A phase II study of Navitoclax (ABT-263) as single agent in women heavily pretreated for recurrent epithelial ovarian cancer: The MONAVI - GINECO study.

Background: There are limited treatment options for ovarian cancer patients with early relapse after platinum chemotherapy. In preclinical studies, we previously demonstrated the promising activity of ABT-737, a Bcl-2/Bcl-x _L anti-apoptotic protein inhibitor, in chemo-resistant ovarian cancer cells and tumors, suggesting its potential activity in platinum-resistant patients.
Methods: We conducted a prospective multicenter single-arm phase II study to assess the efficacy of Navitoclax (orally available ABT-737 analogue) monotherapy in 46 heavily pretreated (2-12 lines, median = 4) patients with high-grade serous platinum-resistant ovarian tumors. Navitoclax was administered at the daily dose of 150 mg during a lead-in period (7-14 days) and then increased to 250 mg daily in the absence of dose-limiting thrombocytopenia (<G3). Progression-free survival (PFS) based on RECIST v1.1 criteria was the primary endpoint. Analysis of efficacy according to the expression of Bcl-2 family proteins in tumor biopsies was also planned.
Results: The 3-month PFS was 22.7% [ _95% CI: 13.2-39.2], median PFS was 1.64 months [ _95% CI: 1.58-2.30]. There were 16 (35.6%, _95% CI: 22.3-51.3) overall responses (RECIST v1.1): 1 partial response and 15 stable diseases. No correlation between the expression of Bim, Mcl-1 and P-ERK with clinical response was found in this study. Thrombocytopenia was the major side-effect (G3/4: n = 12; 26%), leading to pursue at the daily dose of 150 mg in 8 patients and to discontinue treatment in 3 patients. Neither significant bleeding nor toxic death were observed.
Conclusions: Navitoclax monotherapy had poor activity that was not correlated with the expression of Bim, Mcl-1 and P-ERK, without unacceptable toxicity.
Trial Registration: Clinicaltrials.gov identifier: NCT02591095.
Competing Interests: Declaration of Competing Interest F. Joly: Abbvie for Navitoclax provision, consulting for Roche, GSK, Astra Zeneca, Clovis, MSD, Ipsen, Janssen, Astellas, Pfizer, Sanofi, BMS, Bayer. M. Fabbro: Consulting for GSK, Astra-Zeneca, and Clovis Oncology. P. Follana: GSK, Astra Zeneca, Clovis, MSD, Novartis, DAIICHI. J.S. Frenel: Consulting for Novartis, Pfizer, Astra Zeneca, Lilly, Roche, BIOCAD, DAIICHI, GSK-Tesaro, Pierre Fabre, and Clovis oncology. B.You: Consulting for MSD, Astra-Zeneca, GSK-TESARO, BAYER, Roche-Genentech, ECS Progastrine, Novartis, LEK, Amgen, Clovis Oncology, Merck Serono, BMS, SEAGEN, and Myriad. J. Lequesne, J. Medioni, A. Lesoin, S. Abadie-Lacourtoisie, A. Floquet, L. Gladieff, C. Gavoille, E. Kalbacher, M. Briand, P.E. Brachet, F. Giffard, L-B. Weiswald, P.A. Just, C. Blanc-Fournier, A. Leconte, B. Clarisse, A. Leary, L. Poulain: no conflicts of interest to disclose in relation with this work.
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