Phase Ib study evaluating safety and pharmacokinetics (PK) of the oral transforming growth factor-beta (TGF-ß) receptor I kinase inhibitor LY2157299 monohydrate (LY) when combined with chemoradiotherapy in newly diagnosed malignant gliomas.

2039 Background: Based on preclinical data suggesting an additive antitumor effect of combining TGF-s inhibitors with temozolomide based chemoradiation (TMZ/RT), a Phase 1b study was initiated to evaluate the safety and PK of LY combined with TMZ/RT in patients with newly diagnosed glioma. Methods: LY was evaluated sequentially in 2 doses (160 mg/day and 300 mg/day) combined with TMZ/RT. TMZ/RT was administered as approved and LY given as intermittent dosing (14 days on/14 days off=1 cycle). Toxicity was assessed using the CTCAE, version 4. The PK profile of LY in combination with TMZ/RT was determined. Results: 19 patients with glioma (16 World Health Organization Grade 4; 3 Grade 3 were treated with LY (160 mg/day, n=10; 300 mg/day, n=9) and TMZ. The median number of cycles was 5 (range 1-13). Regardless of relatedness to study treatment, the following treatment-emergent adverse events (TEAEs) were observed in ≥25% of patients: nausea (n=11), fatigue (n=11), thrombocytopenia (n=11), headache (n=9), vomi...