A phase II study of XL184 in patients (pts) with progressive glioblastoma multiforme (GBM) in first or second relapse

Abstract

2047 Background: XL184 is a potent orally bioavailable inhibitor of MET, RET, KIT, and VEGFR2. Elevated levels of VEGFR2 and its ligand VEGF are found in GBM, and elevated levels of MET and KIT are correlated with poor prognosis in GBM pts. Treatment with XL184 results in potent inhibition of GBM in preclinical models. Methods: This is a phase II study of 46 pts with recurrent GBM who received XL184 175mg PO qd. Co-primary objectives are 6-month progression-free survival (PFS6) and safety. Secondary objectives include response rate (per MacDonald Criteria), duration of response, overall survival, pharmacodynamic and pharmacokinetic parameters, vascular imaging, and changes in steroid usage. Results: As of January 6, 2009, all 46 pts have been enrolled. At least 1 post-baseline tumor assessment at 4 weeks was available for 26 pts. Of these, 17 pts had not received prior therapy with an anti-angiogenic agent, whereas 9 pts had received prior therapy with bevacizumab (n = 6), vandetanib (n = 2), or VEGF-TRAP (n = 1). Safety: 6 pts have experienced a total of 9 possibly related grade 3/4 SAEs including increased troponin I and myocarditis (n = 1); dehydration, nausea, and fatigue (n = 1); elevated ALT (n = 1); pulmonary embolism (n = 2); and CNS hemorrhage (n = 1). 24/46 (52%) pts have required a dose interruption or reduction due to AEs or SAEs. Based on investigator assessment of bidimensional contrast-enhancing tumor measurements, 10 pts (38%) had a best radiologic response of >= 50% reduction from baseline (including 1 pt with a 100% reduction), 9 pts (35%) had tumor measurement changes ranging from +24% and -49%, and 7 pts (27%) had a >= 25% increase in tumor burden. Of the 17 anti-angiogenic-naïve pts, 9 (53%) had a best radiologic response of >= 50% reduction in tumor burden. 1 pt with prior vandetanib therapy has experienced a best radiologic response of >= 50%. Of the 4 pts with > 6 months follow-up, 3 remain on study with a sustained radiologic response. Conclusions: XL184 at a dose of 175 mg PO qd, has demonstrated substantial activity in pts with progressive or recurrent GBM. Updated safety and efficacy results including centrally reviewed PFS6 and response rate will be reported. [Table: see text]