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Phase I study of weekly nab-paclitaxel combined with S-1 in patients with human epidermal growth factor receptor type 2-negative metastatic breast cancer.

ABSTRACT: We conducted a phase I study of a weekly nab-paclitaxel and S-1 combination therapy in patients with human epidermal growth factor receptor type 2-negative metastatic breast cancer. The primary objective was to estimate the maximum tolerated and recommended doses. Each treatment was repeated every 21 days. Levels 1, 2a, 2b, and 3 were set depending on the S-1 dose (65 or 80 mg/m(2) ) and nab-paclitaxel infusion schedule (days 1 and 8 or days 1, 8, and 15). Fifteen patients were enrolled. Dose-limiting toxicity was observed in one patient at Level 3 (100 mg/m(2) nab-paclitaxel on days 1, 8, and 15 with 80 mg/m(2) S-1 daily for 14 days, followed by 7 days of rest). Although the maximum tolerated dose was not reached, the recommended dose was determined to be Level 3. Neutropenia was the most frequent grade 3-4 treatment-related adverse event. For patients with measurable lesions, the response rate was 50.0% and the median time to treatment failure and median progression-free survival was 13.2 and 21.0 months, respectively. The present results show the feasibility and potential for long-term administration of this combination therapy.

SUBMITTER: Tsurutani J

PROVIDER: S-EPMC4471786 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Phase I study of weekly nab-paclitaxel combined with S-1 in patients with human epidermal growth factor receptor type 2-negative metastatic breast cancer.

Tsurutani Junji J Kuroi Katsumasa K Iwasa Tsutomu T Miyazaki Masaki M Nishina Shinichi S Makimura Chihiro C Tanizaki Junko J Okamoto Kunio K Yamashita Toshinari T Aruga Tomoyuki T Shigekawa Takashi T Komoike Yoshifumi Y Saeki Toshiaki T Nakagawa Kazuhiko K

Cancer science 20150409 6

We conducted a phase I study of a weekly nab-paclitaxel and S-1 combination therapy in patients with human epidermal growth factor receptor type 2-negative metastatic breast cancer. The primary objective was to estimate the maximum tolerated and recommended doses. Each treatment was repeated every 21 days. Levels 1, 2a, 2b, and 3 were set depending on the S-1 dose (65 or 80 mg/m(2) ) and nab-paclitaxel infusion schedule (days 1 and 8 or days 1, 8, and 15). Fifteen patients were enrolled. Dose-li ...[more]

PMID: 25786335

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Project description:PurposePIK3CA mutations are common in breast cancer and promote tumor progression and treatment resistance. We conducted a phase I/II trial of alpelisib (α-specific PI3K inhibitor) plus nab-paclitaxel in patients with HER2-negative metastatic breast cancer (MBC).Patients and methodsEligible patients had HER2-negative MBC with any number of prior chemotherapies. Phase I was 3+3 dose-escalation design with three dose levels of alpelisib (250, 300, and 350 mg) daily plus nab-paclitaxel 100 mg/m2 administered on days 1, 8, and 15 every 28 days. Phase II was according to Simon's two-stage design. PIK3CA mutations in tumor/circulating tumor DNA (ctDNA) were assessed. Primary endpoints were recommended phase II dose (RP2D) and objective response rate (ORR). Additional endpoints included safety, pharmacokinetics, progression-free survival (PFS), and association of PIK3CA mutation with outcomes.ResultsA total of 43 patients were enrolled (phase I, n = 13 and phase II, n = 30). A total of 84% had visceral disease and 84% had prior taxane. No dose-limiting toxicities occurred in phase I. RP2D was alpelisib 350 mg daily plus nab-paclitaxel 100 mg/m2 on days 1, 8, and 15. Hyperglycemia (grade 3, 26% and grade 4, 0%), neutropenia (grade 3, 23% and grade 4, 7%), diarrhea (grade 3, 5% and grade 4, 0%), and rash (grade 3, 7% and grade 4, 0%) were the most common adverse events. Among 42 evaluable patients, ORR was 59% (complete response, 7% and partial response, 52%), 21% of whom had response lasting >12 months; median PFS was 8.7 months. A total of 40% of patients demonstrated tumor and/or ctDNA PIK3CA mutation; patients with tumor/ctDNA mutation demonstrated better PFS compared with those without mutation (11.9 vs. 7.5 months; HR, 0.44; P = 0.027). Patients with normal metabolic status had longer PFS compared with prediabetic/diabetic patients (12 vs. 7.5 months; P = 0.014). No pharmacokinetics interactions were detected.ConclusionsThe alpelisib plus nab-paclitaxel combination was well tolerated and shows encouraging efficacy, especially in patients with PIK3CA-mutated tumor/ctDNA. The impact of metabolic status on response to this combination merits further investigation.

Dataset Information

Phase I study of weekly nab-paclitaxel combined with S-1 in patients with human epidermal growth factor receptor type 2-negative metastatic breast cancer.

Publications

Phase I study of weekly nab-paclitaxel combined with S-1 in patients with human epidermal growth factor receptor type 2-negative metastatic breast cancer.

Similar Datasets

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