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Piperno-Neumann, S.; Carlino, M.S.; Boni, V.; Loirat, D.; Speetjens, F.M.; Park, J.J.; ... ; Kapiteijn, E. (2023)

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

Article / Letter to editor
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 & GE;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...Show moreBackground: 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 & GE;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.Show less
All authors
Piperno-Neumann, S.; 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.
Date
2023-01-09
Journal
British Journal of Cancer
Volume
128
Pages
1040 - 1051
DOI
doi:10.1038/s41416-022-02133-6