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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01005199
Recruitment Status : Completed
First Posted : October 30, 2009
Last Update Posted : May 15, 2019
Information provided by (Responsible Party):
Swiss Group for Clinical Cancer Research

Brief Summary:

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.

Condition or disease Intervention/treatment Phase
Liver Cancer Drug: everolimus Drug: sorafenib tosylate Phase 2

Detailed Description:


  • 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 106 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Sorafenib Alone or in Combination With Everolimus in Patients With Unresectable Hepatocellular Carcinoma. A Randomized Multicenter Phase II Trial.
Study Start Date : November 2009
Actual Primary Completion Date : June 2013
Actual Study Completion Date : March 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Liver Cancer

Arm Intervention/treatment
Experimental: Arm A: Sorafenib standard
• Arm A (standard treatment): Sorafenib 2 x 400 mg daily until progressive disease, unacceptable toxicity, or consent withdrawal. (46 patients).
Drug: sorafenib tosylate
Sorafenib 2 x 400 mg daily
Other Name: BAY 43-9006

Experimental: Arm B: Sorafenib + everolimus
• 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
Sorafenib 2 x 400 mg daily plus everolimus 1 x 5 mg daily
Other Name: RAD001

Drug: sorafenib tosylate
Sorafenib 2 x 400 mg daily
Other Name: BAY 43-9006

Primary Outcome Measures :
  1. Progression-free survival [ Time Frame: at 12 weeks ]

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

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No


  • 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)


  • 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


  • 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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01005199

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Medizinische Universität Wien
Wien, Austria, 1090
Szent Laszlo Korhaz
Budapest, Hungary, 1097
Saint Claraspital AG
Basel, Switzerland, CH-4016
Clinical Cancer Research Center at University Hospital Basel
Basel, Switzerland, CH-4031
Istituto Oncologico della Svizzera Italiana - Ospedale Regionale Bellinzona e Valli
Bellinzona, Switzerland, 6500
Inselspital Bern
Bern, Switzerland, CH-3010
Kantonsspital Bruderholz
Bruderholz, Switzerland, CH-4101
Hopital Cantonal Universitaire de Geneve
Geneva, Switzerland, CH-1211
Centre Hospitalier Universitaire Vaudois
Lausanne, Switzerland, CH-1011
Kantonsspital Liestal
Liestal, Switzerland, CH-4410
CHCVS - Hôpital de Sion
Sion, Switzerland, 1950
Kantonsspital - St. Gallen
St. Gallen, Switzerland, CH-9007
Thun, Switzerland, 3600
City Hospital Triemli
Zurich, Switzerland, CH-8063
UniversitaetsSpital Zuerich
Zurich, Switzerland, CH-8091
Sponsors and Collaborators
Swiss Group for Clinical Cancer Research
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Study Chair: Dieter Koeberle, MD Cantonal Hospital of St. Gallen
Study Chair: Jean-Francois Dufour, MD University Hospital Inselspital, Berne
Study Chair: Gyorgy Bodoky, MD, PhD Szent Laszlo Korhaz
Study Chair: Michael Montemurro, MD CHUV Lausanne

Publications of Results:
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Responsible Party: Swiss Group for Clinical Cancer Research Identifier: NCT01005199    
Other Study ID Numbers: SAKK 77/08 and SASL 29
SWS-SAKK-77/08 ( Other Identifier: SAKK )
2009-011884-35 ( EudraCT Number )
First Posted: October 30, 2009    Key Record Dates
Last Update Posted: May 15, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Swiss Group for Clinical Cancer Research:
adult primary hepatocellular carcinoma
localized unresectable adult primary liver cancer
Additional relevant MeSH terms:
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Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action