AGGIORNAMENTO STUDI CLINICI IN CORSO

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1 AGGIORNAMENTO STUDI CLINICI IN CORSO
RIUNIONE MITO NAPOLI 25/01/2018 AGGIORNAMENTO STUDI CLINICI IN CORSO Domenica Lorusso

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

3 PAOLA -1 Study design

4 Date ARCAGY - GINECO 2015

5 Date ARCAGY - GINECO 2015

6 1/14/2019

7 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

8 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

9 STATISTICAL CONSIDERATION
Etude ENDOPIK STATISTICAL CONSIDERATION The first step will include 22 patients in each arm (total = 66 patients for the 3 arms); An interim analysis will be conducted when 22 patients in each arm will have completed their 6 courses of chemotherapy: - if a chemotherapy regimen is associated with more than 8/22 treatment failure , the regimen will be considered as having insufficient activity (expected number of failure n= 3) and the regimen will be dropped for the second step of the study; - if a chemotherapy regimen is associated with more than 6/22 major adverse event leading either to early treatment stopping, or to hospitalization for toxicity or to death, the regimen will be considered as having too high toxicity (expected number of major adverse event n= 3) and the regimen will be The second step of the study will be run with the chemotherapy regimens considered as active enough and tolerable at the interim analysis. This step will include an additional 58 patients per arm with the following assumptions: - a risk of accepting a regimen having insufficient activity α1 = 0,05, - a risk of accepting a regimen with too high toxicity α2 = 0,05, - a risk of rejecting regimen active enough (1-β) = 0,1 - with an unacceptable rate of disease progression at 6 month of > 0,4 - and an unacceptable toxicity rate > 0,3. The total number of patients per arm will be of 80 for a maximum total number of patients of 240 if all 3 regimens are selected for step 2. After completion of the 6 chemotherapy cycles, conditions to reject the experimental arms are the following: number of patients with insufficient efficacy n> 26/80 and/or number of patients with unacceptable toxicity n> 18/80 (expected tumour progression or treatment failure: 9, major adverse events: 9).

10 – UPDATE

11 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.

12 ITALIAN SITES ( 21 pts included; 9 randomized)
Principal Investigator Upadate IRCCS Istituto Nazionale Tumori – Milano Francesco Raspagliesi/ Domenica Lorusso Activated, 11 patients Istituto Nazionale Tumori Pascale - Napoli Sandro Pignata Waiting contract Policlinico Universitario A. Gemelli - Roma Giovanni Scambia Suspended IRCCS Arcispedale Santa Maria Nuova – Reggio Emilia Alessandra Bologna Refusal by the ethics committee CRO IRCCS - Aviano Roberto Sorio Activated, 1 patients AOU Federico II Sabino De Placido IRE-Istituto Nazionale Tumori REGINA ELENA - Roma Patrizia Vici Fondazione del Piemonte per l'Oncologia - Istituto di Candiolo Giorgio Valabrega Activated U.O.Oncologia Medica - Ospedale Vito Fazzi - Lecce Graziana Ronzino ULLS 13, Mirano - Venezia Grazia Artioli Activated, 5 patients Casa Sollievo della Sofferenza - S.Giovanni Rotondo Francesco Petruzzelli Fondazione IRCCS Policlinico S.Matteo di Pavia Stefano Bogliolo Ospedale SS.Trinità - Sora Teresa Gamucci No updates AULSS 21 LEGNAGO Filippo Greco Activated, 2 patients Ospedale di Sassuolo Giovanni Partesotti

13 PRIMA Trial Design 450 pts

14 Inclusion criteria

15 Accrual close on February 2018

16 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

17 PLD Rechallenge: Efficacy
PLD first use PLD second use CR PR SD Total PD PLD 0 (0%) 4 (100%) 4 3 (23.1%) 4 (30.8%) 13 Carboplatino-PLD 10 (45.4%) 1 (4.5%) 22 3 (60%) 1 (20%) 5 Trabectedina-PLD 1 (100%) 1 2 (22.2%) 1 (11.1%) 6 (66.7%) 9 11 (40.7%) 14 (51.8%) 1 (3.7%) 27 5 (18.5%) 8 (29.6%) 10 (37.0%) 4 (14.8%)

18 Table 2. Side effect at first treatment with PLD
Toxicity Grade 1 (%) Grade 2 (%) Grade 3 (%) Grade 4 (%) Grade 5 (%) 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 Neurologic Toxicity 1 (3.7) Cardiologic Toxicity

19 Table 3. Side effect rechallenge with PLD
Toxicity Grade 1 (%) Grade 2 (%) Grade 3 (%) Grade 4 (%) Grade 5 (%) 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 Neurologic Toxicity Cardiologic Toxicity

20 OVAIO RECIDIVA PLATINO SENSIBILE
MITO 17 (INT Napoli) Retrospetive trial on tertiary cytoreductive surgery in recurrent ovarian cancer MITO 18 Horse (Policlinico Gemelli Roma) ENGOT –OV 27 (INT Napoli) Farletuzumab in platinum sensitive ovarian cancer with low (<105 u/mL) CA125 (INT Napoli) ICON 9 (Policlinico Gemelli Roma) BACO study (Policlinico Gemelli Roma) Coming soon: OREO OVAIO RECIDIVA PLATINO SENSIBILE

21 Tertiary cytoreductive surgery in recurrent epithelial ovarian cancer:
a multicentre retrospective study 17 Published on Gynecologic Oncology on July 2017

22 Tertiary cytoreductive surgery in recurrent epithelial ovarian cancer
a multicentre retrospective study Study design Multicenter, retrospective Objectives To evaluate the impact of TCS on survival; To determine predictors of complete TCS; To formulate a hypothesis for selection criteria/predictive factors for successful complete TCS (such hypothesis is intended to form the basis for a subsequently planned prospective trial evaluating a predictive model for complete TCS in recurrent EOC).

23 Tertiary cytoreductive surgery in recurrent epithelial ovarian cancer
a multicentre retrospective study Inclusion criteria - Patients with a second relapse of EOC (including tubal and peritoneal epithelial cancers) undergoing elective TCS during the period ; - PS according to ECOG 0 – 1; - TFI ≥6 months after completion of first−/second−line therapy. Exclusion criteria - patients operated on for strictly palliative purposes; - performance status according to ECOG >1; - serological recurrence only (CA125 serum levels >35 UI/mL); - non-epithelial or borderline tumors; - TFI <6 months after completion of first−/second−line therapy; - patients with second malignancies who had been treated by laparotomy or who had a therapy that could interfere with the treatment of relapsed ovarian cancer.

24 Tertiary cytoreductive surgery in recurrent epithelial ovarian cancer
a multicentre retrospective study An appropriate data-base has been designed and will be available online to participating centers Centralised analysis c/o NCI – Naples Data Center CONTACT INFORMATION: STEFANO GREGGI, MD, PhD

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 Inclusion Criteria Exclusion Criteria
years -first recurrence of EOC with measurable or not measurable lesions, but evaluable (upwards of Ca125 for 2 consecutive assessments). -ECOG-performance status ≤ 2 -disease limited to the abdominal cavity with or without extraperitoneal spread considered resectable at intraoperative evaluation -recurrence after ≥6 months from primary treatment -Previous-based chemotherapy of carboplatin and taxanes -Peritoneal Washing-positive in the presence of other abdominal disease surgically resectable -Adequate respiratory, hepatic, cardiac, kidney and bone marrow function -Patient compliant and psychologically able to follow the trial procedures Exclusion Criteria - Non-epithelial ovarian cancer or borderline ovarian tumor - Pregnancy or breastfeeding - Major depressive disorder even in treatment or minor mood disorders - Impairment of bone marrow, respiratory, hepatic or renal function -Cardiac, neurological or metabolic uncontrolled disease - Active infection or other neoplastic disease in progress -Bowel obstruction -No clear-peritoneal disease at surgical exploration - Ascites> 500 ml (the TAC) -Secondary or tertiary recurrence, or previous HIPEC, or previous second or third line chemotherapy.

27 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 temperature 41.5C for 60 min 79 HIPEC NO 79 HIPEC YES Pl based CHT Pl based CHT Drop-out FU FU Drop-out

28 Status: On going Enrollement 149 patients 74 ARM A 75 ARM B

29 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 113 57 56 003 Casa di cura Fondazione Giovanni Paolo II Campobasso Vito Chiantera 7 2 5 005 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 6 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 15 8 038 IRCCS Centro di Riferimento Oncologico CRO Aviano (PN) Giorgio Giorda 046 AUSLL 11 di Empoli Ospedale San Giuseppe Empoli (FI) PI Marco Filippeschi - SOMMA 149 74 75

30 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) Primary endpoint: PFS * (Assumed HR = 0.667, investigator read) Secondary endpoints: OS, Pt free interval, OR, TTR, DR, safety, PK and exposure-response

31 ENGOT-ov27 169/210 patients randomized
REGION COUNTRY DATA SITES ACTIVATED SUBJECT ENROLLMENT # of countries Name Ever opened for Recruitment Screened Randomized Europe 5 Italy 12 46 25 Spain 9 34 Belgium 7 24 14 Germany 11 UK 3 4 North America 1 US 44 121 77 Asia-Pacific Japan 8 26 19 Total 92 267 169

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34 618 patients to enroll

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36 6 MITO CENTERS + 5 MANGO CENTERS
Centre Clinician/datamanager Expected no./year 1 Candiolo (TO) Oncologia Medica IRCC Università degli Studi di Torino Giorgio Valabrega/Celeste Cagnazzo 6 2 Roma Ginecologia Oncologica Policlinico A Gemelli Giovanni Scambia, Vanda Salutari/Michela Panella 10 3 Napoli Oncologia Medica Istituto Nazionale Tumori Fondazione G. Pascale Sandro Pignata/Jane Brice 8-10 4 Milano Ginecologia Istituto Nazionale Tumori Domenica Lorusso/Iolanda Pulice 5 Brindisi Oncologia Medica A.O. “A. Perrino” di Brindisi Saverio Cinieri/Pasqualinda Ferrara 5-8 Bologna Oncologia Ospedale S.Orsola Malpighi Università di Bologna Claudio Zamagni TOTAL 44-52 The UK approvals have been received (from ethics and MHRA – regulators). First Patient In (UK) expected in March/April With regards to the Italian level: Research Agreement currently drafting

37 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

38 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

39 CENTRO 002 RASPAGLESI - MILANO
CENTRI Blocchetti tissutali disponibili status CENTRO 001 SCAMBIA - ROMA 12 spediti CENTRO 002 RASPAGLESI - MILANO 17 OK CE , in attesa agrement campioni biologici UCSC CENTRO 011 MOSCONI - PERUGIA 7 Attesa CE CENTRO 013 SABBATINI - MODENA 5 CENTRO 021 ARTIOLI - MIRANO 3 pronti CENTRO 030 PIGNATA - NAPOLI 16 CENTRO 039 SORIO - AVIANO 8

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 14 AGGIORNAMENTO Dott. Enrico Breda

42 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

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45 Mito 22 criteri di inclusione LGSOC/Recidiva Invasiva di SBLT operato
Diagnosi posta tra e il Preparato istologico per revisione centralizzata Età > 18 aa EMENDARE?? …SI POTREBBE SPOSTARE IL TERMINE DELLA DATA DIAGNOSI ALL’ INT Napoli Ist Regina Elena CRO Aviano Pol Univ A. Gemelli Roma

46 Mito 22: 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

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

48 In corso inserimento dei dati nel data base, emissione queries
Dati per Riunione MITO di Giugno STUDIO OSSERVAZIONALE SUL TRATTAMENTO DEI TUMORI A PICCOLE CELLULE DELL’APPARATO GENITALE

49 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

50 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

51 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

52 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

53 Enrollment closed on

54 ITALIAN SITES AIFA approved on 01.12.2015
Principal Investigator Patient enrolled Istituto Nazionale Tumori – Milano – Coordinating center Domenica Lorusso 4 patients Istituto Tumori Pascale - Napoli Sandro Pignata 3 patients Ospedale San Raffaele - Milano Giorgia Mangili 1 patient IRST di Meldola Ugo De Giorgi -

55 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

56 15 CENTRI PARTECIPANTI PZ ATTESE: 300 PZ ARRUOLATE: 338 CENTRO MITO
Referente Pz arruolate (n) 1. Centro Coordinatore OncoEmatologia MIRANO (VE) Artioli G, Borgato L 25 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 8. Oncologia – LEGNAGO (VR) Greco F 14 9. IRCCS Osp. Oncologico (BARI) Kardhashi 8 10. Oncologia Medica (AVELLINO) Gridelli C, Rossi E 11 11. IRST Meldola U. De Giorgi 7 12. Oncologia- FBF Roma I.Spagnoletti 6 13. Oncologia ,Osp. Napoli M.Orditura 5 14. Oncologia, Osp Santa Maria della Misericordia , Perugia Mosconi 15. Oncologia , Osp S. Matteo – Pavia S.Bogliolo 3 TOTALE 338 PZ ATTESE: 300 PZ ARRUOLATE: 338

57 ARRUOLAMENTO chiuso: termine dello studio Dicembre 2017
ANALISI IN CORSO PUBBLICAZIONI: presentazione poster ESGO 2017 Per il 2018 Abstract ESMO 2018 Scrivere paper sui doppi tumori Breast and ovarian cancer

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59 CARCINOMA DELL’ENDOMETRIO
Trattamento conservativo : ECCO study (INT Napoli) Linfonodo sentinella nel carcinoma della cervice (INT Milano) ENGOT EN2-EORTC (Mauriziano-Torino) 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. In attivazione: SIENDO STUDY (Coordinato Candiolo Torino): Coming Soon MITO END 3 (INT-Napoli): Studio randomizzato di fase 2 con Avelumab in combinazione a Carboplatino-paclitaxel vs Carboplatino-Paclitaxel nel carcinoma metastatico/avanzato

60 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

61 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)

62 N° of patients registered
E.C.Co. Endometrial Cancer Conservative treatment A multicentre archive Participation (15/01/2018) 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 Department for Gynecologic Oncology, University of Vienna. Austria 745 Stephan Polterauer September 2017 San Raffaele Hospital, Milan. Italy 321 Patrizia De Marzi October 2015 4 University of Bari, Bari. Italy 111 Gennaro Cormio 1 National Cancer Institute of Rome, Rome. Italy 741 - July 2016 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 62

63 160 Pazienti con ca endometrio tipo I-II early, stadio FIGO I-II
PROTOCOLLO Iniezione isteroscopica vs. cervicale di tracciante per identificazione del linfonodo sentinella nel tumore dell’endometrio: studio randomizzato, multicentrico P I Dr Antonino Ditto, M.D. 160 Pazienti con ca endometrio tipo I-II early, stadio FIGO I-II Work-up and Lps : assenza di diffusione peritoneale e/o linfonodi bulky RANDOMIZZAZIONE 1-1 Inoculo cervicale N= 80 Identificazione ed asportazione linfonodi sentinella pelvici e/o para-aortici Ultrastaging Inoculo endometriale N=80 La linfoadenectomia sistematica è lasciata alla discrezione del chirurgo

64 Centri partecipanti allo studio:
INT Milano; PI. Dr Ditto; Dr. Raspagliesi; Dr Martinelli; Dr Bogani; H San Orsola - Bologna : Dr Perrone; Dr De Iaco; Attivato Ospedale dell’Insubria Varese; Prof. Ghezzi Istituto Tumori Regina Elena Roma, Dr Vizza e Dr Savarese - in corso procedure finali per l’attivazione Ospedale Careggi Firenze; Dr Cariti; Dr Tarani.

65 Stato Avanzamento lavori PI. Dr Ditto
Protocollo attivato presso INT Milano dal 27/3/2017 ; Arruolati 29 pazienti - 1 drop out per carcinosi nel douglas

66 Randomized till date = 192/240
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 = 192/240

67 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

68 Postoperative chemotherapy or no further treatment for patients with node-negative stage I-II intermediate or high risk endometrial cancer ENGOT-EN2-DGCG NCT INSTITUTIONS PI RANDOMIZED PATIENTS Istituto Nazionale Tumori “G. Pascale”, Naples AUTORIZZATO Stefano Greggi 5 Istituto Nazionale Tumori, Milano Domenica Lorusso Istituto Nazionale Tumori “Regina Elena”, Roma Enrico Vizza  - Università Cattolica del Sacro Cuore, Roma Giovanni Scambia Università di Bologna, Bologna Pierandrea De Iaco Università di Bari, Bari Gennaro Cormio Ospedale di Faenza (Ravenna) Stefano Tamberi Ist. Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola (Forlí) Ugo De Giorgi Centro di  Riferimento Oncologico, Aviano Giorgio Giorda

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70 CENTRI MITO Centre 1 Candiolo (TO) Oncologia Medica
Centre 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

71 15 (di 78) pazienti sono stati randomizzati
Danimarca : 3/4 centri aperti, 11 patienti arruolati Finlandia: 1/2 centri aperti , 0 pazienti arruolati Norvegia : 2/2 centri aperti, 1 paziente arruolato GEICO (Spagna): 5/5 centri aperti, 3 pazienti arruolati NOGGO (Germania): 4/6 centri aperti, 0 pazienti arruolati MITO (Italia): 0/6 centri aperti, in attesa di approvazione finale AIFA e EC

72 CARCINOMA DELLA CERVICE UTERINA
BGOG-CX1 (INT Napoli) Nintedanib in cervical cancer In attivazione: Studio RASUCE (INT-Milano) Radicalita’ chirurgica dopo NACT nel ca localmente avanzato della cervice - Studio Abrax (INT Milano) Linfonodo sentinella nella cervice uterina

73 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

74 BGOG-cx1: study design primary endpoint PFS
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

75 Timelines BGOG-cx1: study update Milestone Estimated timing
First patient in March 2014 Last patient in August 2018 Last patient out August 2020 Primary analysis 1,5 y after LPI (March 2020) Secondary analysis 5 y after LPI (August 2023)

76 BGOG-cx1: study update Enrollment graph Group n. Pts. enrolled BGOG 39
GEICO 23 NOGGO 15 MITO-MaNGO 10 Total 87 87 patients

77 BGOG-cx1: study update Site activations Italy Site Group
Expected Accrual Activation Accrual 39001 MITO Istituto Nazionale Tumori-Pascale Napoli - Dr. Pignata 3-6 2/2/2017 1 39002 National Cancer Institute Milano – Dr. Lorusso 8-10 16/5/2017 7 39003 Centro Riferimento Oncologico – Dr. Sorio EXPECTED 01/2018 39004 Policlinico A Gemelli – Dr. Scambia 4-8 EXPECTED 02/2018 39005 Azienda Ospedaliera Cannizzaro – Dr. Scollo 39006 MaNGO Reggio Emilia – Dr. Bologna 4 ESITO NEGATIVO 39007 Pisa – University – Dr. Gadducci NOT EVALUATED 39008 Padova Istituto Oncologico Veneto – Dr. Nicoletto 9/01/2018 39009 Torino – S. Anna, Dr. Zola 2/5/2017 2 39010 Torino – Mauriziano, Dr. Ferrero 9/5/2017 39011 Brescia - Spedali Civili-Università di Brescia, Dr. Tognon TOTAL : 11 centers +/- 40 patients 10 patients

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