Claudia Marchetti Pierluigi Benedetti Panici Randomized phase II randomized trial on Letrozole vs clinician’s choice chemotherapy in heavily pretreated recurrent ovarian, primary peritoneal or fallopian tube cancers MITO – XX Claudia Marchetti Pierluigi Benedetti Panici

` A maximum of three lines of subsequent relapse treatment seems to be beneficial for patients with recurrent ovarian cancer. Optimal primary tumor debulking and platinum sensitivity remain independent prognostic factors even after more frequent relapses.

RATIONALE AND BACKGROUND

RATIONALE AND BACKGROUND DETERMINAZIONE DELL'AGENZIA ITALIANA DEL FARMACO, 9 DICEMBRE 2008 (Gazzetta Ufficiale n. 1 del 02.01.09, Supplemento ordinario n. 1)

Recurrent ovarian, primary peritoneal or fallopian tube cancers Platinum resistant/refractory >3 lines CT Physician’s choice Random1:1 Recurrent ovarian, primary peritoneal or fallopian tube cancers Letrozole, Oral 2.5 mg daily 5

STUDY OBJECTIVES Primary: DCR= 12-week disease control rate (DCR; CR, PR or SD; according to RECIST v1.1) Secondary: Quality of life using the QLQ-C30 and QLQ-0V28, FOSI (every 3 /4 weeks) TSST PFS OS Radiological response rate (in patients with measurable disease) Duration of response CA-125 response rate per GCIG Toxicity profile Biomarker analysis (ER status) PROs were assessed with three instruments: European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire C30 (EORTC QLQ-C30),5 EORTC QLQ Ovarian Cancer Module 28 (OV28),6 and the eight-item Functional Assessment of Cancer Therapy–Ovarian Cancer Symptom Index (FOSI). 6

INCLUSION CRITERIA Female of age 18 years or older Histologically or cytologically documented invasive epithelial ovarian cancer, primary peritoneal carcinoma, or fallopian tube cancer Platinum resistant or refractory >3 previous chemotherapy lines primary tumor specimen available for measurement of biochemical markers ECOG performance status 0 -2 Measurable and evaluable disease per RECIST 1.1(Subjects with isolated rising CA-125 without radiologically visible disease are excluded) Left Ventricular Ejection Fraction (LVEF) ≥ institutional lower limit normal Adequate organ functions 7

EXCLUSION CRITERIA Known hypersensitivity to any of the components of the trabectedin i.v. formulation or dexamethasone Subjects with borderline ovarian cancer, ie. Subject with low malignant potential tumors are excluded Less than 3 lines of previous therapy Platinum sensitive diseaseor refractory primary tumor specimen unavailable for measurement of biochemical markers Less than 4 weeks from last dose of therapy with any investigational agent, or chemotherapy History of another neoplastic disease (except basal cell carcinoma or cervical carcinoma in situ adequately treated) unless in remission for 3 years or longer 8

STATISTICS PROTOCOL Phase II randomized PICK-THE-WINNER The sample size in this trial was decided to be either 40 or 100 patients depending on the results of the interim efficacy analysis. DCR at week 12 for patients treated with an investigator choice of chemotherapy was assumed to be 30%. The number of patients in the trial would be chosen to give a probability of 67% of correctly picking the letrozole treatment arm as the winner if the DCR for the letrozole arm was 35%. 2-step trial design allowed for an early safety analysis after random assignment of 40 patients (20 per arm) and treatment of at least 12 weeks and after radiological assessment. The trial will continue continue if either > 1 of the first 12 patients with at least one measurable lesion included in the letrozole arm had a complete response (CR) or PR at weeks 6 or 12, or if > 5 of the first 20 patients included in the letrozole arm showed a CR, PR, or stable disease (SD) at week 12. All treated patients who received at least one cycle of letrozole or chemotherapy will be included in the safety and efficacy analyses. 9

ADMINISTRATIVE INFORMATION Academic trial Sapienza University of Roma sponsor Data center: Sapienza of Roma (MITO center) Planned study start: April 2017 Epionpharma support: financial support for insurance, IHC and data management. MITO - 23 10