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

Piperno-Neumann S, Carlino MS, Boni V, Loirat D, Speetjens FM, Park JJ, Calvo E, Carvajal RD, Nyakas M, Gonzalez-Maffe J, Zhu X, Shirley MD, Ramkumar T, Fessehatsion A, Burks HE, Yerramilli-Rao P, Kapiteijn E.  Br J Cancer. 2023 Apr;128(6):1040-1051. doi: 10.1038/s41416-022-02133-6. Epub 2023 Jan 9. PMID: 36624219; PMCID: PMC10006169.


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.