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.

Abstract

2039 Background: Based on preclinical data suggesting an additive antitumor effect of combining TGF-ß 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), vomiting (n=8), lymphopenia (n=6), anorexia (n=6), constipation (n=5), radiation skin injury (n=5), and alopecia (n=5). The following TEAEs were related specifically to at least LY: thrombocytopenia (n=3, 2 Gr 3 and 1 Gr 4), fatigue (n=2), maculopapular rash (n=2, Gr 3), dermatitis acne form (n=3, 1 Gr 3) and in 1 patient each: nausea, vomiting, hypertension, hypersensitivity and leucopenia (Gr 4). No change in the PK profile of LY was shown when LY was combined with TMZ/RT. In the combination therapy, area under the curve (0-∞) at steady state was observed geomean (%CV) to be 5.5 (48%) mg*h/L following 300 mg/day (n=9). Following monotherapy with LY, these exposures were similar with a median (20th-80thpercentiles) of 4.7 (2.5-8.8) mg*h/L (n=37). Conclusions: No dose-limiting toxicities and no clinically meaningful cardiotoxicities were observed; hence, the treatment of LY at 300 mg/day in combination with standard chemoradiation has a manageable toxicity profile. A Phase 2a trial has been initiated to relate the pharmacodynamic effects with overall survival. Clinical trial information: NCT01220271.