A phase I study of veliparib incorporated into front-line platinum based cheotherpy and bevacizumab in epithelial ovarian cancer (NCT00989651): A GOG/nrg trial.

Abstract

5523 Background: Veliparib, a poly-(ADP-ribose)-polymerase inhibitor, increases anti-tumor activity when combined with platinum chemotherapy and has monotherapy activity in BRCA deficient tumors. This study was done to determine the recommended phase II dose (RP2D) of veliparib in combination with front line treatment for epithelial ovarian cancer (EOC). Methods: Eligible patients had newly diagnosed, stage II-IV EOC. Six regimens were evaluated, 3 variations of chemo delivery with either continuous (D1-21) or intermittent (days-2-5) veliparib BID. Chemo included 1: IV q3week carboplatin (C) (AUC 6) and paclitaxel(T) (175mg/m2); 2, IV q3week C (AUC 6) and weekly T(80mg/m2); and 3, IV T (135mg/m2, day 1), IP cisplatin (75mg/m2, day 1 or 2) and IP T (60mg/m2, day 8). Bevacizumab 15mg/kg started cycle 2 and continued as monotherapy cycles 7-22. A 3+3 dose escalation design evaluated dose-limiting toxicities (DLTs) in cycles 1 and 2. Once < 2/6 patients experienced a DLT, that dose level was expanded to evaluate feasibility over 4 cycles. Results: The study accrued 424 treated patients. For regimen 1, continuous (Reg1c) the maximum tolerated dose (MTD) was 250mg veliparib BID but the feasible dose was found to be 150mg BID. For regimen 1, intermittent (Reg1i) the MTD and feasible dose were 400 and 250mg BID respectively. For Reg2c the MTD and feasible dose were the same at 150mg BID. For Reg2i the MTD and feasible dose were 250 and 150mg BID respectively. For Reg3c the MTD and feasible dose are both 150mg BID and for Reg3i, the MTD was 400mg BID and the feasible dose felt to be 300mg BID. Median PFS by residual disease and BRCA status is: (Positive residual disease) 14.6, 19.1 and 16.9 months for BRCA+, BRCAwt and BRCA ukn respectively. For no gross residual disease the PFS is NR, 34.2 and 24.5 months respectively. Conclusions: Given the difficulty with toxicity not defined as a DLT, the RP2D for all regimens is veliparib 150mg BID. This data informed the dose that moved into the phase III trial GOG 3005/Velia: NCT02470585. Velia also incorporated maintenance veliparib instead of maintenance bevacizumab among all high grade serous patients (BRCA+ and wt). These results will determine utilization of veliparib in this space. Clinical trial information: NCT00989651.