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

Clinical article

Eiichi Ishikawa M.D., Ph.D. 1 , 2 , Yoshihiro Muragaki M.D., Ph.D. 5 , 6 , Tetsuya Yamamoto M.D., Ph.D. 1 , 2 , Takashi Maruyama M.D., Ph.D. 6 , Koji Tsuboi M.D., Ph.D. 2 , Soko Ikuta Ph.D. 5 , Koichi Hashimoto Ph.D. 3 , Youji Uemae Ph.D. 4 , 7 , Takeshi Ishihara M.Sc. 7 , Masahide Matsuda M.D., Ph.D. 1 , 2 , Masao Matsutani M.D., Ph.D. 8 , Katsuyuki Karasawa M.D., Ph.D. 9 , Yoichi Nakazato M.D., Ph.D. 10 , Tatsuya Abe M.D., Ph.D. 11 , Tadao Ohno Ph.D. 7 and Akira Matsumura M.D., Ph.D. 1 , 2
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  • 1 Department of Neurosurgery, Faculty of Medicine,
  • 2 Proton Medical Research Center, Faculty of Medicine,
  • 3 Tsukuba Critical Path Research and Education Integrated Leading (CREIL) Center, Faculty of Medicine, and
  • 4 Graduate School of Comprehensive Human Science, University of Tsukuba;
  • 5 Faculty of Advanced Techno-Surgery (FATS), Institute of Advanced Biomedical Engineering & Science, and
  • 6 Department of Neurosurgery, Tokyo Women's Medical University, Tokyo;
  • 7 Cell-Medicine, Inc., Ibaragi;
  • 8 International Medical Center, Saitama Medical University, Saitama;
  • 9 Department of Radiology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo;
  • 10 Department of Human Pathology, Gunma University, Gunma; and
  • 11 Department of Neurosurgery, Faculty of Medicine, Oita University, Oita, Japan
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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).

Abbreviations used in this paper: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.

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Contributor Notes

Address correspondence to: Eiichi Ishikawa, M.D., Ph.D., Department of Neurosurgery, Graduate School of Comprehensive Human Sciences, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan. email: e-ishikawa@md.tsukuba.ac.jp.

Please include this information when citing this paper: published online July 4, 2014; DOI: 10.3171/2014.5.JNS132392.

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