Phase I-II study of the histone deacetylase inhibitor (HDACi) vorinostat plus paclitaxel and bevacizumab in metastatic breast cancer (MBC): New York Cancer Consortium trial P7703.

Abstract

Abstract Abstract #404 Background: The oral HDACi vorinostat (V) sensitizes breast cancer cells to tubulin polymerizing agents and anti-VEGF directed therapies in vitro. We sought to determine the safety and efficacy of V plus paclitaxel (P) and bevacizumab (B) as first-line therapy for MBC.
 Methods: Eligible patients (pts) with measurable disease, ECOG PS 0 or 1, and no prior chemotherapy for MBC, received P (90mg/m2) on days 1, 8, 15 and B (10mg/kg) on days 1,15 every 28 days, plus V 200 mg (N=3) or 300 mg (N=28) BID orally for 3 days given the day before, day of, and day after each P dose. Response was assessed after every 3 cycles (RECIST). The trial was designed to distinguish between a response rate of < 40% vs. > 60% (alpha=0.10, beta=0.10) using Simon's optimal 2-stage design. At least 12 responses were required in the first 28 evaluable pts in the 1st stage and 21 of 41 in the 2nd stage.
 Results: There were no dose-limiting toxicities among the first 6 pts treated at the 1st (200 mg BID; N=3) and 2nd (300 mg BID; N=3) dose levels. Among the 26 evaluable pts treated at the recommended phase II dose of 300mg bid in the 1st stage, 14 patients had a partial response (PR-54%; 90% confidence interval [C.I.] 36%-71%), 6 had stable disease (SD) at 3 months and remain on treatment, 2 had SD as the best response with progressive disease (PD) at 11.8 and 15 months, and 4 had PD as their best response. Additionally, 2 of 3 pts treated at the first V dose level had a PR, indicating PR in 16 of 29 overall (55%, 90% C.I 38%-71%). Only 11 of 29 evaluable pts (38%) have progressed after a median followup of 10.5 months (R-2.3-14.9). Two pts had tumor biopsies and peripheral blood mononuclear cells (PBMC) collected before and 4 hours after the 3rd V dose (300 mg BID) which showed increased acetylation of K69 lysine residue of the chaperone protein Hsp 90, upregulation of Hsp70, and downregulation of AKT by Western Blot, providing evidence of Hsp90 inhibition in tumor and PBMC.
 
 Gr 3-4 toxicities included neutropenia (26%), neuropathy (23%), fatigue (16%), thrombosis (10%), vomiting (6%), hypertension (3%), and diarrhea (3%).
 Conclusions: Our preliminary findings indicate that the HDACi V inhibits Hsp90 and downregulates AKT in breast cancer in vivo, and enhances the effectiveness of P plus B in MBC. Accrual is nearly complete and the final efficacy analysis will be presented. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 404.