MITO 26 PHASE II TRIAL ON TRABECTEDIN IN THE TREATMENT OF ADVANCED UTERINE AND OVARIAN CARCINOSARCOMA (CS)

Study design Study Drug This is a Phase II, multi-centre, single arm study aiming at evaluating efficacy and toxicity of Trabectedin in a population of advanced or recurrent uterine and ovarian carcinosarcoma. A central revision of slides is required. Dr Carcangiu (National Cancer Institute of Milan) and Dr Losito (National Cancer Institute of Naples) will provide the revision. For any patient 4 x 10 μm unstained slides and 5x 4μm stained H&E slides must be provided . Study Drug Trabectedin 1.3 mg/mq iv (central line) d1 q 21 until progression of disease, unacceptable toxicity or patient’s consent withdrawal MITO 26

Objectives Primary: To determine the activity in terms of objective response rate by RECIST version 1.1 (Complete and Partial Response [CR + PR]) with trabectedin in patients with advanced uterine and ovarian carcinosarcoma Secondary: Progression free survival; Overall survival; Duration of response; Toxicity. MITO 26

Inclusion Criteria Histologically documented Stage I-IV or recurrent uterine or ovarian carcinosarcoma not amenable to surgery or radiotherapy; No more than 2 previous chemotherapy lines; PS 0-2 (ECOG); Age> 18; Measurable disease; Life expectancy of at least 3 months; Adequate organ functions; Previous Brachytherapy treatment for uterine carcinosarcoma is allowed; No other invasive malignancy within the past 3 years except non-melanoma skin cancer; Written Informed Consent. MITO 26

Exclusion Criteria More than 2 previous chemotherapy lines;   More than 2 previous chemotherapy lines; Single tumor lesion inside a previous irradiated filed; Pregnant (potentially fertile patients must be not in pregnancy during and for at least 3 months after study participation and must have a negative serum pregnancy test); Active infection requiring antibiotics; Symptomatic peripheral neuropathy > grade 2 according to the NCI Common Toxicity Criteria; Congestive heart failure or angina pectoris even if it is medically controlled. Previous history of myocardial infarction within 1 year from study entry, uncontrolled high risk hypertension or arrhythmia; Unstable or severe intercurrent medical condition that, in the opinion of the investigator, might interfere with achievement of study objectives; Psychological or sociological conditions, addictive disorders, or family problems, which would preclude compliance with the protocol. MITO 26

Statistical consideration The study is planned according to Simon’s Optimal two-stage design. The primary endpoint of this study is to evaluate the activity of trabectedin in terms of the objective response rate (ORR) in patients with advanced uterine and ovarian carcinosarcoma. By considering the expected activity of the new regiment in this disease, the 25% benchmark rate will be adopted as H1 hypothesis, while a 10% rate of H0 hypothesis will be taken as comparator. In stage 1, 18 evaluable patients will be accrued. If 3 patient at least will be responding, enrolment will be extended to the 2nd stage for further 25 patients. If, out of the total of 43 patients, 8 at least will be responding, treatment will be declared worthy for further investigations. MITO 26

Administrative Information Academic trial NCI of Milan sponsor Data center: NCI of Milan (MITO center) Planned study start: February 2017 Pharmamar: drug supply Insurance provided by Coordinator center Approved by EC of NCI Milan on January 2017 Administrative contract in preparation domenica.lorusso@istitutotumori.mi.it Iolanda.pulice@istitutotumori.mi.it elisa.grassi@istitutotumori.mi.it MITO 26

MITO 26 STUDY 1. Dr.ssa Domenica Lorusso_Fondazione IRCCS Istituto Nazionale dei Tumori (Milano) 2. Dr. Stefano Tamberi_ Ospedale degli Infermi (Faenza e Lugo) 3. Dr. ssa Valentina Arcangeli_ Ospedale Infermi (Rimini) 4. Dr. Saverio Cinieri_P.O. “A.Perrino”-ASL Brindisi (Brindisi) 5. Dr. ssa Alessandra Bologna_ A.O. Santa Maria (Reggio Emilia) 6. Dr. ssa Patrizia Vici_Istituto Nazionale Regina Elena-IRE (Roma) 7. Dr. Sandro Pignata_ Istituto Tumori Pascale-IRCCS (Napoli) 8. Dr.ssa Rita Ceccherini_Centro Sociale Oncologico (Trieste) 9. Dr.ssa Giorgia Mangili_Ospedale San Raffaele ( Milano) 10. Dr.ssa Milena Sabrina Nicoloso_Centro di Riferimento Oncologico ( Aviano) 11. Dr.Claudio Zamagni_ Policlinico Sant’Orsola-Malpinghi ( Bologna) 12. Dr.Roberto Sabbatini_ AOU Policlinico di Modena ( Modena) 13. Dr.Daniele Fagnani_ASST Vimercate (Vimercate) 14. Dr.Alessandro Bertolini_ ASST della Valtellina e dell’Alto Lario ( Sondrio) 15. Dr.Giovanni Scambia_Fondazione Policlinico Agostino Gemelli (Roma) 16. Dr.Marco Marinaccio_ Policlinico di Bari-Ospedale Giovanni XXIII (Bari)