Abstract CT033: Phase 1b study of heat shock protein 90 inhibitor onalespib in combination with paclitaxel in patients with advanced, triple-negative breast cancer (NCT02474173)

Background: Heat shock protein 90 (HSP90) is a molecular chaperone that is required for proper folding and stabilization of proteins. Client proteins of HSP90 include many mediators of signal transduction known to be over-activated in triple negative breast cancer such as AKT, EGFR, members of RAS/MAPK signaling pathways and androgen receptor. Expression of HSP90 has been found to be upregulated in multiple triple negative breast cancer cell lines and associated with poor outcome of breast cancer patients. In addition, over-expression of HSP90 client proteins such as AKT and c-RAF has been implicated in paclitaxel resistance. Onalespib (AT13387) is a synthetic non-ansamycin small molecule that acts as an inhibitor of HSP90 by binding to the amino terminal of the protein and has dissociation constant (Kd) of 0.71 nM. Materials and Methods: Patients with inoperable or metastatic triple negative or weakly hormone receptor positive breast cancer are treated with onalespib and paclitaxel on days 1, 8, 15 every 28 days. Paclitaxel is given at a standard dose of 80 mg/m2 while the dose of onalespib is gradually increased using standard 3+3 design (see table). In order to assess the effect of each drug on pharmacokinetics of the other drug, onalespib is given on day -7 prior to cycle 1 and skipped on day 1 of cycle 1 during which paclitaxel in administered alone. The primary objective of the study is to determine recommended phase 2 dose and assess the toxicity profile of the combination. The secondary objectives include effect of onalespib on pharmacokinetics of paclitaxel and effect of paclitaxel on pharmacokinetics of onalespib. Overall response rate, response duration and progression-free survival will also be assessed. Conclusion: The study opened to accrual on January 15, 2016 and is currently enrolling the first 3 patients to dose level 1. Citation Format: Robert Wesolowski, Maryam B. Lustberg, Ewa Mrozek, Rachel Layman, Raquel Reinbolt, Ming Poi, Nadia Osman, Andrea Lively, Julie Stephens, Michael Grever, Bhuvaneswari Ramaswamy. Phase 1b study of heat shock protein 90 inhibitor onalespib in combination with paclitaxel in patients with advanced, triple-negative breast cancer (NCT02474173). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT033.