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Cancer Chemother Pharmacol. 2012 Apr;69(4):1089-97. doi: 10.1007/s00280-011-1789-3. Epub 2011 Nov 29.

A phase I trial of docetaxel and pulse-dose 17-allylamino-17-demethoxygeldanamycin in adult patients with solid tumors.

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1
Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.

Abstract

PURPOSE:

To define maximum tolerated dose (MTD), clinical toxicities, and pharmacokinetics of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when administered in combination with docetaxel once every 21 days in patients with advanced solid tumor malignancies.

EXPERIMENTAL DESIGN:

Docetaxel was administered over 1 h at doses of 55, 70, and 75 mg/m(2). 17-AAG was administered over 1-2 h, following the completion of the docetaxel infusion, at escalating doses ranging from 80 to 650 mg/m(2) in 12 patient cohorts. Serum was collected for pharmacokinetic and pharmacodynamic studies during cycle 1. Docetaxel, 17-AAG, and 17-AG levels were determined by high-performance liquid chromatography. Biologic effects of 17-AAG were monitored in peripheral blood mononuclear cells by immunoblot.

RESULTS:

Forty-nine patients received docetaxel and 17-AAG. The most common all-cause grade 3 and 4 toxicities were leukopenia, lymphopenia, and neutropenia. An MTD was not defined; however, three dose-limiting toxicities were observed, including 2 incidences of neutropenic fever and 1 of junctional bradycardia. Dose escalation was halted at docetaxel 75 mg/m(2)-17-AAG 650 mg/m(2) due to delayed toxicities attributed to patient intolerance of the DMSO-based 17-AAG formulation. Of 46 evaluable patients, 1 patient with lung cancer experienced a partial response. Minor responses were observed in patients with lung, prostate, melanoma, and bladder cancers. A correlation between reduced docetaxel clearance and 17-AAG dose level was observed.

CONCLUSIONS:

The combination of docetaxel and 17-AAG was well tolerated in adult patients with solid tumors, although patient intolerance to the DMSO formulation precluded further dose escalation. The recommended phase II dose is docetaxel 70 mg/m(2) and 17-AAG 500 mg/m(2).

PMID:
22124669
PMCID:
PMC3471133
DOI:
10.1007/s00280-011-1789-3
[Indexed for MEDLINE]
Free PMC Article

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