Phase I trial of pulse-dose vorinostat with flavopiridol in solid tumors.

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e13511 Background: Preclinical data show that the histone deacetylase inhibitor vorinostat (V) enhances chemotherapy at levels of > 2.5 μM. However the approved oral dose of V of 400 mg/d inconsistently achieves this level in pts. We sought to develop an intermittent oral pulse-dose schedule of V to increase serum drug levels. We combined V with the pan-cyclin dependent kinase inhibitor flavopiridol (F) based on data that sequential treatment with F increases V-induced apoptosis. Methods: This is a phase I trial of V + F in pts with advanced solid tumors. One week before combination therapy, V alone was given daily PO for 3 d (cycle -1). Combination treatment began with cycle 1. V was initially given on d 1-3 and 8-10 of each 21-d cycle. F was given IV on d 2 and d 9 of each cycle. Due to neutropenia, this was modified to V on d 1-3 and 15-17, and F on d 2 and 16, of each 28-d cycle. A split-dose schedule of F 30 mg/m2 over 30 min followed by 30 mg/m2 over 4 h was also investigated. Results: 34 pts were treated; 31 were evaluable for response. Pt characteristics: median age 59 (range 38-85), ECOG PS 1 (0- 1), prior regimens 4 (1-11). With V given on d 1-3 and 8-10, the maximum tolerated dose (MTD) was V 600 mg/d and F 60 mg/m2 over 1 h. Dose-limiting toxicities (DLT) were neutropenia, leukopenia, thrombocytopenia, hemorrhage, and pulmonary embolus. With V given on d 1-3 and 15-17, the MTD was V 800 mg/d and F 30 mg/m2over 30 min and 30 mg/m2 over 4 h. DLTs were neutropenia and infection. V pharmacokinetics increased with dose and the increase was greater than proportional. Mean V Cmax of pts treated at the 800 mg dose was 4.8 μM (± 2.8). V Cmax ≥ 2.5 μM was achieved in 86% of pts treated at the MTD. F co-administration increased the Cmax of V by 27% (95% CI 11%-43%). Flavopiridol Cmax of ≥ 2 μM was achieved in 90% of patients. The best response was stable disease in 8 pts for an average of 5.5 m (range 1.6-13.2 m). Conclusions: Intermittent administration of high dose oral V in combination with F is feasible and achieves target serum levels > 2.5 μM associated with in vitro synergy. V concentrations higher than previously reported with oral dosing were achieved without undue toxicity. The recommended phase II dose is V 800 mg once daily for 3 d (d 1- 3) with F on d 2 given as 30 mg/m2 over 30 min followed by 30 mg/m2 over 4 h, every 14 d. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck