MITO 29 Randomized Phase II study on Decitabine plus Carboplatin versus physician’s choice chemotherapy in recurrent, platinum-resistant ovarian cancer

Rationale Tumors can be driven by patterns of altered gene expression that are mediated by mechanisms of epigenetic regulation, such as DNA methylation. 2. DNA demethylation has the potential to reverse promoter hypermethylation in tumor cells and lead to the reexpression of aberrantly silenced genes, such as tumor suppressor genes (TSGs) and to induce the sensitivity of tumor cell to anticancer agents. 3. Decitabine is a cytidine nucleoside analog able to inactivate DNA methyltransferases (DNMTs) thus reversing DNA hypermethylation. Inhibition of cytosine methylation by decitabine has been shown to correlate with the re-expression of silenced genes and, in tumor cells the re-expression of tumor suppressor gene products 4. DAC has also been proposed to possess immunomodulatory activity that is mediated by the restoration of the proper expression of immune receptors and their ligands. 5. Several preclinical studies of ovarian cancer have indicated that hypomethylating agents, including the deoxycytidine analog decitabine, can reverse platinum resistance in chemoresistant cancer cell lines and mouse-engrafted tumors MITO 29

Rationale for the dose Fong et al in a phase I-II clinical trial reported that decitabine 10 mg/mq, administered dd 1-5 q28 in combination with carboplatin AUC 5 d8 q 28, resulted in 35% RR in platinum-resistant OC patients and 9 of 17 treated patients (53%) were free of disease pogression at 6 months. Most common toxicities were nausea, allergic reactions, neutropenia, fatigue, anorexia, vomiting, and abdominal pain, the majority being grades 1-2. Glasspol et al in a randomized trial on decitabine (90 mg/mq d1 q 28) plus carboplatin (AUC 6 d1 q 28) vs carboplatin alone in 15 platinum sensitive recurrent ovarian cancer patients reported the lack of efficacy and poor treatment tolerability for combination; The authors concluded that with this schedule, the addition of decitabine appears to reduce rather than increase the efficacy of carboplatin in partially platinum-sensitive ovarian cancer and is difficult to deliver and that different patient-selection strategies and different schedules should be considered in future combination studies.

Study design Random1.1 MITO 29 ARM A: Inclusion criteria: Platinum resistant (no refractory) OC, primary peritoneal and fallopian tube patients No more than 2 previous chemotherapy lines Stratification factors: number of previous chemotherapy lines (1 vs 2); presence / absence of measurable disease. Random1.1 ARM A: Carboplatin AUC5 d 8 q28 plus Decitabine 10 mg/mq iv d1-5 q28 ARM B: Pegylated Liposomal Doxorubicin 40 mg/mq q28 Gemcitabine 1000 mg/mq dd 1, 8, 15 q28 Weekly Paclitaxel 80 mg/ m2 dd 1, 8, 15 q28 Subjects will continue to receive chemotherapy treatment until disease progression, intolerability, withdrawal of consent, investigator decision or death from any cause. MITO 29

Objectives Primary: Secondary: To compare the treatment groups in terms of progression free survival (PFS) Secondary: - Overall survival (OS) - Radiological response rate (in patients with measurable disease) - Duration of response - CA-125 response rate per GCIG and change in CA-125 - Toxicity profile Quality of life will be evaluated using the FACT-O and FACT-O ovarian cancer-specific subscale (OCS) questionnaire. MITO 29

Inclusion Criteria MITO 29   Cytologic / histologic diagnosis of stage IC-IV epithelial, fallopian tube and primary peritoneal cancer (carcinosarcomas are included); Patient could have received no more than 2 prior lines of treatments; Patient relapsed within 1- 6 months after platinum containing regimen; Disease measurable or evaluable by RECIST version 1.1; No residual peripheral neurotoxicity > Grade 1 from previous chemotherapy treatment; PS 0-1; Age ³ 18 years; Life expectancy of at least 3 months; Written informed consent prior to performance of study specific procedures or assessments; Ability and willingness to comply with treatment and follow up assessments and procedures; Adequate organ functions; No other invasive malignancy within the past 3 years except non-melanoma skin cancer and in situ cervical cancer; Absence of any psychological, familial, sociological or geographical conditions potentially hampering compliance with the study protocol and follow-up schedule. MITO 29

Statistical consideration This is a randomize phase II trial. The sample size is based on the primary efficacy endpoint, PFS. Because of the nature of the study design, randomized phase II, relaxed statistical parameters were used (one-sided alfa 0.10, beta 80%) The required sample size was calculated assuming exponential distributions and that a median PFS of 3 months from study drug administration would be observed in the wPTX /PLD/GEM (control arm). Overall, 119 patients and 112 events were needed to detect an improvement with Carboplatin-Decitabine (experimental arm) in median PFS to 4.5 months, corresponding to a hazard ratio (HR) of 0.667, based on a one-sided log-rank test at the error alpha=0.10 (one-sided) and a power of 80%. Expecting ~10% of dropout, a total of 132 patients will be enrolled. Supposing a recruitment rate of 2 patients/week it is expected to complete the recruitment in ~1.6 years. MITO 29

Administrative Information Academic trial NCI of Milan sponsor Data center: NCI of Milan (MITO center) Planned study start: February 2018 Assurance and Decitabina provided Jansen Cilag support: Decitabina and financial support for data management, insurance and drug management; 15 MITO centres engaged Drug shipment: to be defined For information please contact: domenica.lorusso@istitutotumori.mi.it Iolanda.pulice@istitutotumori.mi.it MITO 29