Abstract P3-13-08: A phase I study of weekly nab-paclitaxel in combination with S-1 in patients with metastatic breast cancer

Abstract

Abstract Background: S-1 is an oral, fixed dose combination product comprised of tegafur, a fluoropyrimidine prodrug of 5-fluorouracil (5-FU), and modulators of 5-FU metabolism, 5-chloro-2.4-dihydrooxypyridine and oteracil potassium. S-1 is designed to provide oral delivery of 5-FU, a pyrimidine analog antimetabolite antineoplastic agent, while reducing the rate of degradation of 5-FU and its conversion in the gastrointestinal tract to its toxic phosphorylated metabolite. S-1 is active in breast cancer and a variety of solid tumors. nab™-Paclitaxel (nab-P) is a treatment option in metastatic breast cancer (MBC) (approved 260 mg/m2 q3w dosing schedule), and high activity of nab-P with single-agent weekly administration at 100 mg/m2 has been investigated in MBC as well as other disease states. Since these two agents differed in their mechanisms of action and toxicity profiles, we sought to test their combined activity in a phase I study of nab-P/S-1 for HER2-negative MBC. The primary objectives of this study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of nab-P/S-1 in patients with HER-2 negative MBC. The secondary objective of this study was to evaluate pharmacokinetic (PK) parameters of both agents. Methods: Patients received treatment on 3 week cycles. S-1 was administered orally at a twice-daily dose of 65 mg/m2 (dose level 1 and 2b) or 80 mg/m2 (dose level 2a and 3) for 14 days and nab-P was administered as a 30-minute IV infusion at a dose of 100 mg/m2 on days 1 and 8 (dose level 1 and 2b) or 100 mg/m2 on days 1, 8 and 15 (dose level 2a and 3). Results: Fifteen patients were enrolled in this study; nab-P/S-1 was given as first-line chemotherapy for MBC in 9 patients, and as second-line therapy subsequent to an anthracycline-containing therapy in 6 patients. At dose level 3, one patient experienced a DLT. The observed DLT was delay of initiation of next cycle, G4 neutropenia had not recovered to G1/G0 in a period defined on the protocol. No cases of febrile neutropenia were observed. Judged from the status of dose reduction and the extension of drug holidays (cycle start delay), and the occurrence of non-severe adverse events after 2 cycles, the dose level was not increased above level 3. Seven patients were able to be treated 10 cycles or more. Additionally, three patients were able to be treated 20 cycles or more. Among of the 12 patients who had a measurable lesion which was evaluable by RECISTv1.1, the overall response rate was 50%, with 1 CR, 5 PR, 4 SD, and 1 PD. Pharmacokinetics of Paclitaxel and 5-FU in the combination therapy were comparable to those after single-agent administration of nab-P and S-1, respectively. Conclusion: Based on the results of this study, the RD was determined to be dose level 3 (S-1 80 mg/m2 twice daily plus nab-P 100 mg/m2 on days 1, 8, and 15). Since this combination therapy was generally well tolerated even with prolonged treatment, it is suggested that this combination therapy may be a promising treatment regimen in HER-2 negative MBC and merits further evaluation. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-13-08.