Cancer Therapy : Clinical A Phase II , Randomized , Study of Weekly APG 101 þ Reirradiation versus Reirradiation in Progressive Glioblastoma

Purpose: Preclinical data indicate anti-invasive activity of APG101, a CD95 ligand (CD95L)–binding fusion protein, in glioblastoma. Experimental Design: Patients (N 1⁄4 91) with glioblastoma at first or second progression were randomized 1:2 between second radiotherapy (rRT; 36 Gy; five times 2 Gy per week) or rRTþAPG101 (400 mg weekly i.v.). Patient characteristics [N 1⁄4 84 (26 patients rRT, 58 patients rRTþAPG101)] were balanced. Results: Progression-free survival at 6 months (PFS-6) rates were 3.8% [95% confidence interval (CI), 0.1–19.6] for rRT and 20.7% (95%CI, 11.2–33.4) for rRTþAPG101 (P1⁄4 0.048). Median PFSwas 2.5 (95% CI, 2.3–3.8) months and 4.5 (95% CI, 3.7–5.4) months with a hazard ratio (HR) of 0.49 (95% CI, 0.27– 0.88; P1⁄4 0.0162) adjusted for tumor size. Cox regression analysis adjusted for tumor size revealed a HR of 0.60 (95% CI, 0.36–1.01; P 1⁄4 0.0559) for rRTþAPG101 for death of any cause. Lower methylation levels at CpG2 in the CD95L promoter in the tumor conferred a stronger risk reduction (HR, 0.19; 95% CI, 0.06– 0.58) for treatment with APG101, suggesting a potential biomarker. Conclusions: CD95 pathway inhibition in combination with rRT is an innovative concept with clinical efficacy. It warrants further clinical development. CD95L promoter methylation in the tumor may be developed as a biomarker. Clin Cancer Res; 1–10. 2014 AACR.