This randomized, open-label, active-controlled, dose-finding phase IIb study evaluated the efficacy and safety of trabedersen (AP 12009) administered intratumorally by convection-enhanced delivery compared with standard chemotherapy in patients with recurrent/refractory high-grade glioma. One hundred and forty-five patients with central reference histopathology of recurrent/refractory glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA) were randomly assigned to receive trabedersen at doses of 10 or 80 µM or standard chemotherapy (temozolomide or procarbazine/lomustine/vincristine). Primary endpoint was 6-month tumor control rate, and secondary endpoints included response at further timepoints, survival, and safety. Six-month tumor control rates were not significantly different in the entire study population (AA and GBM). Prespecified AA subgroup analysis showed a significant benefit regarding the 14-month tumor control rate for 10 µM trabedersen vs chemotherapy (p= .0032). The 2-year survival rate had a trend for superiority for 10 µM trabedersen vs chemotherapy (p = .10). Median survival for 10 µM trabedersen was 39.1 months compared with 35.2 months for 80 µM trabedersen and 21.7 months for chemotherapy (not significant). In GBM patients, response and survival results were comparable among the 3 arms. Exploratory analysis on GBM patients aged ≤55 years with Karnofsky performance status >80% at baseline indicated a 3-fold survival at 2 and 3 years for 10 µM trabedersen vs chemotherapy. The frequency of patients with related or possibly drug-related adverse events was higher with standard chemotherapy (64%) than with 80 µM trabedersen (43%) and 10 µM trabedersen (27%). Superior efficacy and safety for 10 µM trabedersen over 80 µM trabedersen and chemotherapy and positive risk–benefit assessment suggest it as the optimal dose for further clinical development in high-grade glioma.

Although contributing to inflammatory responses and to the development of certain autoimmune pathologies, type I interferons (IFNs) are used for the treatment of viral, malignant, and even inflammatory diseases. Interleukin-1 (IL-1) is a strongly pyrogenic cytokine and its importance in the development of several inflammatory diseases is clearly established. While the therapeutic use of IL-1 blocking agents is particularly successful in the treatment of innate-driven inflammatory disorders, IFN treatment has mostly been appreciated in the management of multiple sclerosis. Interestingly, type I IFNs exert multifaceted immunomodulatory effects, including the reduction of IL-1 production, an outcome that could contribute to its efficacy in the treatment of inflammatory diseases. In this review, we summarize the current knowledge on IL-1 and IFN effects in different inflammatory disorders, the influence of IFNs on IL-1 production, and discuss possible therapeutic avenues based on these observations.

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Rituximab treatment should be considered for a patient with fulminant MS who responded well to plasmapheresis.

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2037 Background: High-grade gliomas (HGG) strongly overexpress TGF-beta 2. Trabedersen (AP 12009), a TGF-beta 2-specific inhibitor, was successfully tested in 3 Phase I/II studies in recurrent or refractory HGG. Methods: The Phase IIb study AP 12009-G004 was an open-label, randomized, active-controlled dose-finding study. Main objectives: to compare response rate, survival, and safety of 2 doses of trabedersen (10 μM or 80 μM) vs. standard chemotherapy (TMZ or PCV). 145 patients with recurrent or refractory HGG (AA WHO grade III or GBM WHO grade IV) were randomized and 134 patients (AA = 39; GBM = 95) received study medication. Trabedersen was given intratumorally by convection-enhanced delivery. Results: AA and GBM patients in both trabedersen groups had long-lasting tumor responses (currently up to 4 years). AA: (10 μM trabedersen vs. control): significantly better overall response rate was noted at 14 months (CR+PR; p=0.034*) and lower tumor progression rates at 6, 12 and 14 months; difference at 14 months was statistically significant (p=0.003*). 2-year survival rate was 2-fold higher (p=0.088**). Tumor progression rate at 14 months and 2-year survival rate correlated with a median overall survival benefit of 17.4 months. GBM: 10 μM trabedersen was as efficacious as standard chemotherapy in all patients. It was clearly superior regarding 2-year survival in the pre-specified subgroup of patients younger than 55 years and the subgroup with a KPS > 80. The superior long-term survival of trabedersen-treated AA and GBM patients was the basis for extending the follow-up period of this Phase IIb study. Conclusions: Based on Phase IIb results, the pivotal Phase III study SAPPHIRE in recurrent or refractory AA patients has started. Primary efficacy endpoint is 2-year survival rate; secondary endpoints are progression rate at 14 months, time to death, quality of life, safety and tolerability. A separate study in GBM is being planned. [Table: see text] [Table: see text]