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

Abstract

Purpose: To determine the dose limiting toxicities (DLT), maximum tolerated dose (MTD), and recommended phase II 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 nonhematologic 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. Twenty-two 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. Clin Cancer Res; 24(4); 744-52. ©2017 AACR.

Figure 1.

Graphs of veliparib AUC_0–9h versus dose (A) and topotecan AUC_0−∞ versus veliparib dose (B) following administration of escalating doses of 10 – 400 mg veliparib with 3 mg/m² topotecan.

Figure 2.. Effects of treatment on PAR levels.

A, percent decrease in PAR levels at 2–8 hours on Day 1 versus veliparib AUC_0–9h. Shown is the mean decrease at 2, 4 and 8 hours after veliparib treatment. Values at or below the LLQ were assumed to be at the LLQ. Line shows fit of data to a 3-parameter sigmoidal equation by non-linear regression using SigmaPlot (version 12.0). R² = 0.25, p = 0.031. B, percent decrease in PAR levels at 0 hours on Day 2 versus veliparib AUC_0–9h on Day 1. Samples with values below the LLQ at 0 h on Day 2 were omitted. Line shows fit of data to a 3-parameter sigmoidal equation by non-linear regression using SigmaPlot (version 12.0). R² = 0.33, p = 0.007. Closed circles, patients receiving once daily dosing; open circles, twice daily dosing. C, relationship between mean decrease in PAR levels at hours 2–8 on Day 1 relative to Day 1 baseline vs. decrease in PAR levels at hours 2–8 on Day 2 relative to Day 2 baseline.Dashed line indicates equal % inhibition on Days 1 and 2.