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01.04.2012 | Clinical Trial Report

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

verfasst von: Gopa Iyer, Michael J. Morris, Dana Rathkopf, Susan F. Slovin, Macaulay Steers, Steven M. Larson, Lawrence H. Schwartz, Tracy Curley, Anthony DeLaCruz, Qing Ye, Glenn Heller, Merrill J. Egorin, S. Percy Ivy, Neal Rosen, Howard I. Scher, David B. Solit

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 4/2012

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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/m². 17-AAG was administered over 1–2 h, following the completion of the docetaxel infusion, at escalating doses ranging from 80 to 650 mg/m² 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/m²-17-AAG 650 mg/m² 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/m² and 17-AAG 500 mg/m².

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Titel: A phase I trial of docetaxel and pulse-dose 17-allylamino-17-demethoxygeldanamycin in adult patients with solid tumors
verfasst von: Gopa Iyer
Michael J. Morris
Dana Rathkopf
Susan F. Slovin
Macaulay Steers
Steven M. Larson
Lawrence H. Schwartz
Tracy Curley
Anthony DeLaCruz
Qing Ye
Glenn Heller
Merrill J. Egorin
S. Percy Ivy
Neal Rosen
Howard I. Scher
David B. Solit
Publikationsdatum: 01.04.2012
Verlag: Springer-Verlag
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 4/2012
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-011-1789-3

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