Sorafenib Tosylate With or Without Everolimus in Treating Patients With Localized, Unresectable, or Metastatic Liver Cancer

OBJECTIVES:

• To determine if sorafenib tosylate with versus without everolimus can stop tumor progression in patients with localized, unresectable, or metastatic hepatocellular carcinoma.
• To evaluate changes in symptom-related and global quality of life (QL) and QL benefit over the course of trial treatment in these patients.
• To compare the primary endpoint (i.e., progression-free survival at week 12) to the QL benefit within 12 weeks from baseline.
• To evaluate how symptom-related and global QL indicators map on the single summary index derived from a standardized measure of health status for utility cost analysis.

OUTLINE: This is a multicenter study. Patients are stratified according to WHO performance status (0 vs 1), disease spread (extrahepatic spread vs non-extrahepatic spread), and center. Patients are randomized to 1 of 2 treatment arms.

• Arm A (standard treatment): Patients receive oral sorafenib tosylate twice daily for 4 weeks. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
• Arm B (investigational treatment): Patients receive oral sorafenib tosylate twice daily and oral everolimus once daily for 4 weeks. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

Some patients may undergo CT scan or MRI at baseline and at 6 and 12 weeks during study to assess tumor response, tumor size, and tumor density.

Patients complete quality of life questionnaires at baseline and every 2 weeks for 12 weeks during study treatment.

After completion of study treatment, patients are followed every 2 months for 3 years.

DISEASE CHARACTERISTICS:

• Histologically, cytologically, or radiologically confirmed hepatocellular carcinoma (HCC)

• Localized, unresectable, or metastatic disease
• Child-Pugh class A or mildly decompensated Child-Pugh class B liver dysfunction (Child-Pugh score ≤ 7)
• Stage B or C disease according to the Barcelona Clinic Liver Cancer (BCLC) staging classification
• Measurable disease

• At least 1 unidimensionally measurable site of disease (≥ 10 mm in case of a non-nodal lesion or with a short axis ≥ 15 mm in case of a lymph node) by spiral/multi-slice CT/MRI scan according to revised RECIST criteria
• No locally advanced disease AND a candidate for radical surgery
• No known fibrolamellar HCC or mixed cholangiocarcinoma/HCC
• No clinical symptoms or history of CNS metastases or leptomeningeal disease (no imaging required)

PATIENT CHARACTERISTICS:

• WHO performance status 0-1
• Hemoglobin ≥ 90 g/L
• Neutrophil count ≥ 1.5 x 10^9/L
• Platelet count ≥ 75 x 10^9/L
• Creatinine clearance ≥ 40 mL/min
• ALT ≤ 5 times upper limit of normal
• INR ≤ 2
• Urine dipstick for proteinuria ≤ 1+ OR protein spot urine < 0.6 g/L
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 12 months after completion of study therapy
• No prior malignancy within the past 5 years except adequately treated carcinoma in situ of the cervix or localized nonmelanoma skin cancer
• No history of hemorrhagic or thrombotic cerebrovascular event within the past 12 months
• No documented variceal hemorrhage within the past 3 months
• No requirement for anticoagulant therapy except for low-dose anticoagulants for maintenance of patency of central venous access or prevention of deep vein thrombosis
• No history or presence of clinically significant acute or unstable cardiovascular, cerebrovascular, renal, gastrointestinal, pulmonary, endocrine, central nervous system, or immunological disorders (except for the presence of hepatitis B or C virus or cirrhosis) within the past 6 months
• No encephalopathy
• No known HIV infection
• No active infection requiring IV antibiotics
• No arterial hypertension ≥ 150/100 mm Hg despite therapy
• No ongoing cardiac dysrhythmias of NCI CTCAE grade ≥ 2, atrial fibrillation of any grade, prolongation of QTc > 500 msec on screening electrocardiogram (ECG), or history of familial long QT syndrome
• No repeated paracentesis (more than 1 per month)
• No psychiatric disorder precluding understanding of information of trial-related topics, giving informed consent, or interfering with compliance for oral drug intake
• No concurrent grapefruit, grapefruit juice, or products containing bitter oranges
• Able to take oral medications
• Completed baseline quality of life questionnaire
• Must be compliant and geographically proximal for follow-up

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No prior systemic anticancer treatment for this disease

• The following prior therapies are allowed provided previously treated lesions remain separate from those to be measured in the current trial and prior treatment is completed within the past 4 weeks

• Surgery
• Liver-directed therapy (e.g., transarterial embolization/chemoembolization [limited to 5 treatments], radiofrequency ablation, cryoablation, radiotherapy, or percutaneous ethanol injection)
• No prior organ transplantation
• No concurrent estrogen-containing supplementary therapy
• No concurrent full-dose anticoagulation with coumarin derivatives
• No concurrent elective major surgery
• No concurrent radiotherapy (concurrent analgesic radiotherapy of non-target lesions allowed)
• No concurrent or anticipated need for CYP3A4 inhibitors or inducers, unless the drugs are medically necessary and no substitutes are available, including any of the following:

• Ketoconazole
• Itraconazole
• Voriconazole
• Erythromycin
• Clarithromycin
• Diltiazem
• Verapamil
• Protease inhibitors
• No concurrent strong CYP3A4 inducers*, including any of the following:

• Carbamazepine
• Continuous dexamethasone (> 2 mg/day for > 7 days)
• Phenobarbital
• Phenytoin
• Rifampicin
• St. John's wort NOTE: *Concurrent antacids allowed provided they are administered > 1 hour before or > 1 hour after trial drug administration.
• No other concurrent experimental drugs or anticancer therapy or treatment in another clinical trial within the past 30 days
• No other concurrent investigational drugs
• No chronic systemic steroids or other immunosuppressive agents
• No concurrent angiotension converting enzyme inhibitors (ACE-I)