Phase IB trial of ixabepilone and vorinostat in metastatic breast cancer

Thehang Luu, Kyu pyo Kim, Suzette Blanchard, Bean Anyang, Arti Hurria, Lixin Yang, Jan H. Beumer, George Somlo, Yun Yen

研究成果: 雜誌貢獻文章

4 引文 斯高帕斯(Scopus)

摘要

Background: VOR, an HDAC inhibitor, induces acetylation of tubulin, and decreases resistance by attenuating downstream activation of AKT, c-Raf and HER-2. Patients (pts) with MBC treated with VOR had a TTP of 8.5 months (range 4-14) and stable disease in 29% (Luu et al., 2008). Our preclinical data showed synergistic effect of IXA and VOR in MDA-MB-231 and MCF7. Methods: The primary aims were to: 1) define the maximum tolerated dose (MTD) based on dose limiting toxicities (DLT), and 2) describe the pharmacokinetics (PK) of 2 schedules of VOR and IXA. Secondary aims were to describe: 1) response rate (RR) and 2) clinical benefit rate (CBR). The study included: 1) pts with MBC; 2) ECOG PS 0-2; 3) adequate marrow and organ functions; 4) no prior IXA or VOR; and 5) <grade (gr) 1 neuropathy. Stable brain metastasis were allowed. Pts were randomized to schedule A: VOR (QDx14) + IXA (D2) Q21D; or B: VOR (D1-7 and 15-21) + IXA (D2, 9, 16) Q28D. A modified toxicity probability interval design (target toxicity rate= 0.2 and equivalence range +/- 0.05) (Ji et al, 2010) determined dose escalation guidelines. PK were assessed with LC-MS/MS assays. Results: Among 37 pts randomized, 36 were evaluable [median age (55 yrs); median prior chemotherapy regimens (3); ER and/or PR + (64%); HER2 + (19%)]. In cohort A, 16 pts were treated (1 inevaluable). The MTD was: VOR 300mg (QDx14) + IXA (32mg/m2 D2) Q21D (dose level 1). DLT was experienced by 27% (4/15) pts [gr 4 neutropenia, gr 3 fatigue/AST, hyponatremia and allergic reaction to IXA]. In cohort B, 21 pts were treated (dose level 1, n=15; dose level 2, n=6). The MTD was VOR 300mg QD (D1-7 and 15-21) + IXA 16mg/m2 (D2, 9, 16) Q28D (dose level 1), no DLTs were observed. Dose level 2 was closed with 50% (3/6) of pts experiencing DLTs [gr 3 neutropenia, hypertension, and hypokalemia]. Median cycles treated (cohort A: 6, cohort B: 4). Response in cohort A and B respectively was: 1 CR, 2 PR, 7 SD (RR: 20%, CBR: 67%) and 1 CR, 4 PR, 9 SD (RR: 33%, CBR: 93%). VOR and IXA PK were not influenced by the presence of the other drug, clearance values= 220 L/h and 20 L/h/m2, respectively. Conclusions: We established the MTD of VOR and IXA in pts with MBC. The combination demonstrated clinical activity in these heavily pretreated pts. Further studies are recommended.
原文英語
頁(從 - 到)469-478
頁數10
期刊Breast Cancer Research and Treatment
167
發行號2
DOIs
出版狀態已發佈 - 一月 1 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Luu, T., Kim, K. P., Blanchard, S., Anyang, B., Hurria, A., Yang, L., Beumer, J. H., Somlo, G., & Yen, Y. (2018). Phase IB trial of ixabepilone and vorinostat in metastatic breast cancer. Breast Cancer Research and Treatment, 167(2), 469-478. https://doi.org/10.1007/s10549-017-4516-x