A phase I study of PF-04929113 (SNX-5422), an orally bioavailable heat shock protein 90 inhibitor, in patients with refractory solid tumor malignancies and lymphomas

Arun Rajan, Ronan J. Kelly, Jane B. Trepel, Yeong Sang Kim, Sylvia V. Alarcon, Shivaani Kummar, Martin Gutierrez, Sonja Crandon, Wadih M. Zein, Lokesh Jain, Baskar Mannargudi, William D. Figg, Brett E. Houk, Michael Shnaidman, Nicoletta Brega, Giuseppe Giaccone

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: To determine the maximum tolerated dose (MTD), toxicities, and pharmacokinetic/pharmacodynamic profile of the Hsp90 inhibitor PF-04929113 (SNX-5422) in patients with advanced solid tumors and lymphomas. Methods: This was a single-institution, phase I, dose-escalation study of PF-04929113 administered twice weekly. Endpoints included determination of dose-limiting toxicities (DLT), MTD, the safety profile of PF-04929113, pharmacodynamic assessment of PF-04929113 on Hsp70 induction, pharmacokinetic analysis of PF-04928473 (SNX-2112) and its prodrug PF-04929113, and assessment of response. Results: Thirty-three patients with advancedmalignancies were treated. Dose escalation was continued up to 177 mg/m2 administered orally twice a week. One DLT (nonseptic arthritis) was noted. No grade 4 drugrelated adverse events were seen; grade 3 adverse events included diarrhea (9%), nonseptic arthritis (3%), aspartateaminotransferase elevation (3%), and thrombocytopenia (3%).Noobjective responses were seen in 32 evaluable patients. Fifteen patients (47%) had stable disease; 17 patients (53%) had progressive disease. Pharmacokinetic data revealed rapid absorption, hepatic, and extrahepatic clearance, extensive tissue binding, and almost linear pharmacokinetics of the active drug PF-04928473. Pharmacodynamic studies confirmed inhibition of Hsp90 and a linear correlation between pharmacokinetic parameters and Hsp70 induction. Conclusions: PF-04929113 administered orally twice a week is well tolerated and inhibits its intended target Hsp90. No objective responses were seen, but long-lasting stabilizations were obtained. Although no clinically significant drug-related ocular toxicity was seen in this study, the development of PF-04929113 has been discontinued because of ocular toxicity seen in animal models and in a separate phase I study.

Original languageEnglish (US)
Pages (from-to)6831-6839
Number of pages9
JournalClinical Cancer Research
Volume17
Issue number21
DOIs
StatePublished - Nov 1 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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