A phase Ia/Ib trial of trametinib in combination with sorafenib in patients with advanced hepatocellular cancer.

Abstract

TPS469 Background: MEK inhibitors have demonstrated preclinical activity in hepatocellular carcinoma (HCC). More importantly, in xenograft models, this class of inhibitors acts synergistically with sorafenib to inhibit tumor growth, prevent metastatic spread and increase survival. In preclinical models, sorafenib leads to overactivation of the MAPK pathway, which can be counterbalanced by the use of MEK inhibitors. Trametinib is a reversible, highly selective, allosteric MEK inhibitor. Methods: This is an open label, single group, phase I study with cohort expansion that utilizes the standard 3+3 design for dose escalation. The primary objective of this study is to determine maximally tolerated dose (MTD) of trametinib in combination with sorafenib as first-line systemic treatment for patients with locally advanced or metastatic HCC. Secondary objectives are to explore and characterize the safety and tolerability of this combination at the established MTD and to explore its efficacy profile. Up to 24 patients will be enrolled in 4 dose levels. Once the MTD is reached and/or the recommended dose for expansion is determined, an additional cohort of 10 patients with advanced HCC will be accrued. Only patients with Child-Pugh score A will be included. Trametinib will be administered orally daily beginning day 8 of cycle 1. Sorafenib will be administered twice daily beginning day 1 of 28 days cycle. Patients will get restaging scans every 2 cycles. Correlative studies between various biomarkers and clinical outcomes will also be performed. Biomarkers will be assessed in archival tumor tissue. The pre- and post-dose expression level of biomarkers including pan and phospho-Mek and Erk will be measured on peripheral blood mononuclear cells during treatment. Pre and post treatment biopsies will be performed for patients participating in the dose expansion cohort for correlative studies including gene expression. As per September 2015, 3 patients have been enrolled in this trial. ClinicalTrials.gov identifier: NCT02292173 Clinical trial information: NCT02292173.