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

Autor: Piperno-Neumann S; Institut Curie, Paris, France. sophie.piperno-neumann@curie.fr., Carlino MS; Blacktown and Westmead Hospitals, Sydney, NSW, Australia.; Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia., Boni V; START Madrid-CIOCC, Centro Integral Oncológico Clara Campal, Madrid, Spain., Loirat D; Institut Curie, Paris, France., Speetjens FM; Leiden University Medical Center, Leiden, The Netherlands., Park JJ; Blacktown and Westmead Hospitals, Sydney, NSW, Australia., Calvo E; START Madrid-CIOCC, Centro Integral Oncológico Clara Campal, Madrid, Spain., Carvajal RD; Columbia University Irving Medical Center, New York, NY, USA., Nyakas M; Oslo University Hospital, Oslo, Norway., Gonzalez-Maffe J; Novartis Pharma AG, Basel, Switzerland., Zhu X; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Shirley MD; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Ramkumar T; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Fessehatsion A; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Burks HE; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Yerramilli-Rao P; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Kapiteijn E; Leiden University Medical Center, Leiden, The Netherlands.
Jazyk: angličtina
Zdroj: British journal of cancer [Br J Cancer] 2023 Apr; Vol. 128 (6), pp. 1040-1051. Date of Electronic Publication: 2023 Jan 09.
DOI: 10.1038/s41416-022-02133-6
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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