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Phase 1 study of veliparib with carboplatin and weekly paclitaxel in Japanese patients with newly diagnosed ovarian cancer.

ABSTRACT: 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 b.i.d. 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 five patients, was partial in four and complete in one (objective response rate 100%). The response could not be assessed in four patients who had no measurable disease at baseline. The recommended phase 2 dose of veliparib, when combined with carboplatin/paclitaxel, is 150 mg b.i.d. 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.

SUBMITTER: Nishio S

PROVIDER: S-EPMC5665762 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Phase 1 study of veliparib with carboplatin and weekly paclitaxel in Japanese patients with newly diagnosed ovarian cancer.

Nishio Shin S Takekuma Munetaka M Takeuchi Satoshi S Kawano Kouichirou K Tsuda Naotake N Tasaki Kazuto K Takahashi Nobutaka N Abe Masakazu M Tanaka Aki A Nagasawa Takayuki T Shoji Tadahiro T Xiong Hao H Nuthalapati Silpa S Leahy Terri T Hashiba Hideyuki H Kiriyama Tsukasa T Komarnitsky Philip P Hirashima Yasuyuki Y Ushijima Kimio K

Cancer science 20170918 11

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 b.i.d. on days 1-21 with carboplatin (area under the concentration-time curve 6 mg/mL•min) on day 1 and paclitaxel 80 mg/m<sup>2</sup> on days 1, 8 and 15 every 3 weeks for up to 6 21-day cycles. ...[more]

PMID: 28837250

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Project description:BackgroundA dose-dense weekly schedule of paclitaxel (resulting in a greater frequency of drug delivery) plus carboplatin every 3 weeks or the addition of bevacizumab to paclitaxel and carboplatin administered every 3 weeks has shown efficacy in ovarian cancer. We proposed to determine whether dose-dense weekly paclitaxel and carboplatin would prolong progression-free survival as compared with paclitaxel and carboplatin administered every 3 weeks among patients receiving and those not receiving bevacizumab.MethodsWe prospectively stratified patients according to whether they elected to receive bevacizumab and then randomly assigned them to receive either paclitaxel, administered intravenously at a dose of 175 mg per square meter of body-surface area every 3 weeks, plus carboplatin (dose equivalent to an area under the curve [AUC] of 6) for six cycles or paclitaxel, administered weekly at a dose of 80 mg per square meter, plus carboplatin (AUC, 6) for six cycles. The primary end point was progression-free survival.ResultsA total of 692 patients were enrolled, 84% of whom opted to receive bevacizumab. In the intention-to-treat analysis, weekly paclitaxel was not associated with longer progression-free survival than paclitaxel administered every 3 weeks (14.7 months and 14.0 months, respectively; hazard ratio for disease progression or death, 0.89; 95% confidence interval [CI], 0.74 to 1.06; P=0.18). Among patients who did not receive bevacizumab, weekly paclitaxel was associated with progression-free survival that was 3.9 months longer than that observed with paclitaxel administered every 3 weeks (14.2 vs. 10.3 months; hazard ratio, 0.62; 95% CI, 0.40 to 0.95; P=0.03). However, among patients who received bevacizumab, weekly paclitaxel did not significantly prolong progression-free survival, as compared with paclitaxel administered every 3 weeks (14.9 months and 14.7 months, respectively; hazard ratio, 0.99; 95% CI, 0.83 to 1.20; P=0.60). A test for interaction that assessed homogeneity of the treatment effect showed a significant difference between treatment with bevacizumab and without bevacizumab (P=0.047). Patients who received weekly paclitaxel had a higher rate of grade 3 or 4 anemia than did those who received paclitaxel every 3 weeks (36% vs. 16%), as well as a higher rate of grade 2 to 4 sensory neuropathy (26% vs. 18%); however, they had a lower rate of grade 3 or 4 neutropenia (72% vs. 83%).ConclusionsOverall, weekly paclitaxel, as compared with paclitaxel administered every 3 weeks, did not prolong progression-free survival among patients with ovarian cancer. (Funded by the National Cancer Institute and Genentech; GOG-0262 ClinicalTrials.gov number, NCT01167712.).

Project description:Background:Homologous recombination defects in BRCA1/2-mutated tumors result in sensitivity to poly(ADP-ribose) polymerase inhibitors, which interfere with DNA damage repair. Veliparib, a potent poly(ADP-ribose) polymerase inhibitor, enhanced the antitumor activity of platinum agents and temozolomide in early phase clinical trials. This phase II study examined the safety and efficacy of intermittent veliparib with carboplatin/paclitaxel (VCP) or temozolomide (VT) in patients with BRCA1/2-mutated breast cancer. Patients and methods:Eligible patients ≥18 years with locally recurrent or metastatic breast cancer and a deleterious BRCA1/2 germline mutation were randomized 1 : 1 : 1 to VCP, VT, or placebo plus carboplatin/paclitaxel (PCP). Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS) and overall response rate (ORR). Results:Of 290 randomized patients, 284 were BRCA+, confirmed by central laboratory. For VCP versus PCP, median PFS was 14.1 and 12.3 months, respectively [hazard ratio (HR) 0.789; 95% CI 0.536-1.162; P = 0.227], interim median OS 28.3 and 25.9 months (HR 0.750; 95% CI 0.503-1.117; P = 0.156), and ORR 77.8% and 61.3% (P = 0.027). For VT (versus PCP), median PFS was 7.4 months (HR 1.858; 95% CI 1.278-2.702; P = 0.001), interim median OS 19.1 months (HR 1.483; 95% CI 1.032-2.131; P = 0.032), and ORR 28.6% (P < 0.001). Safety profile was comparable between carboplatin/paclitaxel arms. Adverse events (all grades) of neutropenia, anemia, alopecia, and neuropathy were less frequent with VT versus PCP. Conclusion:Numerical but not statistically significant increases in both PFS and OS were observed in patients with BRCA1/2-mutated recurrent/metastatic breast cancer receiving VCP compared with PCP. The addition of veliparib to carboplatin/paclitaxel significantly improved ORR. There was no clinically meaningful increase in toxicity with VCP versus PCP. VT was inferior to PCP. An ongoing phase III trial is evaluating VCP versus PCP, with optional continuation single-agent therapy with veliparib/placebo if chemotherapy is discontinued without progression, in this patient population. Clinical trial information:NCT01506609.

Project description:BackgroundThis study was performed to assess the efficacy and feasibility of definitive chemoradiotherapy consisting of weekly doses of combined paclitaxel and carboplatin concurrent with radiation therapy, followed by 2 cycles of consolidation chemotherapy for advanced esophageal carcinoma.MethodsEligibility criteria included local, advanced, newly diagnosed and postoperative local regional lymph node metastasis; Eastern Cooperative Oncology Group (ECOG) score ≤ 2; and adequate organ function. Patients received concurrent chemoradiation therapy consisting of radiotherapy (50.4 Gy/28 Fx or 61.2 Gy/34 Fx) and concurrent paclitaxel (50 mg/m2) and carboplatin (area under the curve, AUC = 2) on days 1, 8, 15, 22 and 29. The two-cycle consolidation chemotherapy protocol was paclitaxel (175 mg/m2) plus carboplatin (AUC = 5) administered on days 57 and 85, after concurrent chemoradiotherapy.ResultsBetween August 2013 and February 2015, 65 patients with oesophageal carcinoma were enrolled in the study; 34 (52.3%) were newly diagnosed and 31 (47.6%) had postoperative local regional lymph node metastasis. The median overall survival time was 21.7 months (95% confidence interval [CI] 16.7-26.6), and the median progression-free survival time was 12.1 months (95% CI 9.0-15.3). A total of 96.9% (63/65) and 67.6% (44/65) patients completed ≥5 cycles and all 7 cycles of chemotherapy, respectively. A total of 93.8% (61/65) patients completed radiation therapy. The 1- and 2-year overall survival rates were 73.7 and 42.0%, respectively. The 1- and 2-year progression-free survival rates were 50.6 and 31.1%, respectively. Grade 3-4 toxicity during chemoradiotherapy included neutropenia (24.5%), thrombocytopenia (4.6%), fatigue (1.5%), anaemia (1.5%), radiation dermatitis (1.5%), pneumonitis (1.5%), oesophagitis (4.6%) and vomiting (1.5%).ConclusionsIn patients with locally advanced oesophageal cancer, the combination of weekly doses of paclitaxel and carboplatin was well tolerated and produced comparable results. A three-arm randomised phase III trial (NCT02459457) comparing paclitaxel in combination with cisplatin, carboplatin or 5-fluorouracil with concurrent radiotherapy is on-going at our hospital.

Project description:BackgroundThe ICON8 study reported no significant improvement in progression-free survival (a primary endpoint) with weekly chemotherapy compared with standard 3-weekly treatment among patients with epithelial ovarian cancer. All ICON8 patients were eligible to take part in the accompanying health-related quality-of-life study, which measured the effect of treatment on self-reported wellbeing, reported here.MethodsIn this open-label, randomised, controlled, phase 3, three-arm, Gynecologic Cancer Intergroup (GCIG) trial done at 117 hospital sites in the UK, Australia, New Zealand, Mexico, South Korea, and Republic of Ireland, women (aged at least 18 years) with newly diagnosed, histologically confirmed International Federation of Gynecology and Obstetrics stage IC-IV ovarian cancer and an Eastern Cooperative Oncology Group performance status of 0-2 were randomly assigned (1:1:1) centrally using minimisation to group 1 (intravenous carboplatin area under the curve [AUC]5 or AUC6 and 175 mg/m2 intravenous paclitaxel every 3 weeks), group 2 (carboplatin AUC5 or AUC6 every 3 weeks and 80 mg/m2 paclitaxel weekly), or group 3 (carboplatin AUC2 weekly and 80 mg/m2 paclitaxel weekly). Randomisation was stratified by GCIG group, disease stage, and outcome and timing of surgery. Patients and clinicians were not masked to treatment assignment. Patients underwent immediate or delayed primary surgery according to clinicians' choice. Patients were asked to complete European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-OV28 questionnaires at enrolment, before each chemotherapy cycle, then 6-weekly up to 9 months, 3-monthly up to 2 years, and 6-monthly up to 5 years. Quality of life was a prespecified secondary outcome of the ICON8 study. Within the quality-of-life study, the co-primary endpoints were QLQ-C30 global health score at 9 months (cross-sectional analysis) and mean QLQ-C30 global health score from randomisation to 9 months (longitudinal analysis). Data analyses were done on an intention-to-treat basis. The trial is registered on ClinicalTrials.gov, NCT01654146 and ISRCTN Registry, ISRCTN10356387, and is currently in long-term follow up.FindingsBetween June 6, 2011, and Nov 28, 2014, 1566 patients were recruited into ICON8 (522 were included in group 1, 523 in group 2, and 521 in group 3). Baseline quality-of-life questionnaires were completed by 1438 (92%) of 1566 patients and 9-month questionnaires by 882 (69%) of 1280 patients. We observed no significant difference in global health score at 9 months (cross-sectional analysis) between study groups (group 2 vs group 1, difference in mean score 2·3, 95% CI -0·4 to 4·9, p=0·095; group 3 vs group 1, -0·8, -3·8 to 2·2, p=0·61). Using longitudinal analysis, we found lower global health scores for those receiving weekly paclitaxel than for those receiving 3-weekly chemotherapy (group 2 vs group 1, mean difference -1·8, 95% CI -3·6 to -0·1, p=0·043; group 3 vs group 1, -2·9, -4·7 to -1·1, p=0·0018).InterpretationWe found no evidence of a difference in global quality of life between treatment groups at 9 months; however, patients receiving weekly treatment reported lower mean quality of life across the 9-month period after randomisation. Taken together with the lack of progression-free survival benefit, these findings do not support routine use of weekly paclitaxel-containing regimens in the management of newly diagnosed ovarian cancer.FundingCancer Research UK, Medical Research Council, Health Research Board Ireland, Irish Cancer Society, and Cancer Australia.

Dataset Information

Phase 1 study of veliparib with carboplatin and weekly paclitaxel in Japanese patients with newly diagnosed ovarian cancer.

Publications

Phase 1 study of veliparib with carboplatin and weekly paclitaxel in Japanese patients with newly diagnosed ovarian cancer.

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