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

Phase 2
18 Years
Open (Enrolling)
Liver Cancer

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Trial Information

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


- To determine if sorafenib tosylate with versus without everolimus can stop tumor
progression in patients with localized, unresectable, or metastatic hepatocellular

- 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.

Inclusion Criteria


- Histologically, cytologically, or radiologically confirmed hepatocellular carcinoma

- 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

- 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

- 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

- 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)

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression-free survival

Outcome Time Frame:

at 12 weeks

Safety Issue:


Principal Investigator

Dieter Koeberle, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Kantonsspital St. Gallen


Switzerland: Swissmedic

Study ID:

SAKK 77/08 and SASL 29



Start Date:

November 2009

Completion Date:

June 2017

Related Keywords:

  • Liver Cancer
  • adult primary hepatocellular carcinoma
  • localized unresectable adult primary liver cancer
  • Liver Neoplasms
  • Carcinoma, Hepatocellular