A multicenter phase I trial of combination therapy with interferon-β and temozolomide for high-grade gliomas (INTEGRA study): the final report

• Published in: Journal of neuro-oncology 2011-09, Vol.104 (2), p.573-577
• Main Authors: Wakabayashi, Toshihiko, Kayama, Takamasa, Nishikawa, Ryo, Takahashi, Hiroshi, Hashimoto, Naoya, Takahashi, Jun, Aoki, Tomokazu, Sugiyama, Kazuhiko, Ogura, Masatoshi, Natsume, Atsushi, Yoshida, Jun
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Brain Neoplasms - drug therapy; Brain Neoplasms - mortality; Clinical Study – Patient Study; Dacarbazine - administration & dosage; Dacarbazine - adverse effects; Dacarbazine - analogs & derivatives; Disease-Free Survival; Female; Glioma - drug therapy; Glioma - mortality; Humans; Interferon-beta - administration & dosage; Interferon-beta - adverse effects; Kaplan-Meier Estimate; Male; Medicine; Medicine & Public Health; Middle Aged; Neoplasm Grading; Neurology; Oncology
• ISSN: 0167-594X; 1573-7373
• DOI: 10.1007/s11060-011-0529-1

Our previous study demonstrated that interferon-β markedly enhanced chemosensitivity to temozolomide; one of the major mechanisms is downregulation of O 6 -methylguanine DNA-methyltransferase transcription via p53 induction. This effect was also observed in an experimental animal model. The results of these studies suggest that compared to temozolomide-based chemotherapy performed concomitantly with radiotherapy, chemotherapy with interferon-β and temozolomide and concomitant radiotherapy might further improve the clinical outcomes of patients with malignant gliomas. A multicenter phase I clinical trial—the Integrated Japanese Multicenter Clinical Trial: a Phase I Study of Interferon-β and Temozolomide for Glioma in Combination with Radiotherapy (INTEGRA Study)—was conducted in patients with high-grade gliomas in order to evaluate the safety, feasibility, and preliminary clinical effectiveness of combination therapy with interferon-β and temozolomide. The primary endpoint was the incidence of adverse events. The exploratory endpoints were progression-free survival time and overall survival time. The study population comprised 16 patients with newly diagnosed and 7 patients with recurrent high-grade gliomas. Grades 3–4 leukocytopenia and neutropenia were observed in 6.7 and 13.3% of patients, respectively. Overall, 40% of patients showed an objective response to therapy. In patients with newly diagnosed glioblastoma, the median overall survival time was 17.1 months and the rate of 1-year progression-free survival was 50%. We conclude that this regimen is safe and well tolerated and may prolong survival of patients with glioblastoma. A phase II clinical study is essential to corroborate our findings.