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A phase I study of the heat shock protein 90 inhibitor alvespimycin (17-DMAG) given intravenously to patients with advanced solid tumors.

ABSTRACT: PURPOSE:A phase I study to define toxicity and recommend a phase II dose of the HSP90 inhibitor alvespimycin (17-DMAG; 17-dimethylaminoethylamino-17-demethoxygeldanamycin). Secondary endpoints included evaluation of pharmacokinetic profile, tumor response, and definition of a biologically effective dose (BED). PATIENTS AND METHODS:Patients with advanced solid cancers were treated with weekly, intravenous (i.v.) 17-DMAG. An accelerated titration dose escalation design was used. The maximum tolerated dose (MTD) was the highest dose at which ? 1/6 patients experienced dose limiting toxicity (DLT). Dose de-escalation from the MTD was planned with mandatory, sequential tumor biopsies to determine a BED. Pharmacokinetic and pharmacodynamic assays were validated prior to patient accrual. RESULTS:Twenty-five patients received 17-DMAG (range 2.5-106 mg/m(2)). At 106 mg/m(2) of 17-DMAG 2/4 patients experienced DLT, including one treatment-related death. No DLT occurred at 80 mg/m(2). Common adverse events were gastrointestinal, liver function changes, and ocular. Area under the curve and mean peak concentration increased proportionally with 17-DMAG doses 80 mg/m(2) or less. In peripheral blood mononuclear cells significant (P < 0.05) HSP72 induction was detected (? 20 mg/m(2)) and sustained for 96 hours (? 40 mg/m(2)). Plasma HSP72 levels were greatest in the two patients who experienced DLT. At 80 mg/m(2) client protein (CDK4, LCK) depletion was detected and tumor samples from 3 of 5 patients confirmed HSP90 inhibition. Clinical activity included complete response (castration refractory prostate cancer, CRPC 124 weeks), partial response (melanoma, 159 weeks), and stable disease (chondrosarcoma, CRPC, and renal cancer for 28, 59, and 76 weeks, respectively). CONCLUSIONS:The recommended phase II dose of 17-DMAG is 80 mg/m(2) weekly i.v.

SUBMITTER: Pacey S

PROVIDER: S-EPMC3060938 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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A phase I study of the heat shock protein 90 inhibitor alvespimycin (17-DMAG) given intravenously to patients with advanced solid tumors.

Pacey Simon S Wilson Richard H RH Walton Mike M Eatock Martin M MM Hardcastle Anthea A Zetterlund Anna A Arkenau Hendrik-Tobias HT Moreno-Farre Javier J Banerji Udai U Roels Belle B Peachey Heidi H Aherne Wynne W de Bono Johan S JS Raynaud Florence F Workman Paul P Judson Ian I

Clinical cancer research : an official journal of the American Association for Cancer Research 20110128 6

<h4>Purpose</h4>A phase I study to define toxicity and recommend a phase II dose of the HSP90 inhibitor alvespimycin (17-DMAG; 17-dimethylaminoethylamino-17-demethoxygeldanamycin). Secondary endpoints included evaluation of pharmacokinetic profile, tumor response, and definition of a biologically effective dose (BED).<h4>Patients and methods</h4>Patients with advanced solid cancers were treated with weekly, intravenous (i.v.) 17-DMAG. An accelerated titration dose escalation design was used. The ...[more]

PMID: 21278242

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Project description:PurposeTo identify sources of exposure variability for the tumor growth inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) using a population pharmacokinetic analysis.MethodsA total 67 solid tumor patients at 2 centers were given 1 h infusions of 17-DMAG either as a single dose, daily for 3 days, or daily for 5 days. Blood samples were extensively collected and 17-DMAG plasma concentrations were measured by liquid chromatography/mass spectrometry. Population pharmacokinetic analysis of the 17-DMAG plasma concentration with time was performed using nonlinear mixed effect modeling to evaluate the effects of covariates, inter-individual variability, and between-occasion variability on model parameters using a stepwise forward addition then backward elimination modeling approach. The inter-individual exposure variability and the effects of between-occasion variability on exposure were assessed by simulating the 95 % prediction interval of the AUC per dose, AUC(0-24 h), using the final model and a model with no between-occasion variability, respectively, subject to the five day 17-DMAG infusion protocol with administrations of the median observed dose.ResultsA 3-compartment model with first order elimination (ADVAN11, TRANS4) and a proportional residual error, exponentiated inter-individual variability and between occasion variability on Q2 and V1 best described the 17-DMAG concentration data. No covariates were statistically significant. The simulated 95% prediction interval of the AUC(0-24 h) for the median dose of 36 mg/m(2) was 1,059-9,007 mg/L h and the simulated 95 % prediction interval of the AUC(0-24 h) considering the impact of between-occasion variability alone was 2,910-4,077 mg/L h.ConclusionsPopulation pharmacokinetic analysis of 17-DMAG found no significant covariate effects and considerable inter-individual variability; this implies a wide range of exposures in the population and which may affect treatment outcome. Patients treated with 17-DMAG may require therapeutic drug monitoring which could help achieve more uniform exposure leading to safer and more effective therapy.

Dataset Information

A phase I study of the heat shock protein 90 inhibitor alvespimycin (17-DMAG) given intravenously to patients with advanced solid tumors.

Publications

A phase I study of the heat shock protein 90 inhibitor alvespimycin (17-DMAG) given intravenously to patients with advanced solid tumors.

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