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e13537 Background: NanoBB-1-Dox is a novel drug candidate for systemic chemotherapy of glioblastoma multiforme (GBM). It is a nanoparticle-based formulation of doxorubicin, which enables passage of the drug across the blood-brain barrier and delivery to the tumor inside the brain. Preclinical studies demonstrated that NanoBB-1-Dox enabled considerable growth inhibition of an intracranially implanted 101.8 glioblastoma in rats and long-term remission in >20% animals, whereas the conventional doxorubicin formulation was only marginally effective. Methods: 21 patients with advanced solid tumors (18 with advanced breast cancer, 34 with GBM) were enrolled in the study. The objectives of the study were: 1) to evaluate the safety and pharmacokinetics (PK), 2) to determine the maximum tolerated dose (MTD). A standard “3 + 3” design with 7 dose levels (4, 24, 36, 48, 60, 75 and 90 mg/m2) was used. Each patient received a single i.v. infusion of NanoBB-1-Dox. Doxorubicin serum concentrations were measured immediately before the infusion, and 2 min, 10 min, 20 min, 40 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, 48 h, 72 h, 168 h after the infusion. Results: The PK analysis demonstrated that AUC0-t of doxorubicin after the NanoBB-1-Dox infusion increased in parallel with the dose level from 121.7 to 2054.4 h x ng/ml. T1/2 varied from 45 to 75 h without dose dependence. NanoBB-1-Dox was well tolerated without dose limiting toxicity even at the highest dose of 90 mg/m2, so the MTD was not achieved. The most common AEs included leukopenia, lymphopenia, neutropenia, thrombocytopenia, anemia, nausea, and alopecia. In general, the AE rate and intensity increased with the dose level reaching the maximum at a dose of 90 mg/m2. Only hematological AEs were severe according to CTCAE 4.03. No SAEs were reported. Conclusions: NanoBB-1-Dox after a single i.v. infusion in patients with advanced solid tumors is well tolerated and is characterized by a non-linear PK profile. NanoBB-1-Dox will be investigated in a phase II study in patients with GBM as a second line therapy. [Table: see text]

Purpose: Preclinical data indicate anti-invasive activity of APG101, a CD95 ligand (CD95L)–binding fusion protein, in glioblastoma. Experimental Design: Patients (N = 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 rRT+APG101 (400 mg weekly i.v.). Patient characteristics [N = 84 (26 patients rRT, 58 patients rRT+APG101)] 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 rRT+APG101 (P = 0.048). Median PFS was 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; P = 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 = 0.0559) for rRT+APG101 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; 20(24); 6304–13. ©2014 AACR.

2006^ Background: Preclinical data indicate antiinvasive activity of APG101, a CD95-ligand (CD95L)-binding fusion protein, and synergistic activity with radiotherapy in glioblastoma. In healthy vol...