First-in-human phase I study: Results of a second-generation non-ansamycin heat shock protein 90 (HSP90) inhibitor AT13387 in refractory solid tumors.

Abstract

3028 Background: AT13387 is a second-generation potent, novel non-ansamycin HSP90 inhibitor (IC50 0.71 nM). AT13387 has good tissue distribution, long tumor t1/2 resulting in extended knockdown of client proteins in cells and animal models of gastric, prostate and melanoma. Methods: AT13387 was administered as a 1-hr IV infusion twice weekly on Days 1, 4, 8, 11, 15 and 18 (Part A) and then subsequently, weekly on Days 1, 8 and 15 (Part B) of a 28-day cycle in a standard 3+3 dose-escalation design. The primary endpoint was to determine the MTD; secondary endpoints included PK, PD, safety and tolerability. Results: As of 1 Dec 2011, 53 patients received 1–12 cycles of AT13387 (median 2). In Part A, AT13387 was evaluated at 5 doses (10, 20, 40, 80, 120 mg/m2). In Part B, 4 additional doses (150, 220, 260 and 310 mg/m2) were explored. Common treatment related toxicities (≥ 10%) included transient and reversible GI disturbance (vomiting, nausea, dry mouth, diarrhea, abdominal pain), fatigue, local infusion site irritation and systemic infusion-related symptoms including chills, rash, itch, cardiovascular (tachycardia, bradycardia, hypertension, hypotension), and visual changes (diplopia, transient flashes, delayed light/dark accommodation, blurred vision). Severity of infusion-related symptoms, GI toxicities, and fatigue at 310 mg/m2 prevented further dose escalation. A dose of 260 mg/m2 has been identified as the once weekly MTD and the study is currently accruing at this dose. Biological evidence of HSP90 inhibition, demonstrated by an increase in HSP70 in PBMCs, was detected at all doses and exhibited evidence of dose dependence. PK demonstrated dose proportionality, without significant accumulation. One durable RECIST PR (8 months) in an imatinib relapsed metastatic GIST patient with c-kit mutations in exons 11 and 17 was observed. Three SD ≥ 6 months (follicular cell thyroid carcinoma, metastatic uveal melanoma, GIST) were also observed. Conclusions: The MTD of AT13387, administered as a once weekly IV, is 260 mg/m2. All drug-related toxicities were generally reversible. Single-agent activity was observed. Dose expansion at MTD and phase II studies are ongoing.