Abstract
Preclinical data suggested an additive antitumor effect of TGF-β inhibitors when combined with temozolomide-based chemoradiation (TMZ/RT). Our Phase 1 data showed manageable safety; thus, a Phase 2 randomized study was conducted to evaluate the safety, PK, PD and efficacy of galunisertib (300 mg/day) combined with TMZ/RT, compared to TMZ/RT alone in patients with newly diagnosed glioma. TMZ/RT was administered as approved and galunisertib given as intermittent dosing (14 days on/14 days off=1 cycle). Safety was assessed using CTCAE, version 4. PK, PD and time-to-event variables were determined. 56 patients with glioma (100% of patients with WHO Grade IV) were treated with galunisertib plus TMZ/RT (N=40) and TMZ/RT alone (N=16). Most patients at baseline were white (96.4%), male (59%), less than 60 years of age (50%), and with ECOG 0–1 (100%). Only two study treatment-related grade 3 or 4 treatment-emergent adverse event rates observed in the two arms were > 10%: (Galunisertib/TMZ/RT:TMZ/RT): lymphocytopenia (20%:6.3%); thrombocytopenia (15%:6.3%). Time-to-events (months) including median overall survival (18.2 vs 17.9) and time-to-treatment failure (7.1 vs 8.8) showed no significant differences between the two treatment arms. No change in the PK profile of galunisertib was shown when combined with TMZ/RT. In the combination therapy, area under the curve (0-∞) at steady state was calculated to be 5.0 (47%) mg*h/L following 300 mg/day (n=48). The analysis correlating changes in T-regulatory cells with overall survival is ongoing and will be presented at the meeting. There was no evidence to suggest an improved survival probability between the two treatment arms. Additionally, the safety profile was manageable and not significantly different between the two treatment arms.
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