Safety interim data from a three-arm phase II study evaluating safety and pharmacokinetics of the oral transforming growth factor-beta (TGF-ß) receptor I kinase inhibitor LY2157299 monohydrate in patients with glioblastoma at first progression.

Abstract

2061 Background: Based on preclinical data suggesting an additive antitumor effect of a TGF-ß inhibitor and lomustine, a phase II study was initiated to evaluate the activity of this combination in patients with glioblastoma after first progression. We here report are the safety and PK interim data. Methods: Lomustine was given every 6 weeks as approved, starting on day 7 of cycle 1. LY2157299 (300 mg/day) was administered as intermittent dosing (each cycle = 14 days on followed by 14 days off). Patients received lomustine with either LY2157299 or placebo thereby blinding for LY2157299, while patients receiving LY2157299 alone were unblinded (randomization 2:1:1). Toxicity was assessed using CTCAE, version 4.0. Results: After 31 patients had completed at least 1 cycle (28 days, 3 weeks of lomustine), 50 patients had received at least 1 dose of study drug (LY2157299 or lomustine). Aggregate safety data of the 31 patients are provided: 1 patient died on treatment due to multi-organ failure, not considered related to study treatment. At least 3 patients had the following TEAEs with severity, of grade 3 or 4, and drug relatedness (DR, specific drug not indicated): vomiting (n = 5, 4 DR), fatigue (n = 5, 3 DR,1gr 3), dysphasia (n = 4,1 gr 3), other nervous system disorder (n = 4, 3 gr 3), constipation (n = 3), nausea (n = 3, 3 DR), confusion (n = 3, 1 gr 3). Other grade 3/4 TEAEs observed were: abdominal pain, allergic reaction (DR), fall, syncope, pain, lymphocytes, ANC and thrombocytopenia (all DR) and alanine aminotransferase – in 1patient each. No difference in the LY2157299 concentrations between LY2157299 monotherapy and combination arms was observed. Conclusions: The combination of lomustine with LY2157299 or placebo is consistent with the known profile of lomustine with no unexpected clusters of adverse events and similar to a previous phase I study (Azaro et al. abstract 2042, J Clin Oncol. 30, 2012). The phase II study continues after the first interim assessment on safety. Clinical trial information: NCT01582269.