Abstract A110: A phase 1 study of PF‐04929113 (SNX5422), an orally bioavailable heat shock protein 90 (Hsp90) inhibitor administered twice weekly in patients with refractory solid tumor malignancies and lymphoma

Introduction: Hsp90 inhibitors have the potential for broad anti‐cancer effects based on the spectrum of known client proteins and increased effect on mutations that drive malignant transformation and cancer growth. PF‐04929113 (SNX5422; 113) is a novel, oral, non‐antibiotic, selective Hsp90 inhibitor prodrug, with preclinical anti‐tumor activity in multiple tumor models. The objective of this study was to evaluate the tolerability and describe the PK of 113 and its active moiety (PF‐ 04928473 /SNX2112; 473) in patients with refractory solid tumor malignancies and lymphoma. Methods: Twenty‐six subjects have been enrolled to date in this Phase 1, open‐label, dose‐escalation study. Subjects were treated with oral 113 twice weekly without interruption at doses ranging from 4 to 100 mg/m 2 . PBMCs were isolated and collected at baseline and various time points after‐treatment. Cell lysates from PBMCs were assayed for Hsp70 and AKT protein level using Meso Scale Discovery (MSD) technology. Serial plasma concentrations of 473 were measured by LC‐MS/MS after the first dose (Day 1) and after 6 doses (Day 18). PK parameters (mean ± standard deviation) were calculated using non‐compartmental methods in WinNonlin v5.0. Results: MTD for this schedule has not yet been reached. So far it has been well tolerated. Related adverse events were mainly low grade (most frequent nausea 31%) with grade ≥ 3 were reported in 8% (diarrhea and arthritis, 1 patient each). Based on results of interim pharmacokinetic analysis for doses 4 to 44 mg/m 2 , median time to 473 peak plasma concentrations was 2 h (range 0.33–4 h) and median half‐life was ∼8.5h both at days 1 and 18. The median (range) CL/F m at day 1 and day 18 were, 24.7 (12.9–81.2) L/hr and 22.6 (8.6–55.6) L/hr, respectively and was consistent across the dose range. Hsp70 was elevated with drug treatment, and further elevations were noted with increasing weekly dose. Although to date, no patients have achieved PR, several have experienced prolonged stable disease including medullary thyroid cancer (>450 days), lymphoma (>150 days), and esophagus, colon, adenoid cystic, lung carcinoid, and peritoneal mesothelioma (>100 days). Conclusions: This schedule is well tolerated with no significant drug accumulation, few severe toxicities and potential for efficacy based on prolonged stable disease. Maximal concentrations of 113 were observed 2 h after oral administration of prodrug 113. Concentrations achieved were consistent with the preclinical activity. Accrual to the study to establish MTD is ongoing. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A110.