Phase I/IIa trial of fractionated radiotherapy, temozolomide, and autologous formalin-fixed tumor vaccine for newly diagnosed glioblastoma

Abstract

Object: Temozolomide (TMZ) may enhance antitumor immunity in patients with glioblastoma multiforme (GBM). In this paper the authors report on a prospective Phase I/IIa clinical trial of fractionated radiotherapy (FRT) concomitant with TMZ therapy, followed by treatment with autologous formalin-fixed tumor vaccine (AFTV) and TMZ maintenance in patients with newly diagnosed GBM.

Methods: Twenty-four patients (age 16-75 years, Karnofsky Performance Scale score ≥ 60% before initiation of FRT) with newly diagnosed GBM received a total dose of 60 Gy of FRT with daily concurrent TMZ. After a 4-week interval, the patients received 3 AFTV injections and the first course of TMZ maintenance chemotherapy for 5 days, followed by multiple courses of TMZ for 5 days in each 28-day cycle.

Results: This treatment regimen was well tolerated by all patients. The percentage of patients with progression-free survival (PFS) ≥ 24 months was 33%. The median PFS, median overall survival (OS), and the actuarial 2- and 3-year survival rates of the 24 patients were 8.2 months, 22.2 months, 47%, and 38%, respectively. The median PFS in patients with a delayed-type hypersensitivity (DTH) response after the third AFTV injection (DTH-2) of 10 mm or larger surpassed the median length of follow-up for progression-free patients (29.5 months), which was significantly greater than the median PFS in patients with a smaller DTH-2 response.

Conclusions: The treatment regimen was well tolerated and resulted in favorable PFS and OS for newly diagnosed GBM patients. Clinical trial registration no.: UMIN000001426 (UMIN clinical trials registry, Japan).

Keywords: AFTV = autologous formalin-fixed tumor vaccine; CREIL Center = Critical Path Research and Education Integrated Leading; CTCAE = Common Terminology Criteria for Adverse Events; DTH = delayed-type hypersensitivity; FRT = fractionated radiotherapy; GBM = glioblastoma multiforme; IDH1 = isocitrate dehydrogenase-1; JBTRC = Japan Brain Tumor Reference Center; KPS = Karnofsky Performance Scale; MGMT = O6-methylguanine-DNA methyltransferase; MHC = major histocompatibility complex; MRC = Medical Research Council; OS = overall survival; PFS = progression-free survival; RPA = recursive partitioning analysis; TMZ = temozolomide; autologous formalin-fixed tumor vaccine; brain tumor immunotherapy; clinical trial; glioblastoma; oncology; temozolomide.