Phase I pharmacokinetic study of single agent trametinib in patients with advanced cancer and hepatic dysfunction

Abstract

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 (NCT 02070549) on February 25, 2014. .

Elucidating host cell response pathways and repurposing therapeutics for SARS-CoV-2 and other coronaviruses

“… 1 Cmax after a single dose of 4 mg per individual ranged from 1.6 to 5.7 ng/mL; molecular weight is 455.5 ng/nmol 35 2 Cmax after a single dose of 2 mg per individual is 27.6 ng/mL; molecular weight is 615 ng/nmol 36 3 Cmax after a single dose of 1.25 mg/m2 is: 25.1 ng/mL; molecular weight is 545.6 ng/nmol 37 4 Cmax after the first dose of 1.3 mg/m2 is: 112 ng/mL; molecular weight is 384.24 ng/nmol 38 …”

Nivolumab in combination with dabrafenib and trametinib use in advanced cholangiocarcinoma with a BRAF V600E mutation and severe hepatic dysfunction: A case report and review of the literature

“…Trametinib is an inhibitor of MEK1 and MEK2 [12]. Use of dabrafenib and trametinib concomitantly results in greater growth inhibition of BRAF V600E mutant tumors [13]. The ROAR trial was a phase II open-label, single-arm multicenter basket trial including 43 patients with BRAF V600E mutated advanced adenocarcinoma of the biliary tract or gallbladder lacking alternative treatment options.…”

“…Evaluable dose limiting toxicities were assessed in four patients with severe liver dysfunction: three patients receiving trametinib 1 mg daily and one patient receiving 1.5 mg daily. There was one grade 3 dose limiting toxicity reported in the patient taking 1.5 mg daily which was an acneiform rash [13]. Acneiform rash, however, is an adverse event occurring in >20% of patients receiving trametinib in studies with normal hepatic function [12].…”

“…Acneiform rash, however, is an adverse event occurring in >20% of patients receiving trametinib in studies with normal hepatic function [12]. Pharmacokinetic data were limited to three patients with severe liver dysfunction, defined as bilirubin between >3× and ≤10× upper limit of normal (ULN); however, there were no significant differences observed between patients with normal hepatic function and those with severe hepatic dysfunction [13]. Prescribing information states that a recommended dose of trametinib has not been established for patients with moderate [bilirubin >1.5× to 3× ULN and any aspartate aminotransferase (AST)] or severe (bilirubin >3× to 10× ULN and any AST) hepatic impairment.…”

Elucidating host cell response pathways and repurposing therapeutics for SARS-CoV-2 and other coronaviruses using gene expression profiles of chemical and genetic perturbations

“…Cmax after a single dose of 4mg per individual ranged from 1.6 to 5.7 ng/mL; molecular weight is 455.5 ng/nmol[26].2 Cmax after a single dose of 2 mg per individual is 27.6 ng/mL; molecular weight is 615 ng/nmol[27].3 Cmax after a single dose of 1.25 mg/m 2 is: 25.1 ng/mL; molecular weight is 545.6 ng/nmol[28] 4. Cmax after the first dose of 1.3 mg/m 2 is: 112 ng/mL; molecular weight is 384.24 ng/nmol[29].…”