Phase I pharmacokinetic and safety analysis of epothilone folate (BMS-753493): First-in-human clinical experience of a folate receptor-targeted chemotherapeutic agent administered on days 1, 4, 8, and 11 of a 21-day cycle.

Abstract

2607 Background: The high-affinity folate receptor alpha is selectively overexpressed in some epithelial tumors, including ovarian, endometrial, renal, and breast carcinomas, and in a few nonepithelial neoplasms. BMS-753493, a folate conjugate of epothilone analog BMS-748285, was designed to target folate receptor-expressing tumor cells. Methods: BMS-753493 was investigated in two parallel first-in-human phase I/II studies in subjects with advanced solid cancers. These studies differed only in dosing schedule. Both studies dosed 4 times every 21 days and followed a 3+3 open-label dose escalation scheme during phase I. CA190-001, discussed here, dosed once daily on days 1, 4, 8, and 11, while CA190-002 (companion abstract) dosed once daily on days 1-4. Results: Phase I escalated 5 cohorts to 33 mg. At 33 mg, three dose-limiting toxicities (DLTs) were observed, one each in 3 of 4 patients treated. The first DLT consisted of grade 2 ALT elevation resulting in omission of two doses. The second DLT consisted of grade 3 diarrhea. The third DLT consisted of grade 3 esophagitis. The 26 mg cohort was expanded to confirm the maximum tolerated dose, and one DLT (skipping day 4 and 11 doses due to Grade 2 AST elevation) was observed among 7 subjects treated as of December 2009. The most common related AEs were fatigue, diarrhea, nausea, vomiting, anorexia, and ALT/AST elevations. Although no complete or partial responses occurred, target lesion shrinkage up to 18% from baseline was observed. Plasma exposures (Cmax and AUC) of BMS-753493 and BMS-748285 on Day 1 and Day 4 increased in a dose-related manner in the dose range of 5 to 33 mg. All data are preliminary. Conclusions: At the doses and schedules tested, BMS-753493 demonstrated at best moderate activity with manageable toxicity. Pharmacokinetic data: BMS-753493, day 4 Dose (mg) N Cmax (ng/mL)GeoMean (CV%) AUC(0-T) (ng*h/mL) GeoMean (CV%) 5 3 583 (23) 232.3 (14) 10 4 1,343 (32) 642.4 (38) 17 6 2,427 (30) 1,409.3 (32) 26 3 3,892 (27) 2,467.5 (46) 33 3 3,914 (23) 2,919.9 (4) Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb