First-in-human study of the epichaperome inhibitor PU-H71: clinical results and metabolic profile

Giovanna Speranza, Larry Anderson, Alice P. Chen, Khanh Do, Michelle Eugeni, Marcie Weil, Larry Rubinstein, Eva Majerova, Jerry Collins, Yvonne Horneffer, Lamin Juwara, Jennifer Zlott, Rachel Bishop, Barbara A. Conley, Howard Streicher, Joseph Tomaszewski, James H. Doroshow, Shivaani Kummar

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


Background Molecular chaperone targeting has shown promise as a therapeutic approach in human cancers of various histologies and genetic backgrounds. The purine-scaffold inhibitor PU-H71 (NSC 750424), selective for Hsp90 in epichaperome networks, has demonstrated antitumor activity in multiple preclinical cancer models. The present study was a first in-human trial of PU-H71 aimed at establishing its safety and tolerability and characterizing its pharmacokinetic (PK) profile on a weekly administration schedule in human subjects with solid tumors refractory to standard treatments. Methods PU-H71 was administered intravenously over 1 h on days 1 and 8 of 21-day cycles in patients with refractory solid tumors. Dose escalation followed a modified accelerated design. Blood and urine were collected during cycles 1 and 2 for pharmacokinetics analysis. Results Seventeen patients were enrolled in this trial. Grade 2 and 3 adverse events were observed but no dose limiting toxicities occurred, thus the human maximum tolerated dose was not determined. The mean terminal half-life (T1/2) was 8.4 ± 3.6 h, with no dependency to dose level. A pathway for the metabolic disposal of PU-H71 in humans was derived from microsome studies. Fourteen patients were also evaluable for clinical response; 6 (35%) achieved a best response of stable disease for >2 cycles, with 2 patients remaining on study for 6 cycles. The study closed prematurely due to discontinuation of drug supply. Conclusions PU-H71 was well tolerated at the doses administered during this study (10 to 470 mg/m2/day), with no dose limiting toxicities.

Original languageEnglish (US)
Pages (from-to)230-239
Number of pages10
JournalInvestigational New Drugs
Issue number2
StatePublished - Apr 1 2018
Externally publishedYes


  • Cancer
  • Epichaperome
  • Hsp90
  • PU-H71
  • Pharmacokinetics

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)


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