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

• Incidence of adverse events, as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 3 years ] [ Designated as safety issue: Yes ]
  Incidence of other adverse events (proteinuria, hypertension, and other common side effects of study drugs) will be assessed.
• Progression free survival [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  The stratified log-rank test will be used.

• Toxicity as assessed by NCI CTC v3.0 [ Designated as safety issue: Yes ]
• Time to progression [ Designated as safety issue: No ]
• Progression-free survival [ Designated as safety issue: No ]

This randomized phase III trial studies sorafenib tosylate and doxorubicin hydrochloride to see how well they work compared with sorafenib tosylate alone in treating patients with liver cancer that has spread to nearby tissue or lymph nodes or has spread to other places in the body. 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.

PRIMARY OBJECTIVES:

I. Compare the overall survival (OS) of patients treated with sorafenib (sorafenib tosylate) and doxorubicin (doxorubicin hydrochloride) to that of those treated with sorafenib.

SECONDARY OBJECTIVES:

I. Compare time to progression (TTP) of patients treated with sorafenib and doxorubicin to that of those treated with sorafenib.

II. Compare progression-free-survival (PFS) of patients treated with sorafenib and doxorubicin to that of those treated with sorafenib.

III. Compare tumor response using Response Evaluation Criteria in Solid Tumors (RECIST) criteria of patients treated with sorafenib and doxorubicin to that of those treated with sorafenib.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive doxorubicin hydrochloride intravenously (IV) on day 1 and sorafenib tosylate orally (PO) once daily (QD) or twice daily (BID) 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 sorafenib tosylate PO QD or BID in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive sorafenib tosylate PO QD or BID on days 1-21. Courses repeat 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.

• Adult Hepatocellular Carcinoma
• Advanced Adult Hepatocellular Carcinoma
• BCLC Stage C Adult Hepatocellular Carcinoma
• BCLC Stage D Adult Hepatocellular Carcinoma
• Localized Non-Resectable Adult Liver Carcinoma
• Recurrent Adult Liver Carcinoma

• Drug: Doxorubicin Hydrochloride
  Given IV
• Drug: Sorafenib Tosylate
  Given PO
  Other Names:

  • BAY 54-9085
  • Nexavar
  • SFN
• Other: Laboratory Biomarker Analysis
  Correlative studies
• Other: Pharmacological Study
  Correlative studies
  Other Name: pharmacological studies

• Experimental: Arm I (doxorubicin hydrochloride, sorafenib tosylate)
  Patients receive doxorubicin hydrochloride IV on day 1 and sorafenib tosylate PO QD or BID 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 sorafenib tosylate PO QD or BID in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: Doxorubicin Hydrochloride
  • Drug: Sorafenib Tosylate
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
• Experimental: Arm II (sorafenib tosylate)
  Patients receive sorafenib tosylate PO QD or BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: Sorafenib Tosylate
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study

Inclusion Criteria:

• Patients must have pathologically or cytologically proven hepatocellular carcinoma; known mixed histology (e.g. hepatocellular carcinoma plus cholangiocarcinoma) or fibrolamellar variant is not allowed
• Patients must have locally advanced or metastatic disease; locally advanced disease is defined as disease deemed to be unresectable or non-eligible for transplant without distant metastases
• Lesions must be accurately measurable in at least one dimension (longest diameter to be recorded) as >= 2 cm with conventional techniques or as >= 1 cm with spiral computed tomography (CT) scan
• No prior adjuvant sorafenib or other v-RAF-1 murine leukemia viral oncogene homolog (Raf)/vascular endothelial growth factor (VEGF) inhibitors; other prior adjuvant therapy is allowed if completed > 6 months prior to registration with documented recurrence of hepatocellular carcinoma (HCC)

• Patients may have been treated with loco regional therapies provided that they either have:

  • A target lesion that has not been subjected to local therapy or

  • The target lesion(s) within the field of the local therapy has shown an increase of >= 20% in the size since last treatment

    • Such therapy must be completed at least 4 weeks prior to registration; patients that have received palliative radiation therapy to the bone need not wait 4 weeks to begin protocol therapy

• Prior therapies allowed include the following:

  • Bland embolization, radiation, radioactive microspheres, etc
  • Chemoembolization using any chemotherapy (except, see below)
  • Chemoembolization drug-eluting beads using doxorubicin
  • Prior therapy with chemoembolization using doxorubicin in the non drug eluting beads form is NOT allowed
• No prior systemic therapy for metastatic disease
• No prior exposure to systemic doxorubicin administered intravenously
• Antiviral treatment is allowed, however interferon therapy must be stopped at least 4 weeks prior to registration
• Allografts are not allowed: no prior history of any allograft, including but not limited to liver and bone marrow transplants
• Patients must have completed any major surgery >= 4 weeks from registration
• Concomitant treatment with Rifampin or St John's Wort is not allowed; patients should discontinue these drugs at least 4 weeks prior to registration
• No known central nervous system (CNS) tumors including brain metastases
• No clinically significant gastrointestinal bleeding events requiring intervention, transfusion, or admission to hospital within 30 days prior to registration
• Patients with a history of hypertension should be well controlled (< 140/90 mmHg) on a regimen of anti-hypertensive therapy

• Significant history of cardiac disease is not allowed:

  • Congestive heart failure > class II New York Heart Association (NYHA)
  • Myocardial infarction within 6 months prior to registration
  • Serious myocardial dysfunction, defined as scintigraphically (multigated acquisition scan [MUGA], myocardial scintigram) determined absolute left ventricular ejection fraction (LVEF) below 45% or an LVEF on echocardiogram (ECHO) below the normal limit at the individual institution
• No history of bleeding diathesis
• Patients receiving combination anti-retroviral therapy for human immunodeficiency virus (HIV) are excluded from the study
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Pregnancy/nursing status: women who are pregnant should not go on study; women should not breastfeed while participating in this study
• Granulocytes >= 1,500/uL
• Hemoglobin >= 8.5 g/dL; 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
• Platelets >= 75,000/uL
• Creatinine =< 1.5 x upper limit of normal (ULN) (or creatinine clearance calculated >= 60 cc/minute)
• Child-Pugh score A; patients must meet all laboratory value requirements
• Bilirubin =< 3 mg/dL
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 5 x ULN
• Prothrombin time (PT)-international normalized ratio (INR) =< 1.7 (not required for patients on anticoagulation agents; patients who are being therapeutically anticoagulated with an agent such as Coumadin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists)