| Title: |
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. |
| Authors: |
Stathis, Anastasios, Tolcher, Anthony W., Wang, Judy S., Renouf, Daniel J., Chen, Lin-Chi, Suttner, Leah H., Freshwater, Tomoko, Webber, Andrea L., Nayak, Tapan, Siu, Lillian L. |
| Source: |
Investigational New Drugs; Jun2023, Vol. 41 Issue 3, p380-390, 11p |
| Subject Terms: |
SMALL molecules, CLINICAL drug trials, CLINICAL trials, DRUG tolerance, ORAL drug administration, METASTASIS, ANTINEOPLASTIC agents, INVESTIGATIONAL drugs, TUMOR classification, TRANSFERASES, DESCRIPTIVE statistics, RESEARCH funding, MITOGEN-activated protein kinases, TUMORS, PATIENT safety, PHARMACODYNAMICS |
| Abstract: |
Aim: 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. Methods: 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. Results: 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). Conclusion: 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. [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |
