A phase 2 randomized study has indicated that the combination of a poly(ADP-ribose) polymerase inhibitor (PARPi) with an anti-angiogenic drug is superior to PARPi alone.
Bevacizumab 15 mg/kg IV q 21 days (fixed dose) was administered with escalating dose of niraparib capsules (100, 200, 300 mg daily) in a classic 3 + 3 escalation design. Platinum-sensitive ovarian cancer patients (pts) with high-grade serous/endometrioid carcinoma and with measurable disease (RECIST or GCIG criteria) were eligible. The primary objective was to evaluate the safety and tolerability of the bevacizumab-niraparib combination therapy and determine the RP2D of bevacizumab-niraparib.
Twelve pts (3 + 3+6) were enrolled to three dose levels. Three of 12 pts had gBRCA2 mutation, while the others were non-gBRCAmut. During the first cycle, patients experienced hypertension (G3=5 pts), anemia (G3=3 pts), thrombocytopenia (G3=1 pt), fatigue (G2=1 pt), constipation (G2=1 pt), and nausea (G2=1 pt). One dose-limiting toxicity (Grade 3 thrombocytopenia that persisted for ≥5 days) was observed at the highest dose level, and the RP2D is therefore bevacizumab 15 mg/kg with niraparib capsules 300 mg. Niraparib dose reductions occurred in four pts (cohort 2=1 pt; cohort 3=3 pts), and bevacizumab termination occurred in two pts. Three pts are still on treatment, while nine pts have discontinued treatment (8 progressive disease; 1 withdrawal of consent). Disease control rate was 91%, and response rate was 45% (1 CR; 4 PR). Niraparib pharmacokinetics were consistent with historical data. Overlapping exposure was observed across the dose range tested at both C1D1 and C2D1.
The bevacizumab-niraparib combination has hematologic dose-limiting toxicity and expected, manageable class toxicities with preliminary evidence of efficacy. The PK profiles of niraparib co-administered with bevacizumab are similar to historical data. A phase 2 randomized 2-arm trial is ongoing (AVANOVA2, NCT02354131).
Clinical trial identification
Legal entity responsible for the study
Nordic Society for Gynaecologic Oncology
M.R. Mirza: Advisory board: Tesaro, Roche, AstraZeneca & Clovis Oncology. J. Wang, X. Wang, Z-Y. Zhang, V. Kansra: Employment: Tesaro; Stock: Tesaro. M. Mau-Sørensen: Research grants and support to participate in conferences from Roche. S. Malander: Honoraria: AstraZeneca, Roche. All other authors have declared no conflicts of interest.