ArticleJournal of experimental & clinical cancer research : CR2022
Phase I pharmacokinetic study of single agent trametinib in patients with advanced cancer and hepatic dysfunction.
Article in Journal of experimental & clinical cancer research : CR, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02070549 (A Phase I Trial of Single Agent Trametinib), which is not on this map. Cited by 6 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Phase I Trial of Single Agent Trametinib (GSK1120212) in Advanced Cancer Patients With Hepatic Dysfunction
Who cites it
6 citing papers in PubMed, 1 synthesis or guideline pooled it, 11 citations in OpenAlex.
- Pooled it
- MEK-inhibitors decrease Nfix in muscular dystrophy but induce unexpected calcifications, partially rescued with Cyanidin diet.iScience · 2024Article
- Industry Review of Best Practices for Risk Management of Drug-Induced Liver Injury from Development to Real-World Use.Drug safety · 2024Review
- Radio-sensitizing effect of MEK inhibition in glioblastoma in vitro and in vivo.Journal of cancer research and clinical oncology · 2023Article
- Elucidating host cell response pathways and repurposing therapeutics for SARS-CoV-2 and other coronaviruses.Scientific reports · 2022Article
- Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
19 authors at 9 institutions in 2 countries.
Funding
Abstract
backgroundTrametinib is an oral MEK 1/2 inhibitor, with a single agent recommended phase 2 dose (RP2D) of 2 mg daily (QD). This study was designed to evaluate RP2D, maximum tolerated dose (MTD), and pharmacokinetic (PK) profile of trametinib in patients with advanced solid tumors who had various degrees of hepatic dysfunction (HD).
methodsAdvanced cancer patients were stratified into 4 HD groups based on Organ Dysfunction Working Group hepatic function stratification criteria: normal (Norm), mild (Mild), moderate (Mod), severe (Sev). Dose escalation was based on "3 + 3" design within each HD group. PK samples were collected at cycle 1 days 15-16.
resultsForty-six patients were enrolled with 44 evaluable for safety [Norm=17, Mild=7, Mod (1.5 mg)=4, Mod (2 mg)=5, Sev (1 mg)=9, Sev (1.5 mg)=2] and 22 for PK analysis. Treatment related adverse events were consistent with prior trametinib studies. No treatment related deaths occurred. Dose limiting toxicities (DLTs) were evaluable in 15 patients (Mild=6, Mod (1.5 mg)=3, Mod (2 mg)=2, Sev (1 mg)=3 and Sev (1.5 mg)=1). One DLT (grade 3 acneiform rash) was observed in a Sev patient (1.5 mg). Dose interruptions or reductions due to treatment related adverse events occurred in 15 patients (34%) [Norm=9, 53%; Mild=2, 29%; Mod (1.5 mg)=1, 33%; Mod (2 mg)=2, 33%; Sev (1 mg)=1, 11%; Sev (1.5 mg)=1; 50%]. There were no significant differences across HD groups for all PK parameters when trametinib was normalized to 2 mg. However, only limited PK data were available for the Mod (n = 3) and Sev (n = 3) groups compared to Norm (n = 10) and Mild (n = 6) groups. Trametinib is heavily protein bound, with no correlation between serum albumin level and unbound trametinib fraction (p = 0.26).
conclusionsRP2D for trametinib in Mild HD patients is 2 mg QD. There are insufficient number of evaluable patients due to difficulty of patient accrual to declare RP2D and MTD for Mod and Sev HD groups. DLTs were not observed in the highest dose cohorts that reached three evaluable patients - 1.5 mg QD in Mod group, and 1 mg QD in Sev group.
trial registrationThis study was registered in the ClinicalTrials.gov website ( NCT02070549 ) on February 25, 2014. .
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.