Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer

Abstract

Purpose: To define the maximum tolerated dose (MTD), toxicities, and pharmacokinetics of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when administered using continuous and intermittent dosing schedules.

Experimental design: Patients with progressive solid tumor malignancies were treated with 17-AAG using an accelerated titration dose escalation schema. The starting dose and schedule were 5 mg/m(2) daily for 5 days with cycles repeated every 21 days. Dosing modifications based on safety, pharmacodynamic modeling, and clinical outcomes led to the evaluation of the following schedules: daily x 3 repeated every 14 days; twice weekly (days 1, 4, 8, and 11) for 2 weeks every 3 weeks; and twice weekly (days 1 and 4) without interruption. During cycle 1, blood was collected for pharmacokinetic and pharmacodynamic studies.

Results: Fifty-four eligible patients were treated. The MTD was schedule dependent: 56 mg/m(2) on the daily x 5 schedule; 112 mg/m(2) on the daily x 3 schedule; and 220 mg/m(2) on the days 1, 4, 8, and 11 every-21-day schedule. Continuous twice-weekly dosing was deemed too toxic because of delayed hepatotoxicity. Hepatic toxicity was also dose limiting with the daily x 5 schedule. Other common toxicities encountered were fatigue, myalgias, and nausea. This latter adverse effect may have been attributable, in part, to the DMSO-based formulation. Concentrations of 17-AAG above those required for activity in preclinical models could be safely achieved in plasma. Induction of a heat shock response and down-regulation of Akt and Raf-1 were observed in biomarker studies.

Conclusion: The MTD and toxicity profile of 17-AAG were schedule dependent. Intermittent dosing schedules were less toxic and are recommended for future phase II studies.

Fig. 1

A, time course of PSA change in a patient with prostate cancer treated with 210 mg/m² 17-AAG on the continuous twice-weekly schedule (dose level 15). This patient had a 25% decline in PSA after beginning 17-AAG. Because of delayed grade 2 transaminitis, treatment was held on cycle 3, week 2 (day 53), and again during cycle 4, week 3 (day 81). Following the second treatment delay, 17-AAG was resumed but at the next lower dose level (150 mg/m²) on day 92. Following dose reduction, the patient’s PSA began to increase. B and C, serum levels of 17-AAG and 17-AG (B) and PBMC studies (C) from this patient. Pharmacodynamic studies of PBMCs show a heat shock response with induction of Hsp70 and down-regulation of Akt and Raf-1 by day 15.

Fig. 2

A and B, relationship between 17-AAG dose and 17-AAG C_max (A) and 17-AAG AUC (B). C, relationship between 17-AAG AUC and 17-AG AUC.

Fig. 3

Induction of Hsp70 and down-regulation of Akt expression in PBMCs collected from patients treated with 17-AAG. A, Western blot analysis of PBMCs of patients treated with 17-AAG on the continuous twice-weekly dosing schedule. PBMCs were collected on days 1, 2, 3, 4, 8, and 15 of cycle 1. Samples on days 1, 4, 8, and 15 were collected pretreatment. p85 phosphatidylinositol 3-kinase (PI3k) was used as a loading control because this protein is unaffected by Hsp90 inhibition. B, quantitation of the Akt Western blot results for patients treated at the 210 mg/m² dose level. Akt expression levels were normalized to each patient’s day 1 pretreatment sample.