A phase I and pharmacokinetic study of multiple schedules of ganetespib (STA-9090), a heat shock protein 90 inhibitor, in combination with docetaxel for subjects with advanced solid tumor malignancies.

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3094 Background: Ganetespib is a next-generation Hsp90 inhibitor unrelated to the first-generation ansamycin class of Hsp90 inhibitors and has superior activity to these agents in preclinical studies. Ganetespib is well tolerated with promising antitumor activity. Based on synergy between ganetespib (G) and docetaxel (D), a phase I study evaluating preclinical dosing models was performed. Methods: Patients (pts) with advanced solid tumor malignancies and ECOG performance status (PS) 0-2 were eligible. Sequential cohorts of pts were treated (3+3 design) with increasing doses of D (day 1) and G (days 1, 8) (A) Q 21 days. Following MTD determination, safety and exploratory cohorts of D day 1 with G days 1, 15 (B); or G days 1, 4, 15 (C) were completed. PK sampling was performed during schedule A. The primary endpoint was determination of optimal doses and schedule of the two agents for combination therapy. Results: Twenty-seven patients were enrolled in schedules A (n=12), B (n=8), and C (n=7). Median age-64 (44-75); 11-M, 16-F; ECOG PS: 0 (n=5), 1 (n=21), 2 (n=1). Most pts had NSCLC (n=9), others were head/neck (n=4), and SCLC (n=3). The defined MTD was level 2 (D-75 mg/m2, G-150 mg/m2), as 2 of 4 pts at level 3 (D-75 mg/m2, G-200 mg/m2) had DLTs (febrile neutropenia and one g4 neutropenia of > 7 days), requiring expansion of level 2. The median number of cycles received is 2 (1-11), with 3 pts in schedule C still on study. Among 22 pts evaluable for response, 1 had a PR (head/neck), 12 had SD following 6 weeks evaluation, 10 pts for 12 weeks and 6 pts for 18 weeks. Common AEs included neutropenia, diarrhea, anemia, fatigue, nausea, and febrile neutropenia. Prophylactic filgrastim/pegfilgrastim was not used at any time. PK data indicates similar G exposure alone compared to G administered prior to D. No accumulation was observed following once-weekly dosing, consistent with studies of G alone. Conclusions: The combination is well tolerated at the recommended doses of D 75 mg/m2 and G 150 mg/m2. Promising anti-cancer activity was noted, and a randomized phase 2b/3 study with D day 1 and G days 1, 15 regimen is ongoing in advanced NSCLC (NCT01348126).