AT-58 JCOG0911 INTEGRA TRIAL: A RANDOMIZED SCREENING PHASE II TRIAL OF CHEMORADIOTHERAPY WITH INTERFERON beta PLUS TEMOZOLOMIDE VERSUS CHEMORADIOTHERAPY WITH TEMOZOLOMIDE ALONE FOR NEWLY-DIAGNOSED GLIOBLASTOMA

BACKGROUND: Our lab experiments showed that interferon beta (IFN beta ) markedly enhanced chemosensitivity to temozolomide (TMZ) via the down-regulation of MGMT transcription. Followed by phase I trial, INTEGRA trial investigated the efficacy of TMZ + IFN beta therapy by a randomized screening design as compared to standard TMZ in first-line of newly-diagnosed glioblastoma multiforme (GBM) to decide whether TMZ/IFN beta should be evaluated in a succeeding confirmatory trial. METHODS: Patients were assigned to either the standard arm (RT/TMZ) or the experimental arm (RT/TMZ/IFN beta ). Patients in RT/TMZ received RT (2.0 Gy/fr/day, 30 fr) with TMZ (75 mg/m2, daily) followed by adjuvant TMZ (100-200 mg/m2/day, days 1-5, every 4 weeks) for 2 years. Patients in RT/TMZ/IFN beta received IFN beta (3 MIU/body, alternate days during RT (induction) period and day 1, every 4 weeks during adjuvant period) intravenously, in addition to RT/TMZ. Primary endpoint was overall survival (OS). The planned sample size was 120 in total with 1-sided alpha of 0.2 and power of 0.8. (clinical trial registry: UMIN-CTR:UMIN000003466). RESULTS: Between 2010 and 2012, 122 patients were randomized (63 RT/TMZ, 59 RT/TMZ/IFN beta ). Median OS in RT/TMZ and RT/TMZ/ IFN beta were 20.3 and 24.0 months (HR 1.00; 95% CI 0.65-1.55; 1-sided logrank p = 0.51). Median PFS in RT/TMZ and in RT/TMZ/IFN beta were 10.1 months and 8.5 months (2-sided P = 0.25, HR 1.25 [95%CI: 0.85-1.84]). Incidence of neutropenia and lymphopenia in RT/TMZ and RT/TMZ/IFN beta (Grade greater than or equal to 3, CTCAE ver 3.0) were 12.7% vs. 20.7% and 54.0% vs. 63.8% during induction period, and 3.6% vs. 9.3% and 34.5% vs. 41.9% during adjuvant period. Non-hematological adverse events (Grade greater than or equal to 3) were observed in 19.0% vs. 24.1% during induction period, and 21.8% vs. 13.6% during adjuvant period. One treatment-related death was observed in RT/TMZ/IFN beta . CONCLUSIONS: First-line use of IFN beta was not promising for further investigation for newly-diagnosed GBM.