Results of an open-label phase 1b study of the ERK inhibitor MK-8353 plus the MEK inhibitor selumetinib in patients with advanced or metastatic solid tumors.
Adult
Humans
Middle Aged
Aged
Mitogen-Activated Protein Kinase 3
Neoplasms
/ drug therapy
Protein Kinase Inhibitors
/ adverse effects
Mitogen-Activated Protein Kinase Kinases
Nausea
/ chemically induced
Diarrhea
/ chemically induced
Antineoplastic Combined Chemotherapy Protocols
/ adverse effects
Maximum Tolerated Dose
ERK inhibitor
MEK inhibitor
MK-8353
Selumetinib
Solid tumors
Tolerability
Journal
Investigational new drugs
ISSN: 1573-0646
Titre abrégé: Invest New Drugs
Pays: United States
ID NLM: 8309330
Informations de publication
Date de publication:
Jun 2023
Jun 2023
Historique:
received:
22
12
2022
accepted:
29
12
2022
revised:
22
12
2022
medline:
26
6
2023
pubmed:
12
4
2023
entrez:
11
4
2023
Statut:
ppublish
Résumé
We evaluated MK-8353 (small molecule inhibitor of extracellular signal-regulated kinase 1/2) plus selumetinib (mitogen-activated extracellular signal-regulated kinase 1/2 inhibitor) in patients with advanced solid tumors. This phase 1b, open-label, dose-escalation study (NCT03745989) enrolled adults with histologically/cytologically documented, locally advanced/metastatic solid tumors. MK-8353/selumetinib dose combinations were intended to be investigated in sequence: 50/25, 100/50, 150/75, 200/75, 200/100, and 250/100. Each agent was administered orally BID 4 days on/3 days off in repeating cycles every 21 days. Primary objectives were safety and tolerability and to establish preliminary recommended phase 2 doses for combination therapy. Thirty patients were enrolled. Median (range) age was 61.5 (26-78) years and 93% had received previous cancer therapy. Among 28 patients in the dose-limiting toxicities [DLT]-evaluable population, 8 experienced DLTs: 1/11 (9%) in the MK-8353/selumetinib 100/50-mg dose level experienced a grade 3 DLT (urticaria), and 7/14 (50%) in the 150/75-mg dose level experienced grade 2/3 DLTs (n = 2 each of blurred vision, retinal detachment, vomiting; n = 1 each of diarrhea, macular edema, nausea, retinopathy). The DLT rate in the latter dose level exceeded the prespecified target DLT rate (~30%). Twenty-six patients (87%) experienced treatment-related adverse events (grade 3, 30%; no grade 4/5), most commonly diarrhea (67%), nausea (37%), and acneiform dermatitis (33%). Three patients (10%) experienced treatment-related adverse events leading to treatment discontinuation. Best response was stable disease in 14 patients (n = 10 with MK-8353/selumetinib 150/75 mg). MK-8353/selumetinib 50/25 mg and 100/50 mg had acceptable safety and tolerability, whereas 150/75 mg was not tolerable. No responses were observed.
Identifiants
pubmed: 37040046
doi: 10.1007/s10637-022-01326-3
pii: 10.1007/s10637-022-01326-3
pmc: PMC10289957
doi:
Substances chimiques
AZD 6244
0
MK-8353
0
Mitogen-Activated Protein Kinase 3
EC 2.7.11.24
Protein Kinase Inhibitors
0
Mitogen-Activated Protein Kinase Kinases
EC 2.7.12.2
Types de publication
Clinical Trial, Phase I
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
380-390Informations de copyright
© 2023. The Author(s).
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