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Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics
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A first-in-human phase I, dose-escalation, multicentre study of HSP990 administered orally in adult patients with

A Spreafico1, J-P Delord2, L De Mattos-Arruda3

  • 1Drug Development Program, UHN - Princess Margaret Cancer Centre, Division of Medical Oncology and Hematology, Department of Medicine, University of Toronto, Toronto, ON, Canada.

British Journal of Cancer
|January 28, 2015
PubMed
Abstract

Insights

Heat-shock protein 990 (HSP990), a novel HSP90 inhibitor, demonstrated acceptable tolerability in a Phase I trial. The recommended dose for further studies was established at 50 mg once weekly, with neurological toxicity as the main dose-limiting factor.

Area of Science:

  • Oncology
  • Pharmacology
  • Clinical Trials

Background:

  • Heat-shock protein 990 (HSP990) is a novel, potent, and selective small-molecule inhibitor targeting HSP90.
  • HSP90 inhibition is a promising strategy in cancer therapy by destabilizing client proteins crucial for tumor cell survival and proliferation.

Purpose of the Study:

  • To evaluate the safety and tolerability of HSP990 in patients with advanced solid tumors.
  • To determine the dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD), and recommended Phase II dose (RP2D) of HSP990.
  • To characterize the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of HSP990.

Main Methods:

  • A Phase I, first-in-human study involving oral administration of HSP990.
  • Dose escalation was performed using a Bayesian logistic regression model with overdose control.
  • Patients received HSP990 once or twice weekly on a 28-day cycle.

Main Results:

  • Sixty-four patients with advanced solid tumors were enrolled.
  • The maximum-tolerated dose (MTD) was determined to be 50 mg once weekly due to dose-limiting neurological toxicities.
  • Common adverse events included diarrhea, fatigue, and decreased appetite; no objective responses were observed, but 25 patients achieved stable disease.

Conclusions:

  • HSP990 exhibits a manageable safety profile, with neurological toxicity being the primary dose-limiting factor.
  • The recommended Phase II dose (RP2D) for single-agent HSP990 was established at 50 mg once weekly.
  • Further investigation of HSP990 in combination therapies or specific patient populations may be warranted.

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