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 ( NCT02070549 ) on February 25, 2014. .

Keywords: Dose escalation; Hepatic dysfunction; Pharmacokinetics; Phase I trial; Trametinib.

Conflict of interest statement

PJV: None.

EXC: Honoraria from Taiho, Bayer, and Eisai; institution funding for clinical trials from AZ, BMS, Merck, Zymeworks, and Novartis.

HXC: None.

ACL: Consulting role for Novartis.

KK: Clinical trial support from Novartis for upcoming capmatinib study.

UNV: Research funding from Merck and Bristol Myers Squibb. Consulting fees and Honoraria from Merck, Bayer, BMS, AAA, Pfizer, Exelixis Inc.

SS: Research funding from Merck, Bristol Myers Squibb and Brooklyn ImmunoTherapeutics; Advisory Board: Merck and Boehringer Ingelheim.

VS: Grants or research support from Novartis, AbbVie, Agensys, Alfasigma, Altum, Amgen, Bayer, Berghealth, Blueprint Medicines, Boston Biomedical, Boston Pharmaceuticals, D3 Pharma, Dragonfly Therapeutics, Exelixis, Fujifilm, Idera Pharmaceuticals, Incyte, Inhibrx, Loxo Oncology, MedImmune, MultiVir, National Comprehensive Cancer Network, NCI-Cancer Therapy Evaluation Program, Novartis, Pfizer, PharmaMar, Takeda, The University of Texas MD Anderson Cancer Center, and Turning Point Therapeutics and advisory/board member role in Eli Lilly, Helsinn, Incyte, Relay Therapeutics, Loxo Oncology, MedImmune, Novartis, QED Therapeutics, and R-Pharma US.

DJR: Research funding and honoraria from Bayer and Roche, and travel funding and honoraria from Servier, Celgene, Taiho, Ipsen, and Astra Zeneca.

ARR: Consulting/advisory roles for Eli-Lilly, Medison, GSK, Merck, Bayer, and Adaptimmune; institutional research funding from Boerhinger-Ingelheim, Eli-Lilly, Boston Biomedicals, Deciphera, Karyopharm Therapeutics, Pfizer, Roche/Genentech, BMS, Medimmune, Amgen, GSK, Blueprint Medicines, Symphogen, Merck, AbbVie, Adaptimmune, and Iterion Therapeutics.

SPI: None.

SJH: None.

AS (Singh): None.

PLB: Consulting/advisory arrangements (uncompensated) with BristolMyersSquibb, Sanofi, Pfizer, Genentech/Roche, Amgen, Lilly, SeaGen, Merck, and Gilead; and institution receives clinical trials supports from Novartis, BristolMyersSquibb, Sanofi, Genentech/Roche, GlaxoSmithKline, Nektar Therapeutics, Merck, Lilly, Servier, PTC Therapeutics, SeaGen, Sanofi, Mersana, Amgen, Zymeworks, VelosBio, Bicara Therapeutics, AstraZeneca, and Pfizer.

ARH: Research and Consulting: Genentech Inc., Hoffmann La Roche Inc., Merck Serono S.A., GlaxoSmithKline Inc., Bristol-Myers Squibb Company, Novartis Pharmaceuticals Canada Inc., Boehringer Ingelheim International GmbH, AstraZeneca Pharmaceuticals LP, MedImmune LL and Pfizer Inc.

LW: None.

LAS: None.

LLS: Consulting/advisory arrangements with Merck, Pfizer, Celgene, AstraZeneca, Morphosys, Roche, Oncorus, Symphogen, Seattle Genetics, GlaxoSmithKline, Voronoi, Arvinas, Tessa, Navire, Relay, Rubius, Janpix, Daiichi Sanyko; stock ownership of Agios (spouse); leadership position in Treadwell Therapeutics (spouse); and institution receives clinical trials support from Novartis, Bristol-Myers Squibb, Pfizer, Boerhinger-Ingelheim, GlaxoSmithKline, Roche/Genentech, Karyopharm, AstraZeneca, Merck, Celgene, Astellas, Bayer, Abbvie, Amgen, Symphogen, Intensity Therapeutics, Mirati Therapeutics, Shattucks, Avid.

AS: Consulting/advisory arrangements within the last 5 years include: Merck, Bristol-Myers Squibb, Oncorus, Janssen. The institution receives clinical trial funding support from Novartis, Bristol-Myers Squibb, Symphogen AstraZeneca/Medimmune, Merck, Bayer, Surface Oncology, Northern Biologics, Janssen Oncology/Johnson & Johnson, Roche, Regeneron, Alkermes, Array Biopharma/Pfizer, GSK, Treadwell.

© 2022. The Author(s).

Figures

Fig. 1

Study patients disposition based on hepatic function

Fig. 2

a. Trametinib concentration-time by hepatic dysfunction group (dose standardized to 2 mg) (n = 22). (A) Individual concentration (B) Mean concentration. b. Unbound trametinib fractions (n = 24). (A) by liver function group and time (B) Linear Regression of Unbound Trametinib Fraction vs. Serum Albumin for Protein Binding Analysis Population (p = 0.26)