A Phase 1 and Pharmacokinetic Study of Ganetespib (STA-9090), a Heat Shock Protein 90 Inhibitor, in Combination With Docetaxel in Subjects With Advanced Solid Tumour Malignancies
R.D. Harvey1, C.M. Lewis1, J.S. Kauh1, T.K. Owonikoko1, A. Akintayo1, M. Karol2, F. Teofilovici2, J.M. Lufkin2, F.R. Khuri1, S.S. Ramalingam1 1Winship Cancer Institute of Emory University, Department of Hematology and Medical Oncology, Atlanta GA, USA ; 2Synta Pharmaceuticals, Clinical Development, Lexington MA, USA
Background: Ganetespib is a potent, next-generation Hsp90 inhibitor that is structurally unrelated to the first-generation ansamycin class of Hsp90 inhibitors and has shown superior activity to these agents in preclinical studies. Ganetespib has been well tolerated and has shown promising single-agent antitumour activity in early trials in multiple cancers. Based on preclinical synergy between ganetespib (G) and docetaxel (D), a phase I pharmacokinetic (PK) and feasibility study was initiated with the combination.
Materials and Methods: Patients (pts) with advanced solid tumour 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) administered as an 1-hr separate infusion in a 3-week cycle. PK sampling was performed on days 1/8 of cycle 1. The primary endpoint was determination of optimal doses of the two agents for combination therapy.
Results: Thirteen pts were enrolled in the dose escalation phase. Median age-63 (44–72); 2-M, 11-F; ECOG PS 0–1, 1, 12. At dose levels 1 (D-60mg/m2, G-150mg/m2) and 2 (D-75mg/m2, G-150mg/m2), none of 6 pts initially treated had a DLT. Two of 4 pts at dose level 3 (D-75mg/m2, G-200mg/m2) had DLTs (g4 febrile neutropenia and one g4 neutropenia of >7 days), requiring expansion of dose level 2. As no other DLTS were observed; level 2 was the expansion cohort. Common AEs included neutropenia (n=10), diarrhea, anemia and fatigue (n=4 each), nausea and febrile neutropenia (n=3 each). Common g 3/4 AEs included neutropenia (n=10) and febrile neutropenia (n=3). The median number of cycles received is 4 (1–8), with 6 pts still on study. Among 10 pts evaluable for response, 7 had disease stabilization following cycle 2 (6 weeks), 4 pts to 12 weeks and 1 pt to 18 weeks. PK data from dose level 1 indicates PK similarity between G administered alone and G administered prior to D. No drug accumulation was observed following once-weekly dosing which is consistent with other studies where G was administered alone. Additional PK data will be presented.
Conclusions: The combination of docetaxel and ganetespib is well tolerated at the recommended doses of 75mg/m2 and 150mg/m2. Promising anti-cancer activity was noted, and a randomized phase II study of the combination has been initiated in advanced NSCLC.