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.
ASJC Scopus subject areas
- Cancer Research
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