Sapanisertib or Sorafenib Tosylate in Treating Patients with Advanced or Metastatic Liver Cancer

Inclusion Criteria

• Voluntary written consent must be signed before performance of any study related procedure not part of standard medical care, with the understanding that the subject may withdraw consent at any time without prejudice to future medical care
• Females of childbearing potential must agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 90 days after the last dose of study drug, or agree to completely abstain from heterosexual intercourse
• Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to prior to registration for protocol therapy; NOTE: Female subjects are considered of childbearing potential unless they are surgically sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months
• Male subjects, even if surgically sterilized (i.e., status post-vasectomy), must agree to practice effective barrier contraception during the entire study treatment period and through 120 days after the last dose of study drug, or agree to completely abstain from heterosexual intercourse
• Subjects must have a diagnosis of measurable advanced or metastatic hepatocellular carcinoma; advanced HCC is defined as disease not amenable to surgery, ablation, transplant, or embolic therapy
• Phase II subjects must be willing to provide a tissue biopsy prior to registration if archived HCC tumor tissue is not available for correlative studies
• For the phase I cohort, subjects will have no restrictions on the number of prior systemic therapies; phase I patients may also be treatment naive
• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (within 28 days before study registration)
• Platelet count >= 50 x 10^9/L (within 28 days before study registration)
• Hemoglobin >= 9 g/dL (within 28 days before study registration)
• Total bilirubin =< 2 x upper limit of normal (ULN) (within 28 days before study registration)
• Aspartate aminotransferase/serum glutamic oxaloacetic transaminase-AST/SGOT and alanine aminotransferase/serum glutamic pyruvic transaminase-ALT/SGPT =< 5 x ULN (within 28 days before study registration)
• Creatinine clearance >= 50 mL/min based either on Cockcroft-Gault estimate or based on urine collection (12 or 24 hour) (within 28 days before study registration)
• Glycosylated hemoglobin (HbA1c) =< 7.0% (within 28 days before study registration)
• Fasting serum glucose (=< 130 mg/dL) (within 28 days before study registration)
• Fasting triglycerides =< 300 mg/dL (within 28 days before study registration)
• NOTE: Subjects with a history of transient glucose intolerance due to corticosteroid administration are allowed in this study if all other inclusion/exclusion criteria are met
• Ability to swallow oral medications
• Measurable disease according to RECIST version (v)1.1 and obtained by imaging within 28 days prior to registration for protocol therapy; NOTE: A subject with prior brain metastasis may be considered if they comply with inclusion criteria below
• Subjects who have a history of brain metastasis are eligible for the study provided all the following criteria are met: * Must have completed their treatment for brain metastasis * Must be asymptomatic * Must not have evidence of disease progression for >= 3 months or hemorrhage after treatment * Must be off-treatment from dexamethasone for 4 weeks prior to study registration and * Must not have an ongoing requirement for dexamethasone or anti-epileptic drugs
• Prior locoregional liver directed therapy is allowed as long as treatment was at least 6 weeks prior to study registration, and clear progression is demonstrated by RECIST v1.1 criteria; subject must have recovered from the acute toxic effects (=< grade 1 Common Terminology Criteria for Adverse Events [CTCAE] v4) of previous anti-cancer treatment prior to study enrollment; the only exception is that grade 2 neuropathy is permitted
• Prior radiation therapy is allowed to < 25% of the bone marrow, but is not permitted within 28 days prior to study registration
• Estimated life expectancy >= 3 months as determined by the treating physician

Exclusion Criteria

• Female subjects who are both lactating and breastfeeding
• Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol
• Treatment with any investigational products within 28 days prior to study registration
• No prior systemic treatment is allowed for subjects in the phase II cohort
• Failed to recover from the reversible effects of prior anticancer therapies with the exception of alopecia and grade 2 neuropathy
• Have initiated treatment with bisphosphonates less than 30 days prior to study registration; concurrent bisphosphonate use is only allowed if the bisphosphonate was initiated at least 30 days prior to study registration
• Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown reason that may alter the absorption of TAK-228
• No condition that could affect the absorption of study drug, including any of the following: * Malabsorption syndrome * Disease significantly affecting gastrointestinal function * Bowel obstruction or sub-obstruction
• History of any of the following within the last 6 months prior to study registration: * Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures * Ischemic cerebrovascular event, including transient ischemic attack (TIA) and artery revascularization procedures * Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation or ventricular tachycardia) * Placement of a pacemaker for control of rhythm * New York Heart Association (NYHA) class III or IV heart failure * Pulmonary embolism
• Significant active cardiovascular or pulmonary disease at the time of study registration, including: * Uncontrolled high blood pressure (i.e., systolic blood pressure > 160 mm Hg, diastolic blood pressure > 95 mm Hg) * Pulmonary hypertension * Uncontrolled asthma or oxygen (O2) saturation < 90% by ABG (arterial blood gas) analysis or pulse oximetry on room air * Significant valvular disease; severe regurgitation or stenosis by imaging independent of symptom control with medical intervention, or history of valve replacement * Medically significant (symptomatic) bradycardia * History of arrhythmia requiring an implantable cardiac defibrillator * Baseline prolongation of the rate-corrected QT interval (QTc) (e.g., repeated demonstration of QTc interval > 480 milliseconds, or history of congenital long QT syndrome, or torsades de pointes)
• Initiation of treatment with hematopoietic growth factors, transfusions of blood and blood products, or systemic corticosteroids (either intravenous [IV] or oral steroids, excluding inhalers) within 1 week prior to study registration (subjects already receiving erythropoietin on a chronic basis for >= 28 days are eligible)
• Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active central nervous system disease, active infection, or any other condition that could compromise participation of the subject in the study
• Cirrhosis with Child-Pugh score > 7
• Variceal bleeding within 1 month prior to study registration
• Refractory encephalopathy or ascites
• Known human immunodeficiency virus (HIV) positivity
• Hepatitis B surface antigen (HBsAg) positivity without active treatment; a subject found to be HBsAg positive should be on antiviral therapy for at least two weeks prior to study registration
• Subjects who are taking proton pump inhibitors (PPIs) within 7 days of study registration or who require treatment with PPIs throughout the trial or those who are taking histamine (H)2 receptor antagonists within 24 hours of study registration