Phase I study of the heat shock protein 90 (Hsp90) inhibitor onalespib (AT13387) administered on a daily for 2 consecutive days per week dosing schedule in patients with advanced solid tumors

Khanh Do, Giovanna Speranza, Lun Ching Chang, Eric C. Polley, Rachel Bishop, Weimin Zhu, Jane B. Trepel, Sunmin Lee, Min Jung Lee, Robert J. Kinders, Larry Phillips, Jerry Collins, John Lyons, Woondong Jeong, Ramya Antony, Alice P. Chen, Len Neckers, James H. Doroshow, Shivaani Kummar

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Inhibition of heat shock 90 (Hsp90) molecular chaperones allows targeting of multiple proteins involved in tumorigenesis. We investigated the safety, recommended phase 2 dose (RP2D), and pharmacokinetic and pharmacodynamic profile of onalespib (AT13387), a potent synthetic Hsp90 inhibitor, administered on days 1, 2, 8, 9, 15, and 16 of 28 day cycles (QDx2/week) in a phase I trial. This study followed an accelerated titration design with a starting dose of 20 mg/m2/dose and a standard 3+3 dose escalation design for dose level 4 (120 mg/m2/dose) and above. Additional patients were enrolled at the RP2D with mandatory paired tumor biopsies to assess modulation of 210 client proteins using reverse phase protein array analysis. Thirty-one patients were treated; RP2D was established at 160 mg/m2/dose on the QDx2/week schedule. Common toxicities were gastrointestinal, hepatic, and hematologic. Pharmacokinetic profile was linear and plasma levels increased proportionally with dose (T1/2 ∼8 h). No responses were observed; eight patients had stable disease for > 2 cycles with one patient remaining on study for 6 cycles. Target engagement was demonstrated by transcriptional upregulation of Hsp70 and Hsp27 in PBMCs. Statistically significant modulation of client proteins was not achieved in the 9 paired tumor biopsies evaluated; however, hierarchical clustering revealed two subgroups of patients with differential patterns of protein expression. Further combination studies are needed in order to target prospective driver oncoproteins.

Original languageEnglish (US)
Pages (from-to)921-930
Number of pages10
JournalInvestigational New Drugs
Volume33
Issue number4
DOIs
StatePublished - Aug 1 2015

Keywords

  • Hsp27 heat-shock proteins
  • Hsp70 heat-shock proteins
  • Hsp90 inhibitor
  • Molecular chaperones
  • Proteolysis

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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    Do, K., Speranza, G., Chang, L. C., Polley, E. C., Bishop, R., Zhu, W., Trepel, J. B., Lee, S., Lee, M. J., Kinders, R. J., Phillips, L., Collins, J., Lyons, J., Jeong, W., Antony, R., Chen, A. P., Neckers, L., Doroshow, J. H., & Kummar, S. (2015). Phase I study of the heat shock protein 90 (Hsp90) inhibitor onalespib (AT13387) administered on a daily for 2 consecutive days per week dosing schedule in patients with advanced solid tumors. Investigational New Drugs, 33(4), 921-930. https://doi.org/10.1007/s10637-015-0255-1