Phase I trial of BMS-690514 in combination with paclitaxel/carboplatin (PC) in patients with advanced or metastatic solid tumors.

Abstract

2547 Background: BMS-690514 is a potent, reversible oral inhibitor of EGFR, HER2, HER4, and VEGFR 1, 2, and 3. PC is a common chemotherapy regimen used in solid tumors. Methods: This phase I study was designed to determine the maximum tolerated dose (MTD) of BMS-690514 plus PC. Secondary endpoints included safety, antitumor efficacy, and PK. Pts with advanced or metastatic solid tumors (age ≥ 18 yrs, ECOG ≤1) received escalating doses of BMS-690514 plus fixed IV doses of PC (P: 200 mg/m2; C: AUC= 6 mg/mL min). BMS-690514 starting at 100 mg/d (days 4–19 of 21-day cycle) was escalated by 50 mg/d until MTD was defined. PK samples were collected on C1D4, C1D19, and C2D19. Results: BMS-690514 dose cohorts were (pts):100 mg (7), 150 mg (6), and 200 mg (4). The MTD of BMS-690514 was defined at 150 mg/d. DLTs were severe grade (Gr) 3 diarrhea 1 pt;100 mg, 1 pt; 150 mg, 2 pts; 200 mg. After determination of the MTD, 18 pts were included in an expansion cohort of BMS-609514 at the MTD of 150 mg plus PC. Of 30 pts enrolled on study to date, 22 were chemotherapy-naive. Tumor types included NSCLC (n=12, 8 evaluable), gastric (n=5, 2 evaluable), and other (n=13, 8 evaluable). Treatment-related Gr 3/4 AEs occurred in 13/30. Severe AEs of pulmonary embolism (2pts, 200 mg), neutropenia (2pts; 100 mg), acute renal failure (1pt; 100 mg), and reversible posterior leukoencephalopathy (1pt, 150 mg) led to treatment discontinuation. At the MTD of BMS-690514 plus PC, Gr 3/4 treatment-related AEs occurred in 8/19 pts, those occurring in ≥10% of pts included diarrhea (21%) and leukopenia (11%). At or below 150 mg BMS-690514 plus PC, the majority of AEs were mild-moderate and commonly (≥10%) included diarrhea, nausea, rash, fatigue, headache, and hypertension. Of 30 pts in this ongoing study, 9 partial responses (PR), 6 stable disease (SD), and 3 progressive disease (PD) were observed, 12 are not yet evaluable. Specifically, in NSCLC pts (n=8), Pr=5, SD=1 and PD=2.The PK of BMS-690514 plus PC was comparable to that previously observed for BMS-690514 monotherapy. Conclusions: The MTD of BMS-609514 in combination with PC was 150 mg/d. This combination was generally well tolerated and demonstrated activity in a variety of tumor types, in particular in NSCLC. 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