Sorafenib Tosylate With or Without Doxorubicin Hydrochloride in Treating Patients With Locally Advanced or Metastatic Liver Cancer

Official Title: “Phase III Randomized Study of Sorafenib Plus Doxorubicin Versus Sorafenib in Patients With Advanced Hepatocellular Carcinoma (HCC)”

RATIONALE: Sorafenib tosylate 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. Drugs used in chemotherapy, such as doxorubicin hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known whether giving sorafenib tosylate together with doxorubicin hydrochloride is more effective than sorafenib tosylate alone in treating liver cancer.

PURPOSE: This randomized phase III trial is studying sorafenib tosylate and doxorubicin hydrochloride to see how well they work compared with sorafenib tosylate alone in treating patients with locally advanced or metastatic liver cancer.

OBJECTIVES:

Primary - To compare the overall survival of patients with locally advanced or metastatic hepatocellular carcinoma treated with sorafenib tosylate with vs without doxorubicin hydrochloride.

Secondary - To compare the time to progression in patients treated with these regimens. - To compare the progression-free-survival of patients treated with these regimens. - To compare the tumor response using RECIST criteria in patients treated with these regimens.

OUTLINE: This is a multicenter study. Patients are stratified according to extent of disease (locally advanced vs metastatic). Patients are randomized to 1 of 2 treatment arms. - Arm I: Patients receive doxorubicin hydrochloride IV on day 1 and oral sorafenib tosylate twice daily on days 1-21. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. After 6 courses, patients may continue to receive oral sorafenib tosylate twice daily in the absence of disease progression or unacceptable toxicity. - Arm II: Patients receive oral sorafenib tosylate twice daily on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year and then every 6 months for 2 years.

Intervention(s) in this Clinical Trial

• Drug: doxorubicin hydrochloride
  • Given IV
• Drug: sorafenib tosylate
  • Given orally

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Arm I
  • Patients receive doxorubicin hydrochloride IV on day 1 and oral sorafenib tosylate twice daily on days 1-21. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. After 6 courses, patients may continue to receive oral sorafenib tosylate twice daily in the absence of disease progression or unacceptable toxicity.
• Experimental: Arm II
  • Patients receive oral sorafenib tosylate twice daily on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

Primary Measures

• Overall survival
  • Safety Issue?: No

Secondary Measures

• Toxicity as assessed by NCI CTC v3.0
  • Safety Issue?: Yes
• Time to progression
  • Safety Issue?: No
• Progression-free survival
  • Safety Issue?: No

DISEASE CHARACTERISTICS:

• Pathologically or cytologically proven hepatocellular carcinoma (HCC)
• No known mixed histology or fibrolamellar variant
• Locally advanced or metastatic disease
• Patients with locally advanced disease must have disease deemed to be unresectable OR not be eligible for transplantation
• Measurable disease, defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 2 cm with conventional techniques or as ≥ 1 cm with spiral CT scan
• Child-Pugh score A
• No known CNS tumors, including brain metastases

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Granulocytes ≥ 1,500/μL
• Platelets ≥ 75,000/μL
• Hemoglobin ≥ 8.5 g/dL
• Bilirubin ≤ 3 mg/dL
• ALT and AST ≤ 5 times upper limit of normal (ULN)
• PT/INR ≤ 1.7 (therapeutic anticoagulation [e.g., coumadin or heparin] allowed provided there is no prior evidence of underlying abnormality in these parameters)
• Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 60 mL/min
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception before, during, and for 30 days after completion of study therapy
• No clinically significant gastrointestinal bleeding events requiring intervention, transfusion, or admission to hospital within the past 30 days
• Patients with recent or ongoing gastrointestinal bleed may not be transfused to reach the entry hemoglobin of 8.5 g/dL
• Physicians should ensure patients requiring transfusion prior to registration do not have an occult or clinically apparent gastrointestinal bleed
• No history of bleeding diathesis
• No significant history of cardiac disease, including any of the following:
• NYHA class III-IV congestive heart failure
• Myocardial infarction within the past 6 months
• Cardiac arrhythmias requiring anti-arrhythmic therapy (other than beta blockers or digoxin)
• LVEF < 45% (or below the normal limit at the individual institution) by scintigraphy (MUGA or myocardial scintigram)
• History of hypertension allowed provided it is well controlled (i.e., BP < 140/90 mm
• Hg) on a regimen of anti-hypertensive therapy

PRIOR CONCURRENT THERAPY:

• No prior allografts including, but not limited to, liver or bone marrow transplants
• No prior adjuvant therapy with sorafenib tosylate or other Raf/VEGFR inhibitors
• Other prior adjuvant therapy is allowed provided it was completed > 6 months ago
• AND there is documented recurrence of HCC
• No prior systemic therapy for metastatic disease
• At least 4 weeks since prior locoregional therapy (e.g., embolization, chemoembolization [except with doxorubicin hydrochloride], radiotherapy, or radioactive microspheres)
• No prior local therapy for the target lesion unless the target lesion located within the field of local therapy has shown ≥ 25% increase in size since last treatment
• At least 4 weeks since prior and no concurrent palliative radiotherapy
• Patients who have received palliative radiation therapy to the bone need not wait 4 weeks to begin protocol therapy
• At least 4 weeks since prior interferon therapy
• At least 4 weeks since prior major surgery
• At least 4 weeks since prior and no concurrent rifampin or St John's wort
• Prior antiviral treatment allowed
• No concurrent combination anti-retroviral therapy for HIV
• No concurrent hormonal therapy or other chemotherapy, except for the following:
• Steroids administered for adrenal failure
• Hormones administered for non-disease-related conditions (e.g., insulin for diabetes)
• Intermittent use of dexamethasone as an antiemetic

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: Cancer and Leukemia Group B Other

Overall Clinical Trial Officials and Contacts

Ghassan Abou-Alfa, MD Study Chair Memorial Sloan-Kettering Cancer Center  

Information obtained from ClinicalTrials.gov on February 09, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT01015833

Study ID Number: CDR0000659348

ClinicalTrials.gov Identifier: NCT01015833

Health Authority: Unspecified

Clinical trial summary from the National Cancer Institute's PDQ® database