Phase I multicenter trial of BMS-690514: Safety, pharmacokinetic profile, biological effects, and early clinical evaluation in patients with advanced solid tumors and non-small cell lung cancer

Abstract

2564 Background: BMS-690514 is an oral selective pan-HER and VEGFR2 inhibitor with activity in a wide range of tumor cell lines dependent on ErbB signaling. Methods: This is a dose-escalation study to define the MTD and to characterize the pharmacokinetics, pharmacodynamics and safety profile of BMS-690514 in patients with advanced tumors. Patients≥ 18 years with advanced or metastatic measurable tumors, refractory to standard therapies, ECOG ≤ 1, and adequate cardiovascular, bone marrow, renal and hepatic functions. Biomarkers of ErbB and VEGFR signaling include tumor tissue for ErbB pathway gene amplification and mutations, single nucleotide polymorphism, skin biopsies, circulating proteins, and DCE-MRI. Dosing initiated at 40 mg/d with dose escalation based on a modified Fibonacci scheme. At the MTD, an expansion cohort (n=60) enrolled patients with erlotinib-naive and erlotinib-resistant NSCLC. Results: The study has treated 65 patients (39 M/ 26 F), median age 56.2 years (range 27–77) between Oct 2006 and Dec 2007. A total of 110 cycles have been given and 19 patients are still on study. BMS-690514 dose cohorts were (no. pts): 40mg (4), 80mg (4), 160mg (4), 200mg (6), 250mg (4), 300mg (6). The dose-limiting toxicities in 2 subjects each at 250 and 300 mg were grade 3/4 diarrhea (2 patients had associated reversible grade 3 renal insufficiency). Other grade 3–4-adverse events possibly related to BMS-690514 included fatigue, rash, angioedema, arterial hypertension, left ventricular dysfunction, and pulmonary embolism. One patient with esophageal cancer experienced an objective response at 300 mg. At or below the MTD of 200 mg, the majority of AEs were mild-moderate and included diarrhea, rash, nausea, vomiting, hypertension, dyspnea, asthenia and renal insufficiency. 37 patients with NSCLC have enrolled into the expansion cohort (14 erlotinib-naie,18 erlotinib- resistant, 5 pending). An objective tumor response has been observed at the MTD in 1 pt as well as SD ≥ 2 months in 14 pts. Conclusions: BMS-690514 has been well tolerated, with mild-moderate, reversible, target-related AEs. The MTD is 200 mg daily. Additional clinical, PK and translational data will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb