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

• Toxicity as assessed by NCI CTC v3.0 [ Time Frame: Up to 3 years ] [ Designated as safety issue: Yes ]
  The 1-sided, alpha = 0.10, Lan-DeMets boundaries (Pocock analogue) will be used.
• Progression free survival [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]

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

SECONDARY OBJECTIVES:

I. To compare the time to progression in patients treated with these regimens. II. To compare the progression-free-survival of patients treated with these regimens.

III. 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 3 years.

• Adult Primary Hepatocellular Carcinoma
• Advanced Adult Primary Liver Cancer
• Localized Unresectable Adult Primary Liver Cancer
• Recurrent Adult Primary Liver Cancer

• Drug: doxorubicin hydrochloride
  Given IV
  Other Names:

  • ADM
  • ADR
  • Adria
  • Adriamycin PFS
  • Adriamycin RDF
• Drug: sorafenib tosylate
  Given orally
  Other Names:

  • BAY 43-9006
  • BAY 43-9006 Tosylate Salt
  • BAY 54-9085
  • Nexavar
  • SFN

• 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.
  Interventions:

  • Drug: doxorubicin hydrochloride
  • Drug: sorafenib tosylate
• 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.
  Interventions:

  • Drug: doxorubicin hydrochloride
  • Drug: sorafenib tosylate

Inclusion Criteria:

• Patients must have pathologically or cytologically proven hepatocelluar 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 CT scan
• No prior adjuvant sorafenib or other Raf/VEGF inhibitors; Other prior adjuvant therapy is allowed if completed >6 months prior to registration with documented recurrence of HCC

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

  • 1) a target lesion that has not been subjected to local therapy or

  • 2) 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:

  • A) bland embolization, radiation, radioactive microspheres, etc
  • B) chemoembolization using any chemotherapy (except, see "D", below)
  • C) chemoembolization drug-eluting beads using doxorubicin
  • D) 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
• No known 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 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
• 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 Assocation (NYHA)
  • Myocardial infarction within 6 months prior to registration
  • Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin
  • Serious myocardial dysfunction, defined as scintigraphically (MUGA, myocardial scintigram) determined absolute left ventricular ejection fraction (LVEF) below 45% or an LVEF 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 because of possible pharmacokinetic interactions with sorafenib
• ECOG performance status 0-2
• Pregnancy/Nursing Status: The effects of sorafenib on the developing fetus at the recommended therapeutic dose are unknown and may be teratogenic; Thus, women who are pregnant should not go on study. Women should not breastfeed while participating in this study
• Granulocytes ≥ 1,500/μL
• Hemoglobin ≥ 8.5 g/dL
• Platelets ≥ 75,000/μL
• Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 60 mL/min
• Child-Pugh score A
• Bilirubin ≤ 3 mg/dL
• ALT and AST ≤ 5 times upper limit of normal (ULN)
• PT/INR ≤ 1.7 (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)