A Phase I Clinical Trial of the Poly(ADP-ribose) Polymerase Inhibitor Veliparib and Weekly Topotecan in Patients with Solid Tumors

Purpose: To determine the dose limiting toxicities (DLTs), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of veliparib in combination with weekly topotecan in patients with solid tumors. Correlative studies were included to assess the impact of topotecan and veliparib on poly(ADP-ribose) levels in peripheral blood mononuclear cells, serum pharmacokinetics of both agents, and potential association of germline repair gene mutations with outcome. Experimental Design: Eligible patients had metastatic nonhematological malignancies with measurable disease. Using a 3+3 design, patients were treated with veliparib orally twice daily on days 1-3, 8-10 and 15-17 and topotecan intravenously on days 2, 9 and 16 every 28 days. Tumor responses were assessed by RECIST. Results: Of 58 patients enrolled, 51 were evaluable for the primary endpoint. The MTD and RP2D was veliparib 300 mg twice daily on days 1-3, 8-10 and 15-17 along with topotecan 3 mg/m2 on days 2, 9 and 16 of a 28-day cycle. DLTs were grade 4 neutropenia lasting >5 days. The median number of cycles was 2 (1-26). The objective response rate was 10%, with 1 complete and 4 partial responses. 22 patients (42%) had stable disease ranging from 4 to 26 cycles. Patients with germline BRCA1, BRCA2 or RAD51D mutations remained on study longer than those without homologous recombination repair (HRR) gene mutations (median 4 vs. 2 cycles). Conclusions: Weekly topotecan in combination with veliparib has a manageable safety profile and appears to warrant further investigation.

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