Sonidegib in Treating Patients with Advanced or Metastatic Liver Cancer That Cannot Be Removed by Surgery or Child-Pugh A/B7 Cirrhosis

Inclusion Criteria

• Provision of written informed consent prior to any screening procedures
• Histological or radiologic confirmation of advanced or metastatic HCC: * The diagnosis of HCC will be made according to the guidelines of the Barcelona-2000 European Association for the Study of the Liver (EASL) Conference (Bruix et al 2001) and according to successive modifications of the American Association for the Study of Liver Disease (AASLD) (Bruix et al 2005) * Pathological diagnoses of HCC will be made according to the International Working Party criteria (International Working Party 1995)
• HCC not amenable to surgical resection, liver transplantation, chemoembolization, or ablation therapy
• Patients will be staged according to the Barcelona Clinic Liver Cancer (BCLC) criteria
• Patients with Child-Pugh A and Child-Pugh B7 (if due to low albumin but not elevated international normalized ratio [INR] or bilirubin) cirrhosis are allowed; Child-Pugh Turcot (CPT) Classification System score will be based upon INR, total bilirubin and serum albumin, as well as the presence/absence of ascites and hepatic encephalopathy
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• At least one measurable site of disease (as defined by Response Evaluation Criteria in Solid Tumors)
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
• Hemoglobin (Hgb) >= 9 g/dL
• Platelets >= 50 x 10^9/L
• Serum total bilirubin < 2.0 x ULN (upper limit of normal)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 5 x ULN
• Plasma creatinine phosphokinase (CK) < 1.5 x ULN
• Serum creatinine =< 1.5 x ULN or calculated creatinine clearance (CrCl) >= 50 ml/min based upon the Cockcroft-Gault equation
• Inability to tolerate first-line treatment with sorafenib (e.g., unacceptable toxicity), tumor progression on sorafenib, patient preference to stop sorafenib and for alternative therapy/trial, or patient preference to forgo sorafenib for alternative therapy/trial * Note: ** Unacceptable toxicities due to sorafenib include, but are not limited to, the following drug-induced adverse events including: hepatitis, skin rash (grade 3 or higher), hypertension (grade 3 or higher), hand-foot skin reaction (grade 3 or higher), QT prolongation (grade 3 or higher), and/or diarrhea (grade 3 or higher) ** Patient preference to stop sorafenib for alternative therapy/trial will include the following indications: the aforementioned adverse events at lesser grades for which the patient is unwilling to continue therapy, as well as situations in which the patient deems the side effects to be intolerable with their quality of life; examples include, but are not limited to, intolerable nausea, vomiting, abdominal pain, fatigue, loss of appetite, and weight loss ** Patient preference to forgo sorafenib for alternative therapy/trial is based upon the patients' right for autonomy; this allows them to refuse or choose their treatment; the practitioner will always act in the best interest of the patient and recommend that the patient start with known life-prolonging therapies before enrolling in a clinical trial of an investigational agent that has not been determined to be safe and effective in patients with liver cancer
• Patient amenable to liver tumor biopsy
• Patient is able to swallow and retain oral medication

Exclusion Criteria

• Child-Pugh B (except Child-Pugh B7 due to low albumin) or Child-Pugh C cirrhosis
• Patients with known Gilbert’s syndrome
• Ongoing alcohol use or abuse defined as > an average of 2 alcoholic beverages daily
• Patients who have had major surgery within 4 weeks of initiation of study medication
• Patients with known brain metastases should be excluded from this clinical trial
• Patients with concurrent uncontrolled medical conditions that may interfere with their participation in the study or potentially affect the interpretation of the study data
• Patients with known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness
• Patients with hepatitis B and/or hepatitis C infection are excluded if they are on any of the following viral suppressive agents: boceprevir (Victrelis), ribavirin (Rebetol, Ribatab, Ribasphere), telaprevir (Incivek) * Note: patients with active hepatitis B infection must be on treatment with viral suppressive therapies; these agents may include the following: adefovir (Hepsera), entecavir (Baraclude), lamivudine (Epivir-HBV), telbivudine (Tyzeka), and/or tenofovir (Viread)
• Patients unable to take oral drugs or with lack of physical integrity of the upper gastrointestinal tract or known malabsorption syndromes
• Patients who have previously been treated with systemic sonidegib or with other Hedgehog (Hh) pathway inhibitors
• Patients who have neuromuscular disorders (e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis and spinal muscular atrophy) or are on concomitant treatment with drugs that are recognized to cause rhabdomyolysis, such as 3-hydroxy-3-methyl-glutaryl-CoA (HMG CoA) inhibitors (statins), clofibrate and gemfibrozil, and that cannot be discontinued at least 2 weeks prior to starting sonidegib study treatment; if it is essential that the patient stays on a statin to control hyperlipidemia, only pravastatin may be used with extra caution
• Patients who are planning on embarking on a new strenuous exercise regimen after initiation of study treatment; note: muscular activities, such as strenuous exercise, that can result in significant increases in plasma CK levels should be avoided whilst on sonidegib study treatment
• Patients who have taken part in an experimental drug study within 4 weeks of initiating study treatment with sonidegib
• Patients who are receiving other anti-neoplastic therapy (e.g. chemotherapy, targeted therapy or radiotherapy) concurrently or within 2 weeks of starting study treatment with sonidegib
• Patients who are receiving any anti-coagulation or anti-platelet therapy including, but not limited to, Clopidogrel, vitamin K antagonists (e.g. warfarin) , heparin, low molecular weight heparin, dabigatran, rivaroxaban, and apixaban
• Patients who are receiving treatment with medications known to be strong inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)/5 or drugs metabolized by cytochrome P450, family 2, subfamily B, polypeptide 6 (CYP2B6) or cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9) that have narrow therapeutic index, and that cannot be discontinued before starting study treatment with sonidegib * Note: if patients can stop receiving these medications, strong CYP3A4/5 inhibitors should be discontinued at least 7 days prior to starting study treatment with sonidegib and strong CYP3A/5 inducers should be discontinued at least 2 weeks prior to starting study treatment with sonidegib
• Impaired cardiac function or clinically significant heart disease, including any one of the following: * Angina pectoris within 3 months * Acute myocardial infarction within 3 months * Corrected QT interval (QTc) > 480 msec on the screening electrocardiogram (ECG) * A past medical history of clinically significant ECG abnormalities * Other clinically significant heart disease (e.g. congestive heart failure, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen)
• Patients with one or more of the following contraindications for MRI and/or MRI contrast agents such as: * Severe claustrophobia * Aversion to MRI * Metallic fragments, clips or devices in the brain, eye, and/or spinal canal in which movement in the bore of the magnet may damage sensitive tissues, unless deemed to be safe by the manufacturer; note: metallic fragments, clips or devices outside the brain, eye, and/or spinal canal may be safe if deemed by the manufacturer; caution is needed to determine safety for each patient that may have the following conditions: cardiac pacemaker; heart valve replacement, venous umbrella, being a sheet-metal worker or welder; aneurysm surgery, renal or aortic clips, prosthetic devices such as middle ear, eye, joint, or penile implants, joint replacement, hearing aid, neurostimulator, insulin pump, intrauterine devices (IUD), shunts/stents/metal mesh/coil implants, metal plate/pin/screw/wires, or any other metal implants, and permanent eyeliner and/or eyebrows
• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test (> 5 mIU/mL)
• Patients who are not willing to apply highly effective contraception during the study and through the duration as defined below after the final dose of study treatment * Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use highly effective contraception during the study and through 6 months after the final dose of study treatment; highly effective contraception is defined as either: ** Total abstinence: when this is in line with the preferred and usual lifestyle of the patient; periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception ** Sterilization: patient has had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment; in case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment ** Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate); (for female study patients, the vasectomized male partner should be the sole partner for that patient); OR ** Use a combination of the following (both a+b): *** Placement of a non-hormonal intrauterine device (IUD) or non-hormonal intrauterine system (IUS) *** Barrier method of contraception: condom or occlusive cap (diaphragm or cervical vault caps) with spermicidal foam/gel/film/cream/vaginal suppository ** Note: hormonal contraception methods (e.g. oral, injected, implanted) are not allowed ** Note: women are considered post-menopausal and not child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum follicle-stimulating hormone (FSH) levels > 40 mIU/mL and estradiol < 20 pg/mL or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago; in the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential * Male patient must use highly effective (double barrier) methods of contraception (e.g., spermicidal gel plus condom) for the entire duration of the study, and continuing using contraception and refrain from fathering a child for 6 months following the study drug; a condom is required to be used also by vasectomized men as well as during intercourse with a male partner in order to prevent delivery of the study treatment via seminal fluid
• Sexually active males who are unwilling to use a condom during intercourse while taking drug and for 6 months after stopping investigational medications and agree not to father a child in this period
• Patients unwilling or unable to comply with the protocol