Phase 1 study of onalespib, HSP90 inhibitor, and AT7519M, CDK9 inhibitor, in patients with advanced solid tumors.

Abstract

TPS2617 Background: The 90kDa heat shock chaperone protein (HSP90) exerts housekeeping functions within cells. HSP90 participates in the folding, stabilization, activation, and proteolytic turnover of mutant or over-expressed “client proteins” that contribute to the growth and survival of cancer cells. HSP90 inhibition leads to degradation of these aberrant proteins through the ubiquitin-proteasome pathway, allowing for simultaneous targeting of multiple pathways. Inhibition of HSP90 alone stimulates a compensatory upregulation of HSP70, which is anti-apoptotic at the pre-mitochondrial, mitochondrial and post-mitochondrial levels. The transcriptional induction of HSP70 has been linked to the activity of CDK9. In vitro and in vivo studies show that disruption of HSP70 induction by CDK9 inhibition can augment HSP90 inhibitor responses. Combined inhibition of HSP90 and CDK9 may produce synergistic anti-tumor activity. Methods: We are conducting an a phase I trial of the combination of the HSP90 inhibitor onalespib, and the CDK9 inhibitor AT7519, utilizing a 3+3 trial design, with dose-limiting toxicities defined during cycle 1. Estimated enrollment: 37 patients. Onalespib and AT7519M are both administered on days 1, 4, 8, and 11 of a 21-day cycle following a 1-week lead-in of onalespib alone to facilitate PK/PD endpoints. Patients must have histologically confirmed solid tumors that have progressed on standard of care therapy or for which no standard treatment exists, with an ECOG 0-1. Exclusion criteria include a prolonged QTc interval (Fridericia formula), pre-existing retinal disease, or cardiac dysfunction with EF < 50% at study entry. Current pharmacodynamic analyses include the analysis of HSP70 expression in plasma and peripheral blood mononuclear cells after treatment with onalespib, and after the combination, as proof-of-principle of target inhibition. At this time, DL1 has completed enrollment; accrual is ongoing with measurement of HSP90 client proteins and HSP70 levels in patient plasma and PBMC samples. This trial is open through the ETCTN. Clinical trial information: NCT02503709.