Abstract
BACKGROUND
Microtubule inhibitors are active in preclinical models of glioblastoma (GBM), however, clinical benefit is hampered by poor CNS accumulation. TPI 287, a taxane designed to evade P-glycoprotein mediated efflux, readily penetrates the blood brain barrier and overcomes this limitation. CB-017 is a multi-center phase 1/2 trial designed to determine the optimal dose of TPI 287 and potential efficacy in combination with bevacizumab (BEV) for treatment of recurrent GBM. Final results of the dose escalation Phase 1 stage of this trial are reported.
METHODS
GBM patients at first or second relapse after standard therapy and without prior exposure to anti-angiogenic agents were eligible for enrollment. BEV was administered at 10 mg/kg every 2 weeks and TPI 287 every 3 weeks IV. RANO response was assessed every 6 weeks.
RESULTS
Twenty-four patients were enrolled in seven TPI 287 dose-escalation cohorts (140–220 mg/m2) from 6 U.S. centers. Twenty and 23 patients were evaluable for response and survival, respectively. 12/20 (60%) achieved an objective response (3 CR, 9 PR) and 10/23 patients had stable disease. Two of the patients achieving CR had converted from PR after subsequent treatment cycles. Median and 6-month PFS was 5.5 months and 40%, respectively. Median and 12-month overall survival was 13.4 months and 64%, respectively. Fifteen- and 18-month overall survival was 45% and 27%, respectively. Of the 9 patients from which tumor data was available, eight (89%) harbored an unmethylated MGMT promoter at diagnosis. No DLTs were reported and myelosuppression (n=3) was the only drug-related grade 3/4 adverse event.
CONCLUSION
TPI 287 in combination with BEV is safe and well tolerated at doses up to 220 mg/m2. Final survival results from the Phase 1 portion of this study compare favorably with historical controls and support further investigation of TPI 287 plus BEV for treatment of recurrent GBM.