Related Experiment Video
Updated: Oct 4, 2025
Author Spotlight: Assessing the Potential of Circulating Tumor Cells in Leptomeningeal Disease Research
Published on: March 29, 2024
Phase I pharmacokinetic study of single agent trametinib in patients with advanced cancer and hepatic dysfunction
Pei Jye Voon1, Eric X Chen1, Helen X Chen2
1Princess Margaret Cancer Centre, University of Toronto, 700 University Avenue, office 7-624, ON, Toronto, Canada.
Background:
Trametinib 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).
Methods:
Advanced 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.
Results:
Forty-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).
Conclusions:
RP2D 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 Registration:
This study was registered in the ClinicalTrials.gov website ( NCT02070549 ) on February 25, 2014. .
Insights
The recommended phase 2 dose (RP2D) for trametinib in patients with mild hepatic dysfunction is 2 mg daily. Accrual challenges prevented definitive RP2D and MTD determination in moderate and severe hepatic dysfunction groups.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Trametinib is an oral MEK 1/2 inhibitor used for advanced solid tumors.
- Hepatic dysfunction (HD) can affect drug pharmacokinetics and safety.
- This study evaluated trametinib dosing in patients with varying degrees of hepatic dysfunction.
Purpose of the Study:
- To determine the recommended phase 2 dose (RP2D) of trametinib in patients with hepatic dysfunction.
- To establish the maximum tolerated dose (MTD) of trametinib in these patient groups.
- To assess the pharmacokinetic (PK) profile of trametinib across different levels of hepatic dysfunction.
Main Methods:
- A "3+3" dose escalation design was used within four hepatic dysfunction groups (normal, mild, moderate, severe).
- Patients with advanced solid tumors were enrolled and stratified based on hepatic function criteria.
- Pharmacokinetic samples were collected during the first cycle of treatment.
Main Results:
- The RP2D for trametinib in mild hepatic dysfunction was determined to be 2 mg daily.
- Dose-limiting toxicities (DLTs) were observed, with one grade 3 acneiform rash in a severe HD patient at 1.5 mg.
- Pharmacokinetic parameters showed no significant differences across HD groups when normalized to 2 mg, though data for moderate and severe HD were limited.
Conclusions:
- The RP2D of trametinib is confirmed at 2 mg QD for patients with mild hepatic dysfunction.
- Insufficient patient accrual hindered the determination of RP2D and MTD for moderate and severe hepatic dysfunction.
- No DLTs were observed in the highest dose cohorts evaluated in the moderate (1.5 mg QD) and severe (1 mg QD) groups.
More Related Videos
09:38Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
Published on: August 11, 2017
08:59Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down
Published on: December 11, 2017
Related Concept Videos
01:22Effect of Hepatic Disease on Pharmacokinetics: Pathophysiologic Assessment and Liver Function Test
01:14Effect of Hepatic Disease on Pharmacokinetics: Active Drug, Metabolite and Fraction of Metabolized Drug
01:08Effect of Hepatic Disease on Pharmacokinetics: Dose Adjustments Due to Hepatic Impairment
01:24Pharmacokinetics in Pediatric Patients: Drug Metabolism
01:11Clinical Trials: Overview
01:26Effect of Hepatic Disease on Pharmacokinetics: Drug Dosing and Hepatic Blood Flow