Phase IB trial of ixabepilone and vorinostat in metastatic breast cancer
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To translate promising preclinical data on the combination of vorinostat and ixabepilone for metastatic breast cancer (MBC) into clinical trials.
We conducted a randomized two-arm Phase IB clinical trial of ascending doses of vorinostat and ixabepilone in prior -treated MBC patients. To determine the maximum tolerated dose (MTD), 37 patients were randomized to schedule A: every-3-week ixabepilone + vorinostat (days 1–14), or schedule B: weekly ixabepilone + vorinostat (days 1–7; 15–21) Pharmacokinetics were assessed. Nineteen additional patients were randomized to schedule A or B and objective response rate (ORR), clinical benefit rate (CBR), toxicity, progression-free survival (PFS), and overall survival (OS) were assessed.
The schedule A MTD was vorinostat 300 mg daily (days 1–14), ixabepilone 32 mg/m2 (day 2); 21-day cycle 27% dose-limiting toxicities (DLTs). The schedule B MTD was vorinostat 300 mg daily (days 1–7; 15–21), ixabepilone 16 mg/m2 (days 2, 9, 16); 28-day cycle; no DLTs. Vorinostat and ixabepilone clearances were 194 L/h and 21.3 L/h/m2, respectively. Grade 3 peripheral sensory neuropathy was reported in 8% (A) and 21% (B) of patients. The ORR and CBR were 22 and 22% (A); 30 and 35% (B). Median PFS was 3.9 (A) and 3.7 (B) months. OS was 14.8 (A) and 17.1 (B) months.
We established the MTD of vorinostat and ixabepilone. This drug combination offers a novel therapy for previously treated MBC patients. The potential for lower toxicity and comparable efficacy compared to current therapies warrants further study.
KeywordsPhase IB clinical trial Ixabepilone Vorinostat Metastatic breast cancer Histone deacetylation inhibitors (HDACIs)
The authors thank all participating patients and their families, as well as the network of investigators, research nurses, study coordinators, and operational staff. The authors also thank Nicola Solomon, PhD for assistance in editing the manuscript. This study was supported by Merck and Bristol-Myers Squibb. This project used the UPCI Cancer Pharmacokinetics and Pharmacodynamics Facility (CPPF) and was supported in part by National Institutes of Health award P30CA047904. This study was previously reported at the San Antonio Breast Cancer Symposium 2012; J Clin Oncol 30, 2012 (suppl; abstr 1070).
Compliance with ethical standards
Conflict of interest
JHB received funding from Bristol-Myers Squibb to perform PK analyses. AH has consulted for Pierian Biosciences and Boehringer Ingelheim and received funding from Celgen, Novartis, and GSK. GS has consulted for Genentech, Novartis, AstraZeneca, AbbVie, Pfizer, Nanostring, Celgene, and PUMA, and received funding from Celgene and Genentech.
Experiments comply with the current laws of the USA. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments. Informed consent was obtained from all individual participants included in the study.
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