A phase Ib trial of combined PKC and MEK inhibition with sotrastaurin and binimetinib in patients with metastatic uveal melanoma.

Background

Uveal melanoma is a disease characterized by constitutive activation of the G alpha pathway and downstream signaling of protein kinase C (PKC) and the mitogen-activated protein kinase (MAPK) pathway. While limited clinical activity has been observed in patients with metastatic disease with inhibition of PKC or MEK alone, preclinical data has demonstrated synergistic antitumor effects with concurrent inhibition of PKC and MEK.

Method

We conducted a phase Ib study of the PKC inhibitor sotrastaurin in combination with the MEK inhibitor binimetinib in patients with metastatic uveal melanoma using a Bayesian logistic regression model guided by the escalation with overdose control principle (NCT01801358). Serial blood samples and paired tumor samples were collected for pharmacokinetic (PK) and pharmacodynamic analysis.

Results

Thirty-eight patients were treated across six dose levels. Eleven patients experienced DLTs across the five highest dose levels tested, most commonly including vomiting (n=3), diarrhea (n=3), nausea (n=2), fatigue (n=2) and rash (n=2). Common treatment related adverse events included diarrhea (94.7%), nausea (78.9%), vomiting (71.1%), fatigue (52.6%), rash (39.5%), and elevated blood creating phosphokinase (36.8%). Two dose combinations satisfying criteria for the maximum tolerated dose (MTD) were identified: (1) sotrastaurin 300 mg and binimetinib 30 mg; and, (2) sotrastaurin 200 mg and binimetinib 45 mg. Exposure to both drugs in combination was consistent with single-agent data for either drug, indicating no PK interaction between sotrastaurin and binimetinib. Stable disease was observed in 60.5% of patients treated. No patient achieved a radiographic response per RECIST v1.1.

Conclusions

Concurrent administration of sotrastaurin and binimetinib is feasible but associated with substantial gastrointestinal toxicity. Given the limited clinical activity achieved with this regimen, accrual to the phase II portion of the trial was not initiated.

Informations de copyright

Copyright © 2023 Bauer, Larkin, Hodi, Stephen, Kapiteijn, Schwartz, Calvo, Yerramilli-Rao, Piperno-Neumann and Carvajal.

Déclaration de conflit d'intérêts

The handling editor JK declared a past co-authorship with the authors JL, SH, SP-N, RC. SB reports COI with Blueprint Medicines, Incyte, and Novartis RF-institutional, PharmaMar, Eli Lilly & Co, Novartis Honoraria, Adcendo, Bayer, Blueprint Medicines, Böhringer Ingelheim, Daiichi Sankyo, Deciphera, Eli Lilly & Co, GSK, Exelixis, Nanobiotix, Novartis, Roche SAB, JL reports personal fees from Eisai, Novartis, Incyte, Merck, touchIME, touchEXPERTS, Pfizer, Royal College of Physicians, Cambridge Healthcare Research, Royal College of General Practitioners, VJOncology, Agence Unik, BMS, iOnctura, Apple Tree, Merck, BMS, Eisai, Debipharm, Incyte, Pierre Fabre, BMS, Ipsen, Roche, EUSA Pharma, Novartis, Aptitude, AstraZeneca, GSK, Eisai, Calithera, Ultimovacs, Seagen, Merck, eCancer, Inselgruppe, Pfizer, Goldman Sachs and MSD. He reports grants from Achilles, BMS, MSD, Nektar, Novartis, Pfizer, Roche, Immunocore, Aveo and Pharmacyclics. He reports institutional research support from BMS, MSD, Novartis, Pfizer, Achilles Therapeutics, Roche, Nektar Therapeutics, Covance, Immunocore, Pharmacyclics and Aveo. SH reports grants and personal fees from Bristol-Myers Squibb, personal fees from Merck, personal fees from EMD Serono, grants and personal fees from Novartis, personal fees from Surface, personal fees from Compass Therapeutics, personal fees from Apricity, personal fees from Sanofi, personal fees from Pionyr, personal fees from 7 Hills Pharma, personal fees from Torque, personal fees from Bicara, personal fees from Checkpoint Therapeutics, personal fees from Genentech/Roche, personal fees from Bioentre, personal fees from Gossamer, personal fees from Iovance, personal fees from Trillium, personal fees from Catalym, personal fees from Immunocore, personal fees from Amgen, personal fees from Kairos, personal fees from Eisai, personal fees from Rheos, personal fees from Zumutor, personal fees from Corner Therapeuitcs, outside the submitted work; In addition, Dr. Hodi has a patent Methods for Treating MICA-Related Disorders #20100111973 with royalties paid, a patent Tumor antigens and uses thereof #7250291 issued, a patent Angiopoiten-2 Biomarkers Predictive of Anti-immune checkpoint response #20170248603 pending, a patent Compositions and Methods for Identification, Assessment, Prevention, and Treatment of Melanoma using PD-L1 Isoforms #20160340407 pending, a patent Therapeutic peptides #20160046716 pending, a patent Therapeutic Peptides #20140004112 pending, a patent Therapeutic Peptides #20170022275 pending, a patent Therapeutic Peptides #20170008962 pending, a patent on Therapeutic Peptides, Patent number: 9402905 issued, a patent METHODS OF USING PEMBROLIZUMAB AND TREBANANIB pending, a patent Vaccine compositions and methods for restoring NKG2D pathway function against cancers, patent number 10279021 issued, a patent Antibodies that bind to MHC class I polypeptide-related sequence A, patent number 10106611 issued, and a patent ANTI-GALECTIN ANTIBODY BIOMARKERS PREDICTIVE OF ANTI-IMMUNE CHECKPOINT AND ANTI-ANGIOGENESIS RESPONSES. EK has consultancy/advisory relationships with Bristol-Myers Squibb, Novartis, Merck, Pierre Fabre, EISAI, Bayer, Genzyme-Sanofi, Ipsen and Lilly, and received research grants not related to this paper from Novartis, Pierre Fabre and Bristol-Myers Squibb. GS has consultancy/advisory relationships with Bionaut Labs, Ellipses Pharma, Gencirq, Epizyme, Array BioPharma, Apexigen, Oncogenuity, OnCusp Therapeutics, Concarlo, Shanghai Pharma, Astex Pharmaceuticals, January Therapeutics, Sellas Life Sciences, PureTech Health and Killys Therapeutics. He reports stock and other ownership interests in GenCirq, Bionaut Labs and January Therapuetics. He reports travel support from Array BioPharma and Epizyme. He receives research funding from Astex Pharmaceuticals. He reports institutional research support from Incyte, Calithera Biosciences, Lilly, Daiichi Sankyo, Fortress Biotech, Karyopharm Therapeutics, Oxford BioTherapeutics, Astex, Pharmaceuticals, TopAlliance Biosciences Inc, Adaptimmune, SpringWorks Therapeutics and TRACON Pharma. EC has consultancy/advisory relationships with Nanobiotx, Janssen-Cilag, Roche/Genentech, TargImmune Therapeutics, Servier, Bristol-Myers Squibb, Amunix, Adecendo, Anaveon, AstraZeneca/MedImmune, Chugai Pharma, MonTa, MSD Oncology, Nouscom, Novartis, OncoDNA, T-Knife, Elevation Oncology, PharmaMar. He has stock and other ownership interests in START and Oncoart Associated. He has leadership in START, PharmaMar, the EORTC, Sanofi and BeiGene. PY-R is an employee of Novartis. SP-N has consultancy/advisory relationships with Immunocore. RC has consultancy/advisory relationships with Alkermes, Aura Biosciences, Bristol Myers Squibb, Castle Biosciences, Chimeron, Delcath, Eisai, Hengrui, Ideaya, Immunocore, InxMed, Iovance, Merck, Novartis, Oncosec, Pierre Fabre, PureTech Health, Regeneron, Rgenix, Sanofi Genzyme, Sorrento Therapeutics and Trisalus. He reports institutional research support from Amgen, Astellis, AstraZeneca, Bristol-Myers Squibb, Corvus, Ideaya, Immunocore, Iovance, Merck, Mirati, Novartis, Pfizer, Plexxikon, Regeneron and Roche/Genentech. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.