A phase I trial of docetaxel and pulse-dose 17-allylamino-17- demethoxygeldanamycin in adult patients with solid tumors Journal Article
| Authors: | Iyer, G.; Morris, M. J.; Rathkopf, D.; Slovin, S. F.; Steers, M.; Larson, S. M.; Schwartz, L. H.; Curley, T.; Delacruz, A.; Ye, Q.; Heller, G.; Egorin, M. J.; Ivy, S. P.; Rosen, N.; Scher, H. I.; Solit, D. B. |
| Article Title: | A phase I trial of docetaxel and pulse-dose 17-allylamino-17- demethoxygeldanamycin in adult patients with solid tumors |
| 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. © 2011 Springer-Verlag. |
| Keywords: | docetaxel; 17-aag; geldanamycin; hsp90; phase i |
| Journal Title: | Cancer Chemotherapy and Pharmacology |
| Volume: | 69 |
| Issue: | 4 |
| ISSN: | 0344-5704 |
| Publisher: | Springer |
| Date Published: | 2012-04-01 |
| Start Page: | 1089 |
| End Page: | 1097 |
| Language: | English |
| DOI: | 10.1007/s00280-011-1789-3 |
| PROVIDER: | scopus |
| PUBMED: | 22124669 |
| PMCID: | PMC3471133 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 1 May 2012" - "CODEN: CCPHD" - "Source: Scopus" |
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