MITO 8, 11, CERV2

MITO 8 ENGOT-OV1 A PHASE III INTERNATIONAL MULTICENTRE RANDOMIZED STUDY TESTING THE EFFECT ON SURVIVAL OF PROLONGING PLATINUM-FREE INTERVAL IN PATIENTS WITH OVARIAN CANCER RECURRING BETWEEN 6 AND 12 MONTHS AFTER PREVIOUS PLATINUM BASED CHEMOTHERAPY

Study design (version 2.0)

Facts and Figures 01/12/2014: 208 pts

Studio multicentrico di fase III, prospettico, randomizzato, in aperto a due bracci (1:1) Lo studio è dimensionato sulla sopravvivenza globale, con i seguenti parametri statistici: –errore alfa bilaterale: 0.05 –potenza statistica: 80% –sopravvivenza attesa nel braccio classico (CP  PLD): 18 mesi –sopravvivenza auspicata nel braccio con sequenza inversa (PLD  CP): 27 mesi –hazard ratio: 0.67 –eventi necessari per l’analisi finale: 193 (che si presume verranno registrati entro 5 anni dall’inizio dello studio, prevedendo l’arruolamento di 10 pazienti per mese) –pazienti da arruolare: 250 Non sono previste analisi ad interim Disegno dello studio

Centres enrolling within the last year CentroCod.N. Paz.Data ult. arruol. Divisione Ginecologia Oncologica - Istituto Nazionale Tumori-Milano(MI) /11/2014 Dip. Interaziendale di Oncologia Az.Osp.di Udine S. Maria della Misericordia-Udine(UD)109522/09/2014 U. O. di Ginecologia Oncologica Dip. di Ginecologia ed Ostetricia Policlinico Universitario Gemelli Università Cattolica del Sacro Cuore- Roma(RM) /09/2014 UZ Leuven-Gynecological Oncology-Leuven(Leuven)364710/09/2014 Divisione di Oncologia Medica - Dipartimento Uro-Ginecologico - Istituto Nazionale Tumori-Napoli()14123/07/2014 Ospedale Senatore Antonio Perrino-Oncologia Medica-Brindisi(BR)344517/06/2014 Div. Oncologia Medica Az. Ospedaliera Bianchi Melacrino Morelli Osp. Riuniti-Reggio Calabria(RC)97106/06/2014 U.O. di Oncologia Medica Ospedale S. Chiara-Trento(TN) /05/2014 Osp. S. Massimo-Penne(PE)216402/12/2013 Oncologia Medica - Arcispedale S. Maria Nuova-Reggio Emilia(Reggio Emilia)365812/11/2013

MITO 11 A RANDOMIZED MULTICENTRE PHASE II TRIAL WITH PAZOPANIB AND WEEKLY PACLITAXEL VS WEEKLY PACLITAXEL IN PLATINUM RESISTANT OR REFRACTORY OVARIAN CANCER

Study Outline RANDOM Pazopanib 800 mg/daily + Paclitaxel 80 mg/m 2 d 1, 8, 15, q 28 Primary endpoint: PFS (61 events needed) Both until disease progression or unacceptable toxicity

Patients’ Flow ITT: intention to treat Paclitaxel (wPac) 37 pts PFS analysis (ITT) 36 pts Randomized 74 pts Paclitaxel + Pazopanib (wPP) 37 pts PFS analysis (ITT) 37 pts Consent withdrawn: 1 case

Progression-free survival Probability of PFS Months Patients at risk wPac wPP N Events Median (months) 95% CI wPac wPP tailed P= HR 0.42 (95% CI )

Overall survival Probability of OS NEven ts Median (months) 95% CI wPac NA wPP NA 1-tailed P=0.056HR 0.60 (95% CI ) Patients at risk wP WPP

Activity Analysis (RECIST 1.1) wPac N=33 wPP N=35 p Responders - CR+PR9 (27%) [95%CI: 15%-44%] 20 (57%) [95%CI: 41%-72%] CR1 (4%)3 (9%) PR8 (24%)17 (49%) *All the responses were confirmed at CA125 response analysis

News Results of the trial presented: –ASCO 2014 AM: Oral Abstract Session Gynae –AIOM 2014: Sessione Plenaria Draft of the manuscript has been produced and will be shared shortly among the authors.

MITO CERV-2 A RANDOMIZED PHASE II STUDY OF CARBOPLATIN AND PACLITAXEL +/- CETUXIMAB, IN ADVANCED AND/OR RECURRENT CERVICAL CANCER

Study Outline RANDOM Carbo AUC 5 + Paclitaxel 175 mg/mq q 21 Primary endpoint: Event-free survival (EFS, 89 events needed) Carbo AUC 5 + Paclitaxel 175 mg/mq + Cetuximab 400 mg/m² one week before starting carboplatin and paclitaxel then 250 mg/m² day 1, weekly Chemotherapy is given for a maximum of 6 cycles Cetuximab will be continued until disease progression or unacceptable toxicity

Amendment 1 The study has been amended to introduce a biologic study, looking for possible interactions of cetuximab with tumor mutations (22 genes including all RAS) Analyses will be performed at the Laboratory of Cellular Biology and Biotherapy at the Research Department of the NCI Naples

Operatively The coordinating IEC has approved the amendment 1 on April 16 th 2014 The approved amendment has been submitted during the last week to the participating IEC After the approval, patients will be proposed to sign an addendum to the consent form and a paraffin block from primary surgery or biopsy will be collected

Actions: proposed timeline DEC 2014: collection of samples JAN 2015: L-B ABSTRACT to ASCO 2015 MAY 2015: Final analysis for the ASCO abstract JUNE 2015: Final Study Report and final manuscript first draft