A phase 2 study to determine the efficacy and safety of TVB-2640 in combination with bevacizumab in patients with first relapse of high grade astrocytoma.

Abstract

TPS2080 Background: The mainstay of treatment for Glioblastoma Multiforme (GBM) remains surgical removal followed by combined chemotherapy with temozolomide and radiation therapy. Second line Bevacizumab (Bev) is indicated upon progression, but unfortunately the responses are not very long lasting, and there are no therapeutic options available at that point. We have learned that antiangiogenic resistance in GBM is promoted by hypoxia; moreover, metabolomic profile of GBM under such conditions reveals an increased presence of long chain fatty acids. On second hand, tumor cells compared to normal cells depend more on palmitate, and is Fatty Acid Synthase (FASN) the enzyme capable of catalyzing its biosynthesis. Further studies have shown how GBM overexpress FASN and how its inhibition selectively inhibits growth and viability of tumor cells by inducing tumor cell apoptosis. TVB-2640 emerges as a novel agent that selectively inhibits FASN. This study represents a phase 2 clinical investigation of TVB-2640, which is to be conducted in patients with Recurrent High Grade Astrocytoma. Methods: This is a prospective, randomized, phase 2 study of TVB-2640 in combination with Bev or Bev alone in patients with GBM in first relapse. Primary end point is progression free survival (PFS). Patients 18 years or older, with ECOG 0 to 2 and GBM progression following standard combined modality treatment will qualify for the study. Patients will be randomized into 2 separate arms. Patients in arm number one will receive Bev every 2 weeks in combination with TVB-2640 while patients in arm number two will receive Bev alone every 2 weeks. MR-Spectroscopy will be obtained on all patients at day 1 and 28 of first cycle. Starting on cycle 2 day 1, all patients will converge to a single arm and will continue to receive Bev in combination with TVB-2640. A total sample size of 24 patients will provide 90% power to detect a 4 months difference in PFS (3 months for Bev alone (historic controls) versus 7 months for TVB-2640 in combination with Bev, i.e., a hazard ratio of 0.43) using a one-sided log-rank test with alpha = 0.1. The trial is open and enrollment will begin in Feb 2017. Clinical trial information: NCT03032484.