A Phase 1 Dose-Escalation Study of Veliparib Combined with Carboplatin and Etoposide in Patients with Extensive-Stage Small Cell Lung Cancer and Other Solid Tumors

Purpose: This study examined safety, pharmacokinetics and efficacy of veliparib, a PARP inhibitor, combined with carboplatin and etoposide in patients with extensive-stage (ED) small cell lung cancer (SCLC) and other solid tumors. Experimental Design: 3+3 design was used for dose escalation of oral veliparib in combination with carboplatin (AUC 5 on Day 1) and etoposide (100 mg/m² on Days 1-3) in 21-day cycles. Veliparib dose was explored from 80-240mg twice daily (BID) on 7-day, 14-day or continuous schedules. Patients without disease progression continued on maintenance monotherapy (veliparib 400mg BID) until disease progression or unacceptable toxicity. Results: Thirty-nine patients were enrolled to determine the recommended phase 2 dose (RP2D) of 240 mg veliparib for 14-days combined with carboplatin and etoposide based on long-term tolerability. Dose-limiting toxicity occurred in one patient (grade 2 toxic motor polyneuropathy) at veliparib 240 mg BID 7-days. Most common adverse events related to veliparib were nausea (39%), fatigue (39%), and hematologic toxicities. Continuous dosing of veliparib 240 mg BID with carboplatin and etoposide resulted in excessive chemotherapy dose delays due to hematologic toxicity (grade 3/4 neutropenia/thrombocytopenia). Etoposide pharmacokinetics was not affected by veliparib. Confirmed responses occurred in 17/39 (44%) and 16/25 (64%) of all enrolled and ED SCLC patients, respectively. At the recommended phase 2 dose, confirmed responses occurred in 6/13 (46%) and 5/6 (83%) of all enrolled and ED SCLC patients, respectively. Conclusions: Veliparib (240mg BID 14-days) plus carboplatin/etoposide can be safely combined. Phase 2 of this study is ongoing in first-line patients with ED SCLC.

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