Clinical and dynamic imaging results of the first phase I study of AG–013736, an oral anti-angiogenesis agent, in patients (pts) with advanced solid tumors

Abstract

2503 Background: AG-013736 is a potent and selective inhibitor of VEGF and PDGF receptor tyrosine kinases with broad preclinical activity in xenograft models of solid tumors. Methods: The primary objective was to determine maximum tolerated dose (MTD) and safety. Efficacy, pharmacokinetics (PK), and tumor vascular response were also evaluated. AG–013736 was administered orally once or twice daily in 28-day cycles in escalating doses to pts with solid tumors. Results: 36 pts in 6 cohorts were treated. At least 2 cycles of data are available on the first 30. Tumor diagnoses: breast (11), thyroid (5), renal cell (5), lung (4), and other (5). The MTD was 5 mg twice daily (BID) fasted (no food or beverage within 2 hours of dose). Toxicity: Dose-limiting toxicities (DLTs) at doses >MTD (16 pts) were hypertension (HTN) (6 pts); seizures associated with HTN (2); elevated liver function tests (2); mesenteric vein thrombosis and pancreatitis (1); and stomatitis (2). One pt with a cavitating lung lesion died of hemoptysis while on drug. At doses ≤MTD (14 pts), DLT was limited to grade 2 stomatitis in 1 pt; non-dose limiting HTN, managed by conventional antihypertensive meds, was observed in 6 pts. Response: Two durable partial responses (10+, 5 mo) by RECIST criteria were observed (in renal cell and adenoid cystic carcinomas); 7 pts had stable disease lasting ≥4 mo. PK: AG-013736 plasma concentrations were variable (39%–96% CV), linear within the dose range, with peaks at 2–4 h, and terminal half-life of 3–5 h. Plasma exposures were higher (∼ 49%) and intra-pt variability was reduced in the fasted vs fed state. Vascular response: Dynamic contrast enhanced MRI was performed at baseline, and after 2, 28, and 56 days of therapy. The % change in mean Ktrans and initial area under the contrast intensity X time curve (IAUC) was computed. 6 of 18 pts with evaluable serial scans had a tumor vascular response, defined as ≥50% decrease from baseline parameter values to day 2; correlation with PK and response will be reported. Conclusions: There is sufficient safety and activity of AG–013736 to warrant Phase II trials at a recommended dose of 5 mg BID fasted. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer, Inc. Pfizer, Inc. Pfizer, Inc. Pfizer