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.

Autor: Stathis A; Oncology Institute of Southern Switzerland, EOC, via A. Gallino 12, Bellinzona 6500, Switzerland. anastasios.stathis@eoc.ch., Tolcher AW; NEXT Oncology, San Antonio, TX, USA., Wang JS; Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, FL, USA., Renouf DJ; BC Cancer-Vancouver Center, Vancouver, BC, Canada., Chen LC; Merck & Co., Inc., Rahway, NJ, USA., Suttner LH; Merck & Co., Inc., Rahway, NJ, USA., Freshwater T; Merck & Co., Inc., Rahway, NJ, USA., Webber AL; Merck & Co., Inc., Rahway, NJ, USA., Nayak T; Merck & Co., Inc., Rahway, NJ, USA., Siu LL; Princess Margaret Cancer Centre, Toronto, ON, Canada.
Jazyk: angličtina
Zdroj: Investigational new drugs [Invest New Drugs] 2023 Jun; Vol. 41 (3), pp. 380-390. Date of Electronic Publication: 2023 Apr 11.
DOI: 10.1007/s10637-022-01326-3
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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