Phase I trial of valproic acid and lenalidomide in patients with advanced cancer

The objectives of this study were to evaluate the tolerability and efficacy of valproic acid (VPA) and lenalidomide. In this 3+3 design study, VPA was administered daily on a 7-day-on, 7-day-off schedule, and lenalidomide was administered daily for 28 days. Because of the response noted during the dose-escalation phase, 12 additional patients with adenoid cystic carcinoma (ACC) received the maximum tolerated dose (MTD) in a dose-expansion phase. Twenty-six patients with advanced cancer (14 men/12 women), median age of 56 years (range 38-70 years), and a median number of two prior therapies (range 0-12) were enrolled. The most common toxicities were fatigue, rash, neutropenia, thrombocytopenia, and change in mental status. Dose-limiting toxic (DLT) effects were grade III confusion (n = 3), somnolence (n = 1), and gait disturbance (n = 1). The MTD was reached at VPA 30 mg/kg and lenalidomide 25 mg. Although only two of the 12 patients from the dose-expansion phase had DLT during the first cycle at the MTD, during subsequent cycles the majority of patients required dose reduction of VPA to 5-20 mg/kg because of fatigue and drowsiness. No significant tumor reductions were noticed in patients with ACC, but seven of these patients had stable disease over four cycles. Of non-ACC patients, one patient with melanoma and one patient with parathyroid carcinoma had stable disease for six cycles and eight cycles, respectively. Lenalidomide combined with VPA was well tolerated. We recommend starting VPA at 5 mg/kg and titrating upward to 20 mg/kg. No significant tumor reductions were noticed in patients with ACC.