Trametinib and Sorafenib Tosylate in Treating Patients with Advanced Liver Cancer

Inclusion Criteria

• Subjects who have radiographic or histological diagnosis of hepatocellular cancer (HCC), with advanced stage disease that is not amenable to curative surgical resection; patients without histologic diagnosis must meet the radiographic criteria for HCC
• The Child Pugh score must be 5 or 6 (Child Pugh class A)
• Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1
• Eastern Cooperative Oncology Group (ECOG) performance status =< 1
• Life expectancy of at least 16 weeks
• Absolute neutrophil count >= 1,200/mcL (without growth factor support)
• Platelets >= 75,000/mcL (without transfusion support)
• Hemoglobin >= 9 mg/dL
• Albumin >= 2.8 mg/dL
• Total bilirubin < 2 x upper limits of normal (ULN) except Gilbert’ syndrome where < 3 x ULN is allowed
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 x ULN
• Creatinine =< 1.5 x ULN OR creatinine clearance >= 50 mL/min calculated using the formula of Cockcroft and Gault
• Prothrombin time (PT)/international normalized ratio (INR) =< 1.5 x ULN (except for patients on anticoagulation)
• Left ventricular ejection fraction (LVEF) >= lower limit of normal (LLN) by echocardiogram (Echo) or multi gated acquisition scan (MUGA)
• Female patients of child-bearing potential must agree to use dual methods of contraception and have a negative serum pregnancy test at screening, and male patients must use an effective barrier method of contraception if sexually active with a female of child-bearing potential; acceptable methods of contraception are condoms with contraceptive foam, oral, implantable or injectable contraceptives, contraceptive patch, intrauterine device, diaphragm with spermicidal gel, or a sexual partner who is surgically sterilized or post-menopausal; for both male and female patients, effective methods of contraception must be used throughout the study and for four months following the last dose
• Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels
• Patients in the dose expansion part must have tumor that is amenable for biopsy
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

• Subjects who have received radiation therapy, major surgery, other locoregional therapy, within 4 weeks prior to the first dose of study drug
• All prior treatment-related toxicities must be =< grade 1
• Patients who have received sorafenib or other systemic therapies for treatment of HCC in the past
• Any serious and/or unstable pre-existing medical disorder (aside from malignancy exception), psychiatric disorder, or other conditions that could interfere with subject’s safety, obtaining informed consent or compliance to the study procedures
• History or evidence of cardiovascular risk including any of the following: * A QT interval corrected for heart rate using the Bazett’s correction formula (QTcB) >= 480 msec * History or evidence of current clinically significant uncontrolled arrhythmias; exception: subjects with controlled atrial fibrillation for > 30 days prior to taking study drug are eligible * History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to taking study drug * History or evidence of current >= class II congestive heart failure as defined by New York Heart Association * Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by antihypertensive therapy * Patients with intra-cardiac defibrillators * Known cardiac metastases * Subjects with abnormal left ventricular ejection fraction (< 50%) on echocardiogram or multiple-gated acquisition scan (MUGA)
• Known history of human immunodeficiency virus (HIV) positivity
• History of retinal vein occlusion (RVO)
• Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression
• History of interstitial lung disease or pneumonitis
• Patients who are pregnant or lactating
• Any underlying condition that would significantly interfere with the absorption of an oral medication
• History of another active malignancy in last 3 years; exception: subjects who have been disease-free for 3 years, or subjects with a history of completely resected nonmelanoma skin cancer and/or subjects with indolent second malignancies are eligible
• Uncontrolled infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose; patients with controlled infection or on prophylactic antibiotics are permitted in the study
• Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study drug, or excipients or to dimethyl sulfoxide
• Concurrent therapy with approved or investigational anticancer therapy
• Concomitant use of strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducers