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Background The phase 3 VELIA trial evaluated veliparib with carboplatin/paclitaxel and as maintenance in patients with high-grade serous ovarian carcinoma. Methods Patients with previously untreated stage III–IV high-grade serous ovarian carcinoma were randomized 1:1:1 to control (placebo with carboplatin/paclitaxel and placebo maintenance), veliparib-combination-only (veliparib with carboplatin/paclitaxel and placebo maintenance), or veliparib-throughout (veliparib with carboplatin/paclitaxel and veliparib maintenance). Randomization stratification factors included geographic region (Japan versus North America or rest of the world). Primary end point was investigator-assessed median progression-free survival. Efficacy, safety, and pharmacokinetics were evaluated in a subgroup of Japanese patients. Results Seventy-eight Japanese patients were randomized to control (n = 23), veliparib-combination-only (n = 30), and veliparib-throughout (n = 25) arms. In the Japanese subgroup, median progression-free survival for veliparib-throughout versus control was 27.4 and 19.1 months (hazard ratio, 0.46; 95% confidence interval, 0.18–1.16; p = 0.1 [not significant]). In the veliparib-throughout arm, grade 3/4 leukopenia, neutropenia, and thrombocytopenia rates were higher for Japanese (32%/88%/32%) versus non-Japanese (17%/56%/28%) patients. Grade 3/4 anemia rates were higher in non-Japanese (65%) versus Japanese (48%) patients. Early introduction of olanzapine during veliparib monotherapy maintenance phase may help prevent premature discontinuation of veliparib, via its potent antiemetic efficacy. Conclusions Median progression-free survival was numerically longer in Japanese patients in the veliparib-throughout versus control arm, consistent with results in the overall study population. Pharmacokinetics were comparable between Japanese and non-Japanese patients. Data for the subgroup of Japanese patients were not powered to show statistical significance but to guide further investigation.

This phase 1, open-label, dose-escalation study was conducted to determine the safety, tolerability, pharmacokinetics, and preliminary efficacy of veliparib with carboplatin and weekly paclitaxel in Japanese women with newly diagnosed, advanced ovarian cancer. Patients received veliparib at 100 or 150 mg twice daily on days 1–21 with carboplatin (area under the concentration–time curve 6 mg/mL•min) on day 1 and paclitaxel 80 mg/m2 on days 1, 8, and 15 every 3 weeks for up to 6 21-day cycles. Dose escalation followed a 3+3 design to determine dose-limiting toxicities, maximum tolerated dose, and the recommended phase 2 dose. Nine patients (median age 62 [range 27–72] years) received a median of 5 (range 3–6) cycles of treatment (3 at 100 mg, 6 at 150 mg). There were no dose-limiting toxicities. The most common adverse events of any grade were neutropenia (100%), alopecia (89%), peripheral sensory neuropathy (78%), and anemia, nausea, and malaise (67% each). Grade 3 or 4 adverse events were associated with myelosuppression. Pharmacokinetics of carboplatin/paclitaxel were similar at both veliparib doses. Response, assessed in 5 patients, was partial in 4 and complete in 1 (objective response rate 100%). Response could not be assessed in 4 patients who had no measurable disease at baseline. The recommended phase 2 dose of veliparib, when combined with carboplatin/paclitaxel, is 150 mg twice daily. Findings from this phase 1 trial demonstrate the tolerability and safety of veliparib with carboplatin/paclitaxel, a regimen with potential clinical benefit in Japanese women with ovarian cancer. This article is protected by copyright. All rights reserved.

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).

Background ABBV-181 is a monoclonal antibody that binds to cell surface programmed cell death 1 (PD-1). Dose-finding data have been previously reported (Powderly et al, Ann Oncol 2018). This report summarizes ABBV-181 monotherapy data from Japanese (JPN) and cohort-matched Western (WST) patients (pts) enrolled in the first-in-human study evaluating ABBV-181 in pts with previously treated advanced solid tumors (NCT03000257). Methods Pts received ABBV-181 in a 3 + 3 dose-escalation design at 1, 3, and 10 mg/kg IV every 2 weeks (Q2W) until progression (JPN pts: 3 and 10 mg/kg only) and a basket expansion cohort at a recommended phase 2 dose (RP2D). Response was assessed Q8W per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 and immune RECIST. Serial pharmacokinetic (PK) and pharmacodynamic samples were collected. Results As of Nov 2018, 56 pts (JPN: 11) were enrolled (total and JPN pts, median days on treatment [range], 1 mg/kg: 12, 120 [43-653]; 3 mg/kg: 10 and 4, 64 [1-134] and 29 [15-106]; 10 mg/kg: 11 and 4, 64 [1-225] and 29 [1-85]; basket: 23 and 3, 29 [1-353] and 15 [15-16]). Adverse events (AEs) were reported in (total, JPN pts): 10, 4 (3 mg/kg); 10, 3 (10 mg/kg); and 22, 2 (basket), with 5, 1 (3 mg/kg); 4, 0 (10 mg/kg); and 15, 1 (basket) pts having Grade (G)≥3 AEs. No dose-limiting toxicities or drug-related G5 AEs were reported. The most common G ≥ 1 AEs in JPN pts were (%): pyrexia (36), anemia (27), constipation (18); G ≥ 3 AEs were: anemia, decreased appetite, progression (9% each, all unrelated to ABBV-181). One G5 AE of progression was reported. Seven of 11 JPN pts discontinued ABBV-181 (all for disease progression). ABBV-181 PK appears dose-proportional and comparable in JPN and WST pts. ABBV-181 led to complete PD-1 receptor occupancy, similar kinetics of cytokine induction, and transient T-cell changes in JPN and WST pts. Conclusion These results support a RP2D of 250 mg Q2W, 375 mg Q3W, or 500 mg Q4W in both JPN and WST pts.

Abstact Introduction Veliparib is a potent, orally bioavailable PARP inhibitor that enhances efficacy of DNA-damaging chemotherapeutic agents. The study objectives were to determine the recommended phase 2 dose (RPTD) of veliparib plus carboplatin and paclitaxel, and assess pharmacokinetics (PK), tolerability, and preliminary efficacy in Japanese patients with solid tumors. Methods Carboplatin (AUC 6 mg/mL min) and paclitaxel (200 mg/m2) were administered on day 3 of a 21-day cycle. Oral veliparib (40, 80, or 120 mg BID) was administered on days 1–7. Patients received ≤6 cycles. Adverse events (AEs) were reported using NCI-CTCAE version 4.03, PK parameters were analyzed using noncompartmental methods, and responses were measured by RECIST version 1.1. Results Twelve patients with non-small cell lung cancer (NSCLC) were treated. Common treatment-emergent AEs, consistent with toxicities associated with carboplatin and paclitaxel, included leukopenia (100 %), neutropenia (100 %), anemia (83 %), thrombocytopenia (75 %), increased alanine aminotransferase (67 %), and increased aspartate aminotransferase (67 %). Grade 3/4 AEs (in ≥2 patients) included neutropenia (100 %), leukopenia (33 %), anemia (25 %), and hyponatremia (17 %). No AEs led to veliparib, carboplatin, or paclitaxel interruption; no DLTs were observed. The RPTD was determined to be 120 mg BID. Veliparib Cmax and AUC were approximately dose proportional. Six partial responses were observed. Conclusions Veliparib PK was not impacted by carboplatin and paclitaxel. The safety profile was manageable. The 120 mg BID RPTD confirmed in Japanese patients is the dose being evaluated in global studies of veliparib. Preliminary efficacy suggests veliparib may enhance carboplatin and paclitaxel activity, providing benefit to patients with NSCLC.