A single-center, open-label, dose escalation, safety, and pharmacokinetic study of ENMD-1198 administered orally to patients (pts) with advanced cancer

Abstract

3562 Background: ENMD-1198 (2-methoxyestra-1, 3, 5, (10) 16-tetraene-3-carboxamide), an analog of 2-methoxyestradiol (2ME2), has both antiangiogenic and antiproliferative effects in various tumor types. ENMD-1198 inhibits MT polymerization by binding to β-tubulin at the colchicine-binding site and inhibits HIF-1alpha. This Phase 1 study is evaluating the safety of ENMD-1198 to determine the maximum tolerated dose. Methods: Eligible pts had advanced cancer for which no effective therapy exists that is either evaluable by RECIST criteria or tumor markers that could be monitored for clinical benefit. Phase 1 dose escalation in 3+3 design for first 5 cohorts; modified to 1 pt cohorts for subsequent cohorts until Grade 2 treatment related toxicity, and then standard 3+3 design. All pts treated with once daily oral ENMD-1198 in 28-day cycles (with post-treatment drug-free observation period of 7–14 days in Cycle 1 only). Pts are treated until the appearance of significant treatment-emergent toxicities or disease progression (PD) occurs. Results: To date, 27 pts have been enrolled in 12 dose cohorts (range 5 to 550 mg/m2/d). Median age/performance status is 61/1. Total # of treatment cycles to date is 68, with a median of 2 cycles (range <1 to 15 cycles). Most frequent toxicities (all grades, n=22) were pain (77%), fatigue (55%), constipation (36%), neuropathy and nausea (both 32%), and anemia (27%). 4 pts have experienced stable disease (SD) for more than 2 cycles. There have been no objective responses to date. 2 pts experienced dose limiting toxicity with Grade 4 neutropenia in the 550 mg/m2/d cohort. Following drug holiday, pts restarted at 425 mg/m2/d and continued for at least 1–2 more cycles before being removed from study for PD. One pt (neuroendocrine ca pancreas) is experiencing prolonged SD at 60 mg/m2/d >14 cycles and a 2nd pt (prostate ca) experienced SD at 30mg/m2/d for 10 cycles. ENMD-1198 was absorbed rapidly after oral administration. There was a linear relationship between dose and drug exposure as measured by AUC across all doses (5 - 550 mg/m2). The elimination half-life of ENMD- 1198 averaged more than 12 hours after a single dose. Conclusions: DLT was identified at 550 mg/m2/d. Cohort expansion at 425mg/m2/d is ongoing. [Table: see text]