Integrated data review of the first-in-human dose (FHD) study evaluating safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the oral transforming growth factor-beta (TGF-ß) receptor I kinase inhibitor, LY2157299 monohydrate (LY).

Abstract

2016 Background: Activated TGF-ß signaling has been associated with poor survival in several tumors, including glioma (GM). Hence, we investigated the safety, PK and antitumor responses of the novel TGF-ß inhibitor LY in cancer patients, mainly in GM. Methods: There were 3 study parts: Part A: dose escalation of LY monotherapy in patients with solid tumor (cohorts 1 and 2, continuous dosing) and with GM (cohorts 3 to 5, intermittent dosing 14 days on/14 days off); Part B: intermittent LY dosing in combination with lomustine; Part C: monotherapy of 300 mg/day in solid tumors after completing a relative bioavailability study. Safety, antitumor activity, PK and PD were assessed as previously described (Calvo-Aller, et al. JCO 2008;26:abstract #14554; Rodon, et al. JCO 2011;29:abstract #3011; Azaro, et al. JCO 2012;30:abstract #2042). Results: 79 patients participated in this study (Part A, n = 39, 7 solid tumor, 32 GM; Part B, n = 26, all GM; Part C, n = 14 solid tumor, 9 GM, 2 hepatic cell carcinoma [HCC], 2 gastrointestinal [GI] and 1 melanoma). The integrated safety and efficacy evaluation confirms that LY has a manageable toxicity profile with antitumor activity. For GM patients the median progression-free survival (PFS) in months (range) was: 2.5 (0.0 to 36.9) in Part A; 2.5 (0.0 to 20.5) in Part B; 1.9 (0.0 to 6.4) in Part C. PFS duration in months were (range): 2.1-3.8 for HCC; 1.2-3.9 for GI and 2.2 for melanoma patient. Responders were observed in primary GM (Part A: 3/16; Part B: 2/20) and secondary GM (Part A: 3/14; Part B: 4/6). As of January 2013, 3 GM patients are still on treatment for 54, 36, and 31 months. P450-inducing medications including proton pump inhibitors or enzyme-inducing anti-epileptic drugs did not influence the PK parameters. Approximately, 90 biomarkers have been assayed and the results will be presented during the meeting. Conclusions: Because of the manageable toxicity profile of LY, the 300 mg/day dose administered as an intermittent dosing has been advanced into phase II investigation, either as a monotherapy or in combination with approved chemotherapies. Clinical trial information: NCT01682187.