A phase I trial of LXS196, a protein kinase C (PKC) inhibitor, for metastatic uveal melanoma

Author:

Piperno-Neumann S.ORCID,Carlino M. S.,Boni V.,Loirat D.,Speetjens F. M.,Park J. J.,Calvo E.,Carvajal R. D.,Nyakas M.,Gonzalez-Maffe J.,Zhu X.,Shirley M. D.,Ramkumar T.,Fessehatsion A.,Burks H. E.,Yerramilli-Rao P.,Kapiteijn E.

Abstract

Abstract Background Up to 50% of patients with uveal melanoma develop metastases (MUM) with a poor prognosis and median overall survival of approximately 1 year. Methods This phase I study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of the oral protein kinase C inhibitor LXS196 in 68 patients with MUM (NCT02601378). Patients received LXS196 doses ranging from 100–1000 mg once daily (QD; n = 38) and 200–400 mg twice daily (BID; n = 30). Results First cycle dose-limiting toxicities (DLTs) were observed in 7/38 (18.4%) QD and 2/17 (11.8%) BID patients. Hypotension was the most common DLT, occurring at doses ≥500 mg/day, and manageable with LXS196 interruption and dose reduction. Median duration of exposure to LXS196 was 3.71 months (range: 1.81–15.28) for QD and 4.6 months (range: 0.33–58.32) for BID dosing. Clinical activity was observed in 6/66 (9.1%) evaluable patients achieving response (CR/PR), with a median duration of response of 10.15 months (range: 2.99–41.95); 45/66 had stable disease (SD) per RECIST v1.1. At 300 mg BID, the recommended dose for expansion, 2/18 (11.1%) evaluable patients achieved PR and 12/18 (66.7%) had SD. Conclusion These results suggest manageable toxicity and encouraging clinical activity of single-agent LXS196 in patients with MUM.

Funder

Novartis Pharmaceuticals Corporation

Publisher

Springer Science and Business Media LLC

Subject

Cancer Research,Oncology

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