Trial Design

The primary objective was to determine the maximum tolerated dose (MTD) of veliparib administered daily for 14 days of a 21-day cycle in combination with cisplatin and vinorelbine. Secondary objectives were to assess the safety, tolerability, pharmacokinetic (PK) profile, and preliminary efficacy of the combination, and to quantify PARP inhibition at various dose levels. An exploratory objective was to identify potential biomarkers of response to this PARP inhibition/platinum-based chemotherapy regimen.

This trial [ClinicalTrials.gov: NCT0110429] was conducted at the University of Washington under an investigator initiated IND with Institutional Review Board approval. Veliparib was supplied by Abbott Laboratories (AbbVie).

Cisplatin was administered at 75 mg/m² intravenously over 1 hour on day 1 of each cycle with hydration and mannitol for renal protection. Vinorelbine was given at 25 mg/m² intravenously over 10–20 minutes on day 1 (prior to cisplatin) and on day 8. Peg-filgrastim was administered on day 8 of each cycle. Cycles of chemotherapy were repeated every 3 weeks. Veliparib, at the pre-specified cohort dose level, was self-administered twice daily days 1 through 14, except cycle 1 when administration was days 0 through 13 for PK evaluation of veliparib alone on day 0.

The starting dose of veliparib was 20 mg orally twice daily (BID). Following a standard 3 + 3 design, cohorts of 3 to 6 patients were recruited at each dose level. To be evaluable for cohort dose escalation decisions, a patient must either have experienced a dose limiting toxicity (DLT), or have completed cycle 1 of treatment (at least 75% of the cohort dose for each agent) and been observed for 21 days for adverse events. Patients who were not evaluable for dose escalation were replaced for that purpose, but could remain enrolled. Dose limiting toxicity (DLT) was defined as an adverse event (AE) that occurred in the first cycle, was felt to be related to study therapy, and fulfilled one of the following criteria: grade 4 neutropenia (ANC < 0.5 × 10⁹/L) for > 5 days or ANC < 0.1 × 10⁹/L for > 3 days; grade 3 neutropenia with fever; grade 4 thrombocytopenia; grade 3 or greater non-hematologic toxicity that represented at least a 2 grade increase from baseline (except grade 3 nausea/vomiting and diarrhea without adequate symptomatic treatment, grade 3 creatinine that corrected to grade 1 or baseline within 24 hours and grade 3 metabolic toxicities that corrected to at least grade 2 within 24 hours); or a delay of more than 2 weeks in starting the next cycle due to toxicity. (Further details on dose escalation found in Supplement.) An expansion cohort of 5 patients was enrolled for evaluation at the recommended phase II dose, to further evaluate safety and to aid in planning for a Phase II study.

The planned duration of combination treatment was 6 cycles, to avoid neuropathy associated with cumulative cisplatin of 500–600 mg/m². Patients without progressive disease or significant toxicity could continue the combination regimen for up to 10 cycles. Patients without progressive disease after 6–10 cycles could continue on veliparib monotherapy. The monotherapy dose was initially the same dose that the patient received on enrollment, increased to 400 mg BID during the trial based on external safety data. (Additional details in Supplement.)