The oral transforming growth factor-beta (TGF-ß) receptor I kinase inhibitor LY2157299 plus lomustine in patients with treatment-refractory malignant glioma: The first human dose study.

Abstract

2042 Background: Activated TGF-b signaling has been associated with poor survival in several tumors, including glioma. TGF-b inhibitors are expected to improve outcome. Part B of this Phase I trial assessed safety, pharmacokinetics, pharmacodynamics, and antitumor activity of the intermittent treatment with LY2157299 in combination with lomustine. Methods: After evaluating safety of LY2157299 monotherapy in part A of the study, 2 cohorts of patients were treated with LY2157299 at 160 or 300 mg/day with intermittent dosing (each cycle=14 days on followed by 14 days off) in combination with lomustine at standard dose (100 to 130 mg/m2 every 6 weeks) for ≥2 cycles. Toxicity was assessed using the Common Terminology Criteria for Adverse Events, version 3. Results: Twenty-six patients with glioma (18 WHO Grade IV; 5 Grade III; 3 unspecified grade) were treated with LY2157299 and lomustine (160 mg/day, n=15; 300 mg/day, n=11). There were no dose-limiting toxicities. No clinically meaningful cardiotoxicities were observed. Twenty-one SAEs occurred in 10 patients, all considered to be related to lomustine and none to LY2157299. Of the 26 patients, 7 had thrombocytopenia (27%), and recovery around weeks 4 to 6 was not impacted by the second cycle of LY2157299. Two patients taking 160 mg/day were treated for >6 cycles, with 1 of the 2 patients showing an unconfirmed partial response. At the 300 mg/day dose, no responses were observed; 2 patients were treated for >6 cycles. Co-administration of lomustine did not alter LY2157299 exposure. Observed exposure of LY2157299 increased with dose escalation between the 2 cohorts. On Day 7, the variability estimates (coefficients of variation) of exposure and maximum concentration were slightly higher in presence of lomustine (58%) when compared with LY2157299 alone (47%) and then again reduced on Day 14 (53%). Pharmacodynamic results will be reported at a later date. Conclusions: The 14 days on/14 days off treatment with LY2157299 did not increase the known lomustine toxicity. Given the overall safety profile and antitumor effect, LY2157299 is being investigated in Phase II studies.