A Phase 1 dose-escalation study of the safety and pharmacokinetics (PK) of the oral Hsp90 inhibitor SNX-5422

Abstract

14613 Background: SNX-5422 is an oral pro-drug of SNX-2112, a potent and highly selective small-molecule inhibitor of the molecular chaperone heat shock protein 90 (Hsp90). SNX-2112 potently inhibits solid and hematological tumor cell proliferation with IC50 values of 1–10 nM, and is more potent than 17-AAG and 17-DMAG in a majority of the cell lines tested. Due to its involvement in the maturation and maintenance of numerous proteins critical for tumor cell viability and growth, Hsp90 is an exciting therapeutic target for a broad range of solid tumor and hematological malignancies. Methods: Eligibility included patients (pt) with refractory solid tumors or lymphomas, Karnofsky performance status ≥60, adequate organ function, and no known CNS involvement, primary or metastatic. SNX-5422 was given orally every other day daily for 21 days followed by 7 days of rest. Dose escalation is proceeding at 100% with standard 3 pt cohorts until a grade (gr) 2 adverse event (AE) occurs, then escalation decreases to 33%. The objectives are to determine the dose limiting toxicities (DLTs) and maximum tolerated dose (MTD), safety, and PK of SNX-5422. Results: 11 patients have been dosed to date; 3 in cohort 1 (4 mg/m2); 3 in cohort 2 (5.32 mg/m2); 4 in cohort 3 (10.64 mg/m2); and 1 in cohort 4 (21.28 mg/m2) for a total of 20 cycles. Tumor types included: 3 melanoma; 2 breast cancer; 1 anal; 1 prostate; 1 adrenal; 1 adenocystic; 1 NSCLC; and 1 squamous cell carcinoma of unknown primary. SNX-5422 has been well tolerated with no DLTs observed. All drug related toxicities have been gr 1 (nausea 3 pt and fatigue 2 pt). The predicted effective human dosing range based on animal models is approximately13–53 mg/m2. PK results of the first two cohorts demonstrate dose proportional increases in Cmax and AUC and a half-life of ∼ 8–10 hours. Proof of mechanism will be supported by PBMC evaluation of multiple biomarkers including p-Erk and p-S6. Conclusions: SNX-5422 has been well tolerated through the first three dose levels and is enrolling at 21.28 mg/m2, which is within the effective human dose range predicted by pre-clinical studies. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Serenex, Inc. Serenex, Inc. Serenex, Inc. Serenex, Inc.