare il tipo di mutazione BRCA identificata al fenotipo isto-patologico correlare il tipo di mutazione BRCA identificata all’outcome clinico (PFS e OS) correlare il tipo di mutazione BRCA identificata all’area geografica di appartenenza

64 15 CENTRI PARTECIPANTI PZ ATTESE: 300 PZ ARRUOLATE: 319 TOTALE 15 319
CENTRO MITO Referente Pz arruolate (n) 1. Centro Coordinatore OncoEmatologia MIRANO (VE) Artioli G, Borgato L 24 2. Istituto Nazionale Tumori - MILANO Lorusso D 86 3. Istituto Nazionale Tumori - NAPOLI Pignata S 54 4. Università di Bari - BARI Cormio G 32 5. Centro di Riferimento Oncologico - AVIANO Scalone, Sorio R 28 6. IRCCS IOV - PADOVA Nicoletto MO 23 7 IRCCS - CANDIOLO (TO) Valabrega 18 8. Oncologia – LEGNAGO (VR) Greco F 11 9. IRCCS Osp. Oncologico (BARI) Kardhashi 5 10. Oncologia Medica (AVELLINO) Gridelli C, Rossi E 9 11. IRST Meldola U. De Giorgi 7 12. Oncologia- FBF Roma Spagnoletti 6 13. Oncologia ,Osp. Napoli Orditura 14. Oncologia, Osp Santa Maria della Misericordia , Perugia Mosconi 8 15. Oncologia , Osp S. Matteo – Pavia S. Bogliolo 3 TOTALE 319 PZ ATTESE: 300 PZ ARRUOLATE: 319

65 ARRUOLAMENTO IN CORSO: termine dello studio Dicembre 2017
ANALISI IN CORSO PUBBLICAZIONI: Maggio 2017 Sottomissione di Abstract ad ESGO 2017

66 A TUTTI I CENTRI PARTECIPANTI:
Abs submitted to DOES BREAST CANCER AFFECT PROGNOSIS IN A BRCA-MUTATED OVARIAN CANCER COHORT? THE MITO 21 STUDY - A SUBGROUP ANALYSIS Authors: Borgato L, De Nicolo A, Lorusso D, Pignata S, Cormio G, Scalone S, Nicoletto MO, Valabrega G, Greco F, Rossi E, Spagnoletti I, De Giorgi U, Orditura M, Mosconi A, Kardhashi A, Bogliolo S, Mocellin S, Artioli G Ad interim analysis per descrivere il sottogruppo di pz con doppio tumore (Breast e Ovarian Cancer, BOC) e per valutare se la diagnosi di doppio tumore peggiora la prognosi rispetto alla diagnosi del solo Ovarian Cancer (OC). RISULTATI: 319 pz arruolate nello studio Si tratta della più ampia coorte Italiana di pz BRCA mutate con doppio tumore BOC 72 (23%) BOC e 247 (77%) con solo OC; Nel sottogruppo BOC, 56 (78%) hanno sviluppato come prima malattia il BC e 16 (22%) OC; La mediana dell’età alla prima diagnosi di BC è 50a (32-81a) in caso di BC e di 57a (42-84 a) per OC; BC molto spesso precede la diagnosi di OC. La mediana dell’intervallo tra la prima e la seconda diagnosi di tumore è più corta quando BC segue OC rispetto a quando lo precede (31 m vs 100 mesi). 47 (65%) sono BRCA1 carrier e 25 (35%) BRCA2; la maggior parte delle mutazioni riportate sono frameshift con conseguente premature stop; L’OS non dipende dal gene mutato (BRCA1 vs BRCA2) Le pz che hanno sviluppato anche la neoplasia mammaria presentano una maggior sopravvivenza del gruppo con solo tumore ovarico, infatti l’OS è migliore nel gruppo BOC rispetto al gruppo con diagnosi di solo OC (168m vs. 65 m, p< ). A TUTTI I CENTRI PARTECIPANTI: per favore completate anche i dati relativi alla diagnosi di ca mammario

67 CARCINOMA DELL’ENDOMETRIO
Trattamento conservativo : ECCO study (S. Greggi) ENGOT EN2-EORTC (Coordinamento italiano: Dr Greggi) 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. PALEO study (Policlinico Gemelli Roma): A randomized phase II trial of Palbociclib in combination with letrozole versus letrozole for patients with oestrogen receptor positive recurrent endometrial cancer. Studio chirurgico sul linfonodo sentinella Coordinato INT-Milano SIENDO STUDY (Coordinato Candioolo Torino): Coming Soon MITO END 3 (INT-Napoli): Avelumab nel carcinoma metastatico/avanzato

68 Endometrial Cancer Conservative treatment
E.C.Co. Endometrial Cancer Conservative treatment A multicentre archive Data collection is made by appropriate eCRFs via the Clinical Trials Unit of National Cancer Institute of Naples (Study Data Center) website

69 Endometrial Cancer Conservative treatment
E.C.Co. Endometrial Cancer Conservative treatment A multicentre archive Project Type / Design & Time Perspective Observational / Patient archive, Prospective (a first phase of three years is planned, eventually followed by further three years) Inclusion Criteria - Conservatively treated endometrial cancer - Informed consent to personal data processing - Existence of an IRB-approved local protocol that allows conservative treatment to be performed (or statement that such treatment is considered as a standard) Interventions & Outcome Measures Data collection - Primary Outcome Measures: proportion of complete regression, duration of response, frequency and pattern of relapse, frequency of metachronous ovarian cancer, tumor-related deaths; Secondary Outcome Measures: treatment related morbidity, frequency of spontaneous pregnancies, frequency of pregnancies after ART, pattern of residual disease on definitive surgical specimens Treatment Since this is a archive, treatment is not dictated by a protocol, however, treatment has to be administered according to a IRB-approved local protocol (except for the countries where conservative treatment can be given outside a IRB-approved study because considered as a standard procedure)

70 N° of patients registered
E.C.Co. Endometrial Cancer Conservative treatment A multicentre archive Participation (06/06/2017) Center Code PI Registration date N° of patients registered National Cancer Institute of Naples, Naples. Italy 640 Stefano Greggi March 2014 32 Catholic University of the Sacred Heart, Rome. Italy 145 Giovanni Scambia September 2015 13 Papa Giovanni XXIII Hospital, Bergamo. Italy 254 Chiara Malandrino December 2015 6 San Raffaele Hospital, Milan. Italy 321 Patrizia De Marzi October 2015 4 National Cancer Institute of Rome, Rome. Italy 741 - July 2016 University of Bari, Bari. Italy 111 Gennaro Cormio The Royal Women’s Hospital, Parkville. Australia 668 August 2015 The Obstetrics & Gynecology Hospital of Fudan University, Shanghai. China 676 Leiden Medical University, Leiden. Netherlands 704 Tot N 55

71 Randomized till date = 165/240
Postoperative chemotherapy or no further treatment for patients with node-negative stage I-II intermediate or high risk endometrial cancer.  ENGOT-EN2-DGCG NCT N=240 1:1 randomization Chemotherapy Carboplatin-Paclitaxel x 6 + Brachytherapy Endometrioid: Stage I - G3; II Non-endometrioid: Stage I-II Supported by Observation + Brachytherapy Randomized till date = 165/240

72 Key Inclusion Criteria:
Postoperative chemotherapy or no further treatment for patients with node-negative stage I-II intermediate or high risk endometrial cancer.  ENGOT-EN2-DGCG NCT Key Inclusion Criteria: Only node-negative patients are eligible Endometrial carcinoma with one of the following postoperative FIGO 2009 stage and grade: Stage I grade 3 endometrioid adenocarcinoma Stage II endometrioid adenocarcinoma Stage I and II type 2 histology (clear cell, serous, squamous cell carcinoma, or undifferentiated carcinoma) Hysterectomy; bilateral salpingo-oophorectomy; pelvic lymphadenectomy: min 12 pelvic nodes (6 from each side). Para-aortic LNE is optional Adjuvant vaginal brachytherapy is permitted in both arms WHO performance status of 0-2 Key Exclusion Criteria: External Beam Radiotherapy Concurrent cancer therapy Concurrent treatment with an anticancer investigational agent or participation in another anticancer clinical trial Previous or concurrent malignant disease except for curatively treated carcinoma in situ of the cervix or basal cell carcinoma of the skin

73 Postoperative chemotherapy or no further treatment for patients with node-negative stage I-II intermediate or high risk endometrial cancer.  ENGOT-EN2-DGCG NCT CENTRO MITO PI RANDOM INT Napoli APPROVATO Stefano Greggi 3 INT Milano Domenica Lorusso - INT ROMA DA SOTTOMETTERE CE Enrico Vizza Università Cattolica Rm SOTTOMESSO CE Giovanni Scambia Università Bologna DISPONIBILE Pierandrea De Iaco Università Bari Gennaro Cormio Ospedale Cannizzaro Catania Paolo Scollo Ospedale Faenza Stefano Tamberi IRST Meldola Ugo De Giorgi CRO Aviano Giorgio Giorda Arcispedale S. Maria Nuova Reggio Emilia Mandato V. Dario

74 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

75 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

76 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

77 CARCINOMA DELLA CERVICE UTERINA
- BGOG-CX1 (INT Napoli) Nintedanib in cervical cancer Studio RASUCE(INT-Milano) Radicalita’ chirurgica dopo NACT nel ca localmente avanzato della cervice

78 Coordinating investigator: Prof Dr. Ignace Vergote
BGOG-cx1 Randomized double-blind Phase II study comparing carboplatin + paclitaxel with or without concomitant and maintenance Nintedanib in advanced or recurrent cervical carcinoma ENGOT model A Sponsor: BGOG Coordinating investigator: Prof Dr. Ignace Vergote

79 BGOG-cx1: study design Patients (N= 120) with advanced stage (FIGO stage IVB) OR recurrent carcinoma of the cervix 1:1 Randomization IXRS Nintedanib* 200 mg p.o. BID PLUS Paclitaxel 175 mg/m2 + carboplatin AUC5 Every 21 days for 6 cycles Nintedanib monotherapy up to 120 weeks Placebo* p.o. BID Placebo monotherapy up to 120 weeks Stratification 1. Primary advanced Stage IVB versus recurrent disease. 2. If recurrent, prior line of chemotherapy for metastatic disease or not * Nintedanib/placebo to be omitted on the day of iv. chemotherapy

80 BGOG-cx1: study update Enrollment graph 54/120 PATIENTS RANDOMIZED
Accrual status Randomized 54/120 Treatment discontinued 41/54 Treatment ongoing 12/54 54 patients

81 4 sites activated (1 in February, 3 in May)
BGOG-cx1: study update Status site activations and accrual Country / Group # patients planned # sites randomized Belgium / BGOG +/- 40 pats 10 sites activated FPI Mar2014 30 pats Spain / GEICO +/- 25 pats 5 sites activated FPI Feb 2015 17 pats Italy / MITO and ManGO +/- 11 sites 4 sites activated (1 in February, 3 in May) Germany / NOGGO 6 sites activated FPI Aug 2016 6 pats Total +/- 130 pats 25/32 sites 53 pats

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