Phase I dose-escalation study of the SRC and multi-kinase inhibitor BMS-354825 in patients (pts) with GIST and other solid tumors

Abstract

3034 Background: BMS-354825 is a potent, orally active, inhibitor of several kinase signalling molecules including members of the SRC family of kinases, KIT, PDGFR, and BCR-ABL. This is the first study to evaluate the safety, tolerability, and pharmacologic profiles of BMS-354825 in pts with treatment-resistant GIST and other refractory solid tumors. Methods: Pts with adequate hematologic, renal, cardiac and liver function, received BMS-354825 orally BID for 5 days followed by a 2-day break, every week. Pts in alternate dose groups were treated after a fast or high-fat meal ± antacids. Pts were assessed continuously for safety. EKG monitoring was performed on days 1, 5, 26. Pharmacokinetic (PK) profiling was performed on days 1, 8, 26. Pharmacodynamic (PD) biomarkers (pSrc, pFAK, KIT and SCF) and early imaging with FDG-PET were assessed in the first week of treatment, with a PD biomarker assessment on day 26 also. Serial imaging with CT was performed at least every 8 weeks, with FDG-PET in weeks 1, 4, and 8. Results: 14 pts [M=9, F=5] ECOG PS ≤ 1 with GIST (n=9) or other solid tumors (5) were treated in 1 of 3 escalating dose levels: 35, 50, or 70 mg BID. Toxicity included clinically insignificant grade 3 lymphopenia (2 pts), grade 3 anorexia (1), and elevation of Alk Phosph to grade 3 (1). No dose-limiting toxicity (DLT) has been observed. At 35mg BID, the PK profile in fasting pts resembles the experience in fasting pts with hematologic malignancies, but food and GI pH show an effect on PK parameters [mean T1/2 = 1.3 hrs (fasted); 4.6 hrs (after food)]. There have been no objective responses on CT, but activity has been noted as mixed responses on FDG-PET, resolution of GIST-associated ascites (1 pt) and continued study treatment for ≥ 3 months in two GIST pts. Conclusions: BMS-354825 can be safely administered at doses of up to 70mg BID on a 5-days on, 2-days off, weekly schedule. There have been no DLTs and dose escalation continues. Correlative science studies of tumor biopsies and early FDG-PET and CT imaging results will be reported. The clinical benefits noted in a subset of pts with treatment-resistant GIST is encouraging. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb