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

Study Overview
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Brief Summary
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RATIONALE: Sorafenib tosylate and everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. PURPOSE: This randomized phase II trial is studying giving sorafenib tosylate together with everolimus to see how well it works compared with sorafenib tosylate alone in treating patients with localized, unresectable, or metastatic liver cancer.

Detailed Description
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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.

Official Title
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Sorafenib Alone or in Combination With Everolimus in Patients With Unresectable Hepatocellular Carcinoma. A Randomized Multicenter Phase II Trial.

Conditions
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Liver Cancer

Intervention / Treatment
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* Drug: everolimus
* Drug: sorafenib tosylate


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Sorafenib standard<br>• Arm A (standard treatment): Sorafenib 2 x 400 mg daily until progressive disease, unacceptable toxicity, or consent withdrawal. (46 patients). | Drug: sorafenib tosylate<br>* Sorafenib 2 x 400 mg daily<br>* Other names: BAY 43-9006;|
| Experimental: Arm B: Sorafenib + everolimus<br>• Arm B (investigational treatment): Sorafenib 2 x 400 mg daily plus everolimus 1 x 5 mg daily until progressive disease, unacceptable toxicity, or consent withdrawal. (60 patients) | Drug: everolimus<br>* Sorafenib 2 x 400 mg daily plus everolimus 1 x 5 mg daily<br>* Other names: RAD001;Drug: sorafenib tosylate<br>* Sorafenib 2 x 400 mg daily<br>* Other names: BAY 43-9006;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival |  | at 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response |  | during trial treatment and follow-up (max. 3 years) | 
| Disease stabilization (DS) |  | under trial treatment | 
| Duration of disease stabilization |  | Duration of DS (CR, PR or SD) will be calculated from the time that measurement criteria are met for the first time until documented tumor progression. | 
| Progression-free survival (PFS) |  | PFS will be calculated from randomization until documented tumor progression or death, whichever occurs first | 
| Time to progression (TTP) |  | TTP will be calculated from randomization until documented tumor progression or tumor-related death | 
| Overall survival |  | from randomization until death | 
| Adverse events at baseline and during trial treatment |  | All AEs will be assessed according to NCI CTCAE v3.0. | 
| Serum alpha fetoprotein (AFP) level |  | Serum AFP levels will be measured during the therapy, if AFP is ≥ 1.5 x ULN at baseline. | 
| Viral reactivation in patients with chronic hepatitis B or C virus infection |  | Number of patients with HCV/HBV (re)-activation during trial treatment | 
| Correlation between vitamin B12 and overall survival |  | The baseline vitamin B12 value, collected at trial randomization, is correlated to overall survival when dichotomized by the cut-point of 600 ng/L. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult primary hepatocellular carcinoma, localized unresectable adult primary liver cancer