MPC-3100, a fully synthetic, orally bioavailable Hsp90 inhibitor, in cancer patients.
M. K. Yu, Wolfram E. Samlowski, Vijay R. Baichwal, Bradley D. Brown, B. A. Evans, Deane Woodland, GARY G. MATHER, Akash Patnaik, A. W. Tolcher, K. Papadopoulos · Journal of Clinical Oncology · 2010
e13112 Background: MPC-3100 is a fully synthetic, orally bioavailable, Hsp90 inhibitor developed by Myriad Pharmaceuticals, Inc. This study is designed to determine the safety and tolerability of daily oral administration of MPC-3100. Secondary objectives include characterizing pharmacokinetics and assessing anti-tumor activity. Methods: Patients with recurrent cancer refractory to available systemic therapy are enrolled into this modified Fibonacci dose-escalation study. MPC-3100 is administered by mouth in tablet form for 21 consecutive days in a 28-day cycle. Patients are observed for dose-limiting toxicities (DLTs) during the first cycle of treatment. Single-patient cohorts are planned until a grade 2 or greater toxicity occurs during the first cycle. After the occurrence of a grade 2 or greater toxicity, 2 more patients are studied at the same dose level. Subsequent 3-subject cohorts will be studied in the traditional “3 + 3” design. Plasma and peripheral blood mononuclear cells (PBMCs) are obtained before and after MPC-3100 administration to evaluate drug concentration and Hsp70 levels. Patients are treated until disease progression or toxicity. Results: Six patients (median age, 62 years; range, 50-84 years; 4 male; ECOG of 0 or 1; median number of prior therapies, 3; range 2-12) with metastatic cancer [prostate (n=1), melanoma (n=1), leiomyosarcoma (n=2), colon (n=1), adenocarcinoma of unknown primary (n=1)] have been enrolled to 4 dose levels. The mean duration of therapy as of December 7, 2009, was 2.8 months (range 1-7); three patients are actively receiving therapy. Single-patient cohorts were studied for the first three dose levels (50, 100, and 165 mg/m2). The first patient treated at the 245 mg/m2 dose level developed a grade 2 pre-renal azotemia requiring intravenous fluids during the first 8 days of treatment. As a result, 2 more patients were enrolled to this dose level. One of these 2 additional patients experienced a DLT of supraventricular tachycardia and respiratory failure 24 hours after the day 21 dose. Conclusions: MPC-3100 at dose levels up to 165 mg/m2 in cancer patients is safe and well-tolerated. The 245 mg/m2 cohort has been expanded to 6 patients with the development of the first DLT. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Myriad Pharmaceuticals, Inc. Myriad Pharmaceuticals, Inc.