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.
Tumor Survivin Is Downregulated by the Antisense Oligonucleotide LY2181308: A Proof-of-Concept, First-in-Human Dose Study
