Phase 1 dose-escalation study of single-agent veliparib in Japanese patients with advanced solid tumors

Abstract

Veliparib (ABT-888) is a potent, orally bioavailable poly(ADP-ribose) polymerase-1 and -2 inhibitor. This phase 1 study evaluated the tolerability, pharmacokinetic profile, safety, and preliminary antitumor activity of single-agent veliparib in Japanese patients with advanced solid tumors. Eligible patients were assigned to treatment with veliparib at 200 or 400 mg dose; veliparib was self-administered orally twice daily on days 1-28 of 28-day cycles. Dose escalation, following a 3 + 3 design, defined dose-limiting toxicities, the maximum tolerated dose, and the recommended phase 2 dose. Sixteen patients were enrolled (median age, 59 years). Fourteen patients had high-grade serous ovarian cancer, one had primary peritoneal cancer, and one had BRCA-mutated breast cancer. The most frequent treatment-emergent adverse events were nausea and vomiting (93.8% each), decreased appetite (62.5%), abdominal pain, diarrhea, and malaise (31.3% each). A grade ≥3 toxicity was observed in 50% of patients; one patient each in the 200 mg (n = 4) and 400 mg (n = 12) cohorts experienced serious adverse events. Dose-limiting toxicities were observed for one patient at the 400 mg dose. No toxicities leading to death were reported. The recommended phase 2 dose was defined as 400 mg twice daily. The veliparib pharmacokinetic profile was consistent with that reported for the Western population. Two patients, both with ovarian cancer, had a RECIST partial response. Veliparib monotherapy showed manageable tolerability and safety profiles and a predictable pharmacokinetic profile at a 400 mg twice-daily dose, and supports the inclusion of Japanese patients in the multinational phase 3 study (NCT02470585).

Keywords: High-grade serous ovarian cancer; Japanese; phase 1; poly(ADP-ribose) polymerase; veliparib.

Figure 1

(a) Mean (+SD) plasma concentration‐time profile of veliparib on cycle 1 day 1 following oral administration of 200 and 400 mg veliparib. (b) Comparison of dose‐normalized PK parameters of veliparib across studies. AUC _inf, area under the plasma concentration‐time curve from time 0 to infinity; BID, twice‐daily; C _max, maximum plasma concentration; h, hours; PK, pharmacokinetic.

Figure 2

Computed tomography images showing partial response in a single patient to veliparib 200 mg BID. BID, twice‐daily; C1D1, day 1 of cycle 1; CA‐125, cancer antigen 125; CT, computed tomography; PR, partial response; TL, target lesion.

Figure 3

(a) Best percentage change from baseline in the sum of tumor sizes of target lesions (treated population, in patients with measurable disease at baseline). (b) Percentage change from baseline in CA‐125 (treated population^§). CA‐125, cancer antigen 125. ^†Patients with BRCA mutated tumor. ^‡Platinum resistant patients – defined as patients who progressed on or within 6 months of completion of the last platinum‐based regimen. ^§One patient with breast cancer was not included in the CA‐125 response analysis.