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

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

doi:10.1038/s41416-022-02133-6

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

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

^*Corresponding author for this work

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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.

Original language	English
Pages (from-to)	1040-1051
Number of pages	12
Journal	British Journal of Cancer
Volume	128
Issue number	6
DOIs	https://doi.org/10.1038/s41416-022-02133-6
Publication status	Published - 6 Apr 2023
Externally published	Yes

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Copyright the Author(s) 2023. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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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. (2023). A phase I trial of LXS196, a protein kinase C (PKC) inhibitor, for metastatic uveal melanoma. British Journal of Cancer, 128(6), 1040-1051. https://doi.org/10.1038/s41416-022-02133-6

@article{21e3e6934a1c4bbcb83c1da8dfe65544,

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

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.",

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

note = "Copyright the Author(s) 2023. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",

year = "2023",

month = apr,

day = "6",

doi = "10.1038/s41416-022-02133-6",

language = "English",

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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 2023, 'A phase I trial of LXS196, a protein kinase C (PKC) inhibitor, for metastatic uveal melanoma', British Journal of Cancer, vol. 128, no. 6, pp. 1040-1051. https://doi.org/10.1038/s41416-022-02133-6

TY - JOUR

T1 - A phase I trial of LXS196, a protein kinase C (PKC) inhibitor, for metastatic uveal melanoma

AU - Piperno-Neumann, S.

AU - Carlino, M. S.

AU - Boni, V.

AU - Loirat, D.

AU - Speetjens, F. M.

AU - Park, J. J.

AU - Calvo, E.

AU - Carvajal, R. D.

AU - Nyakas, M.

AU - Gonzalez-Maffe, J.

AU - Zhu, X.

AU - Shirley, M. D.

AU - Ramkumar, T.

AU - Fessehatsion, A.

AU - Burks, H. E.

AU - Yerramilli-Rao, P.

AU - Kapiteijn, E.

N1 - Copyright the Author(s) 2023. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2023/4/6

Y1 - 2023/4/6

N2 - 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.

AB - 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.

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U2 - 10.1038/s41416-022-02133-6

DO - 10.1038/s41416-022-02133-6

M3 - Article

C2 - 36624219

AN - SCOPUS:85145857127

SN - 0007-0920

VL - 128

SP - 1040

EP - 1051

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 6

ER -

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

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