Randomized Placebo-Controlled Trial Of Autologous Formalin-Fixed Tumor Vaccine For Newly Diagnosed Glioblastoma

Abstract Introduction: There is a growing interest in development of novel therapeutic modalities based on tumor-specific immune reactions for management of glioblastoma multiforme (GBM). Autologous formalin-fixed tumor vaccine (AFTV) was designed by our group for in vivo induction of killer lymphocytes and activation of T-lymphocyte (Nat Med 1995, 1996). In first trial for recurrent GBM, 3 responding patients survived more than 20 months after AFTV administration (Cancer Sci, 2007). Efficacy of AFTV concomitant with fractionated radiotherapy (FRT) without chemotherapy with temozolomide (TMZ) in patients with newly-diagnosed GBM was evaluated in prospective phase I/IIa trial (C00002), which showed median overall survival (OS) of 19.8 months (J Neurosurg, 2011). Another prospective multicenter phase I/IIa trial (UMIN01426) for evaluation of the combined use of AFTV and standard chemoradiotherapy with TMZ (AFTV+RT/TMZ: (Stupp regimen) for newly-diagnosed GBM, showing median progression-free survival (PFS) and OS of 8.2 and 22.2 months, respectively (J Neurosurg, 2013). Currently, prospective multicenter placebo-controlled double-blind phase IIb/III trial (UMIN10602) directing on evaluation of AFTV+RT/TMZ for newly-diagnosed GBM is ongoing and recruiting of patients for its phase IIb part has been finished in January 2016. We here report preliminary results before a key opening. METHODS: The phase IIb/III study investigated the AFTV plus chemoradiotherapy with temozolomide (AFTV + RT/TMZ; Stupp protocol) versus placebo plus chemoradio- therapy (Pla + RT/TMZ) for newly diagnosed glioblastoma. After resection surgery, patients with glioblastoma were randomly assigned 1:1 to receive AFTV (2 courses; 3 times, once a week) + RT/TMZ or Pla + RT/TMZ until disease progression. The primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), objective response rate, QOL, and safety. RESULTS: Adult 63 patients with supratentrial glioblastoma were enrolled, although 3 patients withdraw the consents. Among 60 patients for full analysis set, baseline characteristics were balanced. The median age was 61 years old, men vs. women were 33 vs. 27, and the median resection rate was 95%. Mean follow-up period was 15.8 months. The median PFS was 14.2 months and 6-month PFS was 75% both for AFTV+RT/TMZ and Pla+RT/TMZ. The median PFS was 21.4 months and 1-year survival was 86% both for AFTV+RT/TMZ and Pla+RT/TMZ. No severe adverse events caused by AFTV or placebo were observed. CONCLUSION: The phase IIb part of the trial has been done safely and trial would be promising because the median PFS for both groups was more than a year. If AFTV+RT/TMZ would show longer survival time compared to Pla+RT/TMZ by the key open, a phase III would be warranted.