ATCT-34BAYESIAN ADAPTIVE RANDOMIZED PHASE II TRIAL OF BEVACIZUMAB PLUS VORINOSTAT VERSUS BEVACIZUMAB ALONE IN ADULTS WITH RECURRENT GLIOBLASTOMA

BACKGROUND: Antiangiogenic therapy using bevacizumab (Bev) has shown promising activity against recurrent glioblastoma. However, the resistance to such treatment often results in aggressive tumor recurrence. Histone deacetylase (HDAC) inhibitors such as vorinostat (Vor) have pleotropic effects against several pathways that may mitigate resistance mechanism. METHODS: A phase II multicenter clinical trial was conducted using Bayesian adaptive design, which allows the randomization to favor the better-performing treatment arm. Patients with recurrent glioblastoma were randomized to receive Bev alone or Bev + Vor. Primary endpoint was progression-free survival (PFS), while overall survival (OS) and patient-reported symptoms using the M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT) were secondary end points. Eligible patients were adults with histologically confirmed glioblastoma who had recurrent disease after radiation and temozolomide therapy, KPS ≥ 60, no prior Bev or HDAC inhibitors. RESULTS: Ninety patients (Bev + Vor: 49, Bev: 41) were enrolled to the study. Seventy-three patients were evaluable for the primary endpoint (Bev + Vor: 43, Bev: 30). There were no significant differences between the two arms in either median PFS (4.0 vs.3.7 months, p = 0.90) or median OS (9.2 vs. 7.9 months, p = 0.75). Analysis of the MDASI-BT scores showed no significant differences in overall symptom burden or interference (p = 0.48, 0.71 respectively). Fifty-seven patients were deceased by the time of analysis (Bev + Vor: 34, Bev: 23) with one possible treatment-related death due to pulmonary embolism. Toxicity ≥ grade 3 included hypertension (n = 37), neurological changes (n = 2), infections (n = 9), wound dehiscence (n = 2), DVT/PE (n = 2), and colonic perforation (n = 1). CONCLUSIONS: In this trial, Bev + Vor neither improved PFS and OS nor reduced symptom burden compared to Bev alone in patients with recurrent glioblastoma. However, the successful completion of this Bayesian designed study confirmed the feasibility of conducting an adaptive randomized clinical trial in a multicenter setting.