A phase I study of XL647, an EGFR, HER2, VEGFR2 inhibitor, administered orally daily to patients (pts) with advanced solid malignancies (ASM)

Abstract

3528 Background: XL647 is an orally bioavailable small molecule inhibitor of multiple receptor tyrosine kinases involved in tumorigenesis and angiogenesis, including EGFR/ErbB1, HER2/ErbB2 and VEGFR2/KDR. The purpose of the present study is to determine the MTD of daily XL647 dosing, and to evaluate pharmacokinetics and pharmacodynamics in pts with ASM. Methods: Cohorts of ASM pts received escalating dose levels of XL647 daily for repeated 28 day cycles. PK sampling was conducted at each dose level. Plasma markers reflecting effects of XL647 on angiogenesis are being analyzed. Eyebrow hair bulbs from a subset of pts are being evaluated as a potential surrogate for the effects of XL647. DCE-MRI studies are being conducted in pts enrolled in the MTD cohort. Response was assessed by RECIST. Results: Enrollment has been completed with 31 pts enrolled (range 26–79 yrs; 20M/11F). Dose levels of 75 mg (n=3), 150 mg (n=3), 200 mg (n=3), 300 mg (n=18) and 350 mg (n=4) were studied. A DLT of Grade (G) 3 pneumonitis occurred in 1/6 pts at 300 mg. At 350 mg 2/4 pts developed a DLT of clinically asymptomatic G3 QTc prolongation (by machine, G2 by manual re-read): 300 mg was declared the MTD. Twelve pts have been enrolled in the expanded MTD cohort. Nine pts remain on study with the majority discontinued due to PD. Two pts withdrew consent and 2 discontinued due to AEs (G3 pneumonitis and G3/4 transaminitis). To date, twelve pts had SD for > 3mo. The most common AEs include G1/2 rash, diarrhea, fatigue, dysgeusia, and clinically asymptomatic QTc prolongation. Preliminary PK analysis indicates rapid absorption (median tmax = 4 hours) with steady state concentrations reached by Day 15. Average steady state concentrations were about 3.4-fold higher compared to Day 1. XL647 caused a significant reduction in phosphorylation of the downstream signaling kinases AKT and ERK in eyebrow hair bulbs at a dose of 150 mg; analysis continues. Levels of pharmacodynamic plasma markers were not consistently changed after XL647 and no PK/pharmacodynamic relationships have been identified to date. Conclusions: The MTD of XL647 is 300 mg when administered daily. XL647 is generally well-tolerated at doses up to 300 mg. Phase 2 studies are ongoing in NSCLC pts at this dose level. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Exelixis, Inc. Exelixis, Inc. Exelixis, Inc. Exelixis, Inc. Exelixis, Inc.