Abstract
The anti-epileptic diphenylhydantoin (DPH; Dilantin) selectively enhances the in vitro cytotoxicity of vinca microtubule poisons in both parent sensitive and multi-drug resistant (MDR) human tumor cells. The in vivo clinical activity of this combination has not been fully evaluated. To determine the maximum tolerated dose (MTD), dose-limiting toxicities, and preliminary antitumor activity of the combination of intravenous (IV) bolus vinorelbine (VRL) and oral diphenylhydantoin (DPH) in patients (pts) with refractory solid tumors. Cohorts of 3-6 pts with refractory cancer were treated with escalating doses of weekly IV bolus VRL (I -20.0 mg/m(2); II -22.5 mg/m(2); III -25.0 mg/m(2); IV -27.5 mg/m(2); V -30.0 mg/m(2); VI -32.5 mg/m(2)) combined with a fixed oral dose of DPH (400 mg/day) until MTD or progression. During each 35 day cycle, pts received DPH 400 mg/day administered orally on Days -6 to Day +22 and weekly IV bolus infusion of VRL on Days +1, +8, +15, and +22. The cohort treated at the MTD was expanded to further define toxicity. A total of 25 evaluable pts. (9 men; 16 women) were treated with VRL and DPH at dose levels I ( n = 5), II ( n = 3), III ( n = 2), IV ( n = 3), V ( n = 7) and VI ( n = 5) in 5 week cycles over a 16 month period. Dose limiting toxicity occurred at dose level VI (VRL 32.5 mg/m(2)) and included grade 3 leukopenia ( n = 2), grade 3 neutropenia ( n = 1) and grade 4 neutropenia ( n = 1) occurring within the first cycle of treatment. There were no responses, however 9 pts had stable disease of variable duration (8-56 weeks) and received a median of 2 cycles of treatment (range 2-14). Intravenous bolus administration of VRL and oral administration of a fixed dose of DPH was well tolerated according to the schedule reported here. Although there were no responses, several patients had prolonged disease stabilization. The recommended phase II dose of VRL when used in this combination is 30 mg/m(2).
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