Phase I pharmacokinetic profile and early clinical evaluation of the PAN-HER inhibitor BMS-599626

Abstract

3109 Background: BMS-599626 is an orally bioavailable inhibitor of HER1 (EGFR), HER2 (ErbB2) and to a lesser extent HER4. Methods: This is a phase I dose escalation study of BMS-599626 administered by daily oral dosing. Patients: ≥18 yrs with metastatic solid tumors, refractory to standard therapies and whose tumors expressed HER1 or HER2 by IHC (FISH for breast). A large translational ancillary study included skin biopsies (baseline and Day 8) and analysis of biomarkers of HER1 and HER2. Dosing was initiated at 100mg/d and escalated in subsequent cohorts based on a modified Fibonacci scheme. Data from a prior healthy volunteer study, which evaluated single dose PK in 18 subjects, 6 at each dose level (10mg, 30mg and 100mg) is also included. Results: Between May and November 2004, 13 patients have been enrolled; cohort level 5 has reached a dose level of 660 mg. Adverse events at least possibly related to BMS-599626 of 24 Nov 2004 include diarrhea (3), anorexia (1), dyspnea (1), sweating (1) and rash (2); all grades 1 or 2. All 3 patients at 480mg developed grade 1 skin-rash (not yet in database). The healthy volunteer study had one AE: transient grade 2 ALT elevation. Three out of 13 patients allowed fresh tumor sampling before and during treatment. Plasma pharmacokinetics of BMS-599626 for the 100 and 200mg dose were available at the time of abstract submission. For the 100mg dose, the Tmax ranged from 1 to 8h (median 4h), somewhat delayed compared to the healthy volunteer study (median 2 hr). Following a single 100mg dose, the geomean Cmax=62 ng/mL, mean AUC0-∞=1570 ng/mL hr, relatively low compared to the healthy volunteer study, which revealed 120 ng/mL and 2610 ng/mL hr respectively. PK on day 8 and day 29 revealed similar findings, with respective geomean values of Cmax =167 and 210 ng/mL and AUC0-∞=2340 and 2545 ng/mL hr, suggesting no significant accumulation in exposure over time. Terminal half life was about 17 hrs. Exposure increase with the 200 mg dose was linear from the 100 mg dose. Conclusions: BMS-599626 has been well tolerated, with mild target-related AEs. The maximum tolerated dose has not yet been reached. Additional clinical, pharmacological and translational data will be presented. Author Disclosure Employment or Leadership 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