A Phase I Trial of LXS196, a Protein Kinase C (PKC) Inhibitor, for Metastatic Uveal Melanoma

Overview

Journal Br J Cancer

Specialty Oncology

Date 2023 Jan 9

PMID 36624219

Authors

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

Affiliations

Soon will be listed here.

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.

Citing Articles

Artificial intelligence in drug development: reshaping the therapeutic landscape.

Niazi S, Mariam Z Ther Adv Drug Saf. 2025; 16:20420986251321704.

PMID: 40008227 PMC: 11851753. DOI: 10.1177/20420986251321704.

The role of circulating tumor DNA in melanomas of the uveal tract.

Zameer M, Jou E, Middleton M Front Immunol. 2024; 15():1509968.

PMID: 39697328 PMC: 11652350. DOI: 10.3389/fimmu.2024.1509968.

PKCα Activation via the Thyroid Hormone Membrane Receptor Is Key to Thyroid Cancer Growth.

Campos Haedo M, Diaz Albuja J, Camarero S, Cayrol F, Sterle H, Debernardi M Int J Mol Sci. 2024; 25(22).

PMID: 39596225 PMC: 11594262. DOI: 10.3390/ijms252212158.

Pyrazine-based small molecule kinase inhibitors: clinical applications and patent review (2019-2023).

Alsfouk A Future Med Chem. 2024; 16(18):1899-1921.

PMID: 39189138 PMC: 11485930. DOI: 10.1080/17568919.2024.2385293.

Recent Advances in Molecular and Genetic Research on Uveal Melanoma.

Fuentes-Rodriguez A, Mitchell A, Guerin S, Landreville S Cells. 2024; 13(12.

PMID: 38920653 PMC: 11201764. DOI: 10.3390/cells13121023.

References

Singh A, Topham A . Incidence of uveal melanoma in the United States: 1973-1997. Ophthalmology. 2003; 110(5):956-61. DOI: 10.1016/S0161-6420(03)00078-2. View

Naseripoor M, Azimi F, Mirshahi R, Khakpoor G, Poorhosseingholi A, Chaibakhsh S . Global Incidence and Trend of Uveal Melanoma from 1943-2015: A Meta-Analysis. Asian Pac J Cancer Prev. 2022; 23(5):1791-1801. PMC: 9587874. DOI: 10.31557/APJCP.2022.23.5.1791. View

Woodman S . Metastatic uveal melanoma: biology and emerging treatments. Cancer J. 2012; 18(2):148-52. PMC: 3935729. DOI: 10.1097/PPO.0b013e31824bd256. View

Khoja L, Atenafu E, Suciu S, Leyvraz S, Sato T, Marshall E . Meta-analysis in metastatic uveal melanoma to determine progression free and overall survival benchmarks: an international rare cancers initiative (IRCI) ocular melanoma study. Ann Oncol. 2019; 30(8):1370-1380. DOI: 10.1093/annonc/mdz176. View

Augsburger J, Correa Z, Shaikh A . Effectiveness of treatments for metastatic uveal melanoma. Am J Ophthalmol. 2009; 148(1):119-27. DOI: 10.1016/j.ajo.2009.01.023. View

Rodrigues M, Mobuchon L, Houy A, Fievet A, Gardrat S, Barnhill R . Outlier response to anti-PD1 in uveal melanoma reveals germline MBD4 mutations in hypermutated tumors. Nat Commun. 2018; 9(1):1866. PMC: 5951831. DOI: 10.1038/s41467-018-04322-5. View

Piulats J, Espinosa E, de la Cruz Merino L, Varela M, Alonso Carrion L, Martin-Algarra S . Nivolumab Plus Ipilimumab for Treatment-Naïve Metastatic Uveal Melanoma: An Open-Label, Multicenter, Phase II Trial by the Spanish Multidisciplinary Melanoma Group (GEM-1402). J Clin Oncol. 2021; 39(6):586-598. DOI: 10.1200/JCO.20.00550. View

Pelster M, Gruschkus S, Bassett R, Gombos D, Shephard M, Posada L . Nivolumab and Ipilimumab in Metastatic Uveal Melanoma: Results From a Single-Arm Phase II Study. J Clin Oncol. 2020; 39(6):599-607. PMC: 8257877. DOI: 10.1200/JCO.20.00605. View

Nathan P, Hassel J, Rutkowski P, Baurain J, Butler M, Schlaak M . Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma. N Engl J Med. 2021; 385(13):1196-1206. DOI: 10.1056/NEJMoa2103485. View

10.

Van Raamsdonk C, Bezrookove V, Green G, Bauer J, Gaugler L, OBrien J . Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature. 2008; 457(7229):599-602. PMC: 2696133. DOI: 10.1038/nature07586. View

11.

Van Raamsdonk C, Griewank K, Crosby M, Garrido M, Vemula S, Wiesner T . Mutations in GNA11 in uveal melanoma. N Engl J Med. 2010; 363(23):2191-9. PMC: 3107972. DOI: 10.1056/NEJMoa1000584. View

12.

Piperno-Neumann S, Larkin J, Carvajal R, Luke J, Schwartz G, Hodi F . Genomic Profiling of Metastatic Uveal Melanoma and Clinical Results of a Phase I Study of the Protein Kinase C Inhibitor AEB071. Mol Cancer Ther. 2020; 19(4):1031-1039. DOI: 10.1158/1535-7163.MCT-19-0098. View

13.

Robertson A, Shih J, Yau C, Gibb E, Oba J, Mungall K . Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma. Cancer Cell. 2017; 32(2):204-220.e15. PMC: 5619925. DOI: 10.1016/j.ccell.2017.07.003. View

14.

Rozengurt E . Mitogenic signaling pathways induced by G protein-coupled receptors. J Cell Physiol. 2007; 213(3):589-602. DOI: 10.1002/jcp.21246. View

15.

Chen X, Wu Q, Depeille P, Chen P, Thornton S, Kalirai H . RasGRP3 Mediates MAPK Pathway Activation in GNAQ Mutant Uveal Melanoma. Cancer Cell. 2017; 31(5):685-696.e6. PMC: 5499527. DOI: 10.1016/j.ccell.2017.04.002. View

16.

Chen X, Wu Q, Tan L, Porter D, Jager M, Emery C . Combined PKC and MEK inhibition in uveal melanoma with GNAQ and GNA11 mutations. Oncogene. 2013; 33(39):4724-34. PMC: 4524511. DOI: 10.1038/onc.2013.418. View

17.

Carita G, Frisch-Dit-Leitz E, Dahmani A, Raymondie C, Cassoux N, Piperno-Neumann S . Dual inhibition of protein kinase C and p53-MDM2 or PKC and mTORC1 are novel efficient therapeutic approaches for uveal melanoma. Oncotarget. 2016; 7(23):33542-56. PMC: 5085101. DOI: 10.18632/oncotarget.9552. View

18.

Neuenschwander B, Branson M, Gsponer T . Critical aspects of the Bayesian approach to phase I cancer trials. Stat Med. 2008; 27(13):2420-39. DOI: 10.1002/sim.3230. View

19.

Babb J, Rogatko A, Zacks S . Cancer phase I clinical trials: efficient dose escalation with overdose control. Stat Med. 1998; 17(10):1103-20. DOI: 10.1002/(sici)1097-0258(19980530)17:10<1103::aid-sim793>3.0.co;2-9. View

20.

Yap Y, Singh A, Lim J, Ahn J, Jung K, Kim J . Elucidating therapeutic molecular targets in premenopausal Asian women with recurrent breast cancers. NPJ Breast Cancer. 2018; 4:19. PMC: 6062514. DOI: 10.1038/s41523-018-0070-x. View