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 language | English (US) |
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Pages (from-to) | 921-930 |
Number of pages | 10 |
Journal | Investigational New Drugs |
Volume | 33 |
Issue number | 4 |
DOIs | |
State | Published - 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)