Heat shock protein 90 (HSP90) is a molecular chaperone required for proper folding and stabilization of proteins. Client proteins of HSP90 include many oncogenic proteins known to be over-activated in triple negative breast cancer (TNBC) such as AKT, EGFR and members of RAS/MAPK signaling pathway. Over-expression of HSP90 client proteins such as AKT and c-RAF has also been implicated in paclitaxel resistance. Onalespib (AT13387) is a potent non-ansamycin small molecule inhibitor of HSP90.
Patients (pts) with inoperable or metastatic, TNBC were treated with onalespib and paclitaxel on days 1, 8, 15 every 28 days. Paclitaxel was given at a dose of 80 mg/m2 while the dose of onalespib was gradually increased from 120 mg/m2 to 260 mg/m2 in dose levels (DL) 1-4 using standard 3 + 3 design. In order to assess the effect of each drug on pharmacokinetics (PK) of the other drug, onalespib was given on day -7 prior to cycle 1 and skipped on day 1 of cycle 1. The primary objective was to determine dose limiting toxicities (DLT) and maximum tolerated dose (MTD). The secondary objectives were PKs of each agent, overall response rate (ORR), response duration and progression-free survival.
20 pts were enrolled to dose escalation part (5, 3, 7 and 6 to DL 1-4 respectively). One pt in DL 1 did not start therapy due history of severe paclitaxel hypersensitivity and 2 pts (DL1 and DL 3) had to be replaced due to disease progression in cycle 1. One DLT occurred in 1 pt in DL3 (grade 3 nausea, vomiting and abdominal pain). No DLTs were noted in the highest DL testing onalespib at 260 mg/m2. The most common grade 3 or higher adverse events included diarrhea (55%), fatigue (55%), anemia (14%), leukopenia (24%) and neutropenia (41%). Diarrhea was self limiting, lasting 24-48 hrs post infusion and responded well to loperamide. ORR and clinical benefit rate in 16 evaluable pts was 25% and 62.5% respectively. Preliminary PK analysis showed no evidene of interaction between onalespib and paclitaxel.
Study regimen demonstrated acceptable safety profile. MTD of onalespib in combination with standard dose and schedule of paclitaxel was determined to be 260 mg/m2. Dose expansion study at MTD is currently ongoing.
NCI 9876 (NCT02474173).
Not applicable
Robert Wesolowski, MD.
Cancer Therapy Evaluation Program at the National Cancer Institute.
All authors have declared no conflicts of interest.