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 gemcitabine in patients with advanced cancer.

Abstract

2563 Background: Based on animal studies, the combination of a TGF-β inhibitor and gemcitabine is expected to enhance antitumor activity of gemcitabine. Hence, we started a combination study of LY with gemcitabine to assess the safety of this combination therapy. Methods: Gemcitabine was administered as approved and LY was given daily as intermittent dosing (14 days on/14 days off=1 cycle). A dose escalation consisting of 3 cohorts (80 mg/day, 160 mg/day, and 300 mg/day) evaluated the safety of LY in combination with gemcitabine. Toxicity was assessed using the CTCAE, version 4. Pharmacokinetic (PK) profile of LY in combination with gemcitabine was determined. Results: A total of 14 patients were evaluated (cohort 1 [n=5, 4 adenocarcinoma of colon, 1 non-small cell lung cancer, cohort 2 [n=4, adenocarcinoma, 1 each of esophageal, well differentiated, pancreas, lung], cohort 3 [n=5, 3 pancreatic, 2 rectal cancer]) in this study. The median number of cycles was 2 (range (1-6). Regardless of causality, the following treatment-emergent adverse events (TEAEs) were observed in ≥25% of patients: anemia (n=10), nausea (n=8), thrombocytopenia (n=6), neutropenia (n=6), vomiting (n=6), anorexia (n=5), fatigue (n=5), diarrhea (n=5) asthenia (n=5), pyrexia (n=4), AST increased (n=4), and constipation (n=4). Possibly related to LY, (Grade, Gr, 3/4 as mentioned) TEAEs observed were: nausea (n=5), asthenia (n=4), fatigue (n=3, 1 Gr 3), neutropenia (n=3, 1 Gr 3), anemia (n=3, 2 Gr 3 ), and in 2 patients each, thrombocytopenia (both Gr 3), headache, edema peripheral, rash, anorexia, diarrhea (1 Gr 3), mucosal inflammation, vomiting and reversible rhabdomyolysis (n=1, Gr 4). No change in the PK profile of LY was shown when LY was combined with gemcitabine. Conclusions: There were no dose limiting toxicities observed and no clinically meaningful cardiotoxicities were detected. Because of the observed manageable safety profile, LY at 300 mg/day has been advanced into a randomized Phase 2 trial in pancreatic cancer in 1st line setting to assess the antitumor activity of the combination. Clinical trial information: NCT01373164.