A phase I study examining weekly dosing and pharmacokinetics (PK) of a novel spectrum selective kinase inhibitor, XL999, in patients (pts) with advanced solid malignancies (ASM)

Abstract

13024 Background: XL999 is a small molecule inhibitor of multiple kinases involved in tumor cell growth, angiogenesis, and metastasis, including VEGFR2 (KDR), PDGFRα/β, FGFR1/3, FLT-3, and SRC. A phase I study of XL999 administered as a 4 hr infusion every 2 weeks in pts with ASM showed that the maximum tolerated dose (MTD) was 3.2 mg/kg and the plasma t1/2 was approximately 24 hrs. Three pts dosed at 0.2–1.6 mg/kg (anaplastic thyroid cancer [1], renal cell carcinoma [1], hepatic squamous cell carcinoma [1]) had partial responses and 9 pts had stable disease for 3 to 11 months. Based on these data, a weekly (wkly) dosing schedule with PK monitoring was explored. Methods: XL999 at 3.2 mg/kg was administered to pts as a 4 hr infusion on day (d) 1 and 8 with toxicity assessment. Pts received further doses of XL999 wkly in the absence of unacceptable toxicity, disease progression, or accumulation based on PK results. Results: Overall 15 pts were enrolled and 7 were initially dosed at 3.2 mg/kg. Two of these pts experienced severe drug related toxicities, including 1 pt with G3 fatigue who was able to continue wkly XL999 at 2.4 mg/kg and another pt who was discontinued after developing reversible cardiac dysfunction on d1. The next 8 pts were treated at 2.4 mg/kg and none of these has experienced any G2 or worse drug related adverse events. One asymptomatic pt with non-specific ECG changes after d1 was discontinued from study. Four of 11 evaluable pts had SD. In 7 evaluable pts treated at the 2.4 dose level, the mean Cmax was 519 ng/mL with moderate interpatient variability (coefficient of variation, CV) of 38%. Intrapatient variability in the Cmax values on d1 and d15 was moderate (≤3-fold); however, there was no evidence of drug accumulation on repeat dosing. Conclusions: XL999 administered wkly as a 4 hr infusion at a dose of 2.4 mg/kg appears to be well tolerated with no evidence of drug accumulation. The safety and PK data suggest that 2.4 mg/kg on a wkly schedule is appropriate for phase 2 studies. [Table: see text]