Phase III Randomized Study of Sorafenib Plus Doxorubicin Versus Sorafenib in Patients With Advanced Hepatocellular Carcinoma (HCC)
Phase III Randomized Study of Sorafenib Plus Doxorubicin Versus Sorafenib in Patients With Advanced Hepatocellular Carcinoma (HCC)
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.
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
Prior therapies allowed include the following:
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:
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)
Jonesboro, Arkansas 72401, United States
Pleasant Hill, California 94523, United States
San Pablo, California 94806, United States
Washington D.C., District of Columbia 20422, United States
Chicago, Illinois 60657, United States
Highland Park, Illinois 60035, United States
Pekin, Illinois 61554, United States
Saint Louis Park, Minnesota 55416, United States
Las Vegas, Nevada 89109, United States
Las Vegas, Nevada 89113, United States
Las Vegas, Nevada 89149, United States
East Orange, New Jersey 07018-1095, United States
Brooklyn, New York 11209, United States
East Syracuse, New York 13057, United States
Liverpool, New York 13088, United States
New York, New York 10032, United States
Syracuse, New York 13215, United States
Winston-Salem, North Carolina 27104, United States
Lancaster, South Carolina 29720, United States
Sioux Falls, South Dakota 57117-5045, United States
Houston, Texas 77030, United States
Berlin Corners, Vermont 05602, United States
White River Junction, Vermont 05009, United States
Montreal, Quebec H3H 2R9, Canada