Phase I and pharmacologic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with solid tumors

Purpose: To determine the clinical toxicities of 17-(allylamino)-17- demethoxygeldanamycin (17-AAG) given as a 1-hour infusion daily for 5 days every 3 weeks. Patients and Methods: Nineteen patients received 17-AAG over six dose levels (10 to 56 mg/m²) using an accelerated titration scheme. Drug levels of 17-AAG were determined by high-performance liquid chromatography. Biologic effects of 17-AAG were monitored by changes in the content of target proteins by immunoblot analysis of lysates prepared from peripheral-blood mononuclear cells. Results: Toxicity was acceptable at doses up to 28 mg/m ². The cohort was expanded to three patients at 40 mg/m² because a second occurrence of grade 2 hepatic transaminitis occurred. Two of six assessable patients who received 56 mg/m² had reversible, grade 3 hepatic transaminitis. Five additional patients were enrolled at 40 mg/m ²; none had dose-limiting toxicity. The maximum plasma concentrations (C_max) of 17-AAG at 40 and 56 mg/m² were 1,724 and 2,046 ng/mL, respectively; the average plasma exposures (AUC) were 2,809 and 6,708 hours-ng/mL, respectively. Less than 3% of the daily dose was excreted into the urine. Clearance did not correlate with body-surface area. Possible biologic activity was suggested by apparent increased protein content of either glucose-related 78 kd protein or heat shock protein 70 with ≥ 14 mg/m ² and decreased protein content of either Lck or Raf1 with ≥ 28 mg/m² of 17-AAG. Conclusion: 17-AAG 40 mg/m² (median dose, 70 mg) was well tolerated when given daily for 5 days every 3 weeks.