Chemoembolization of the Liver With or Without Sunitinib Malate in Treating Patients With Liver Cancer

A Double-Blind, Randomized, Phase II/III Study Comparing the Use of Chemoembolization Combined With Sunitinib Against Chemoembolization Combined With a Placebo in Patients With Hepatocellular Carcinoma (SATURNE)

RATIONALE: Chemoembolization kills tumor cells by blocking the blood flow to the tumor and keeping anticancer drugs near the tumor. Sunitinib malate 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. It is not yet known whether chemoembolization is more effective with or without sunitinib malate in treating patients with liver cancer.

PURPOSE: This randomized phase II/III trial is studying the side effects of chemoembolization of the liver and to see how well in works when given together with or without sunitinib malate in treating patients with liver cancer.

OBJECTIVES:

Primary

• To evaluate unacceptable bleeding or hepatic failure at 10 weeks post-treatment in patients with unresectable hepatocellular carcinoma treated with transarterial chemoembolization in combination with sunitinib malate versus transarterial chemoembolization alone.
• To evaluate the overall survival of these patients.

Secondary

• To evaluate the tumor stabilization rate in these patients.
• To evaluate the safety of this regimen in these patients.
• To evaluate the disease-free survival of these patients.
• To evaluate the relapse-free survival of these patients.
• To evaluate the quality of life of these patients.
• To evaluate the overall survival rate at 2 years of these patients.

OUTLINE: This is a multicenter study.

Pilot: Patients receive oral sunitinib malate once daily on days 1-28. Beginning 7-10 days later, patients undergo 1-3 courses of transarterial chemoembolization (TACE). Treatment repeats every 6 weeks for 1 year.

Randomization: Patients are stratified according to main tumor diameter (< 5 cm vs ≥ 5 cm), nodular involvement (uninodular vs multinodular), and center. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive sunitinib malate and TACE as in the pilot phase.
• Arm II: Patients receive oral placebo once daily on days 1-28 and TACE as in the pilot phase.

Quality of life is assessed periodically.

DISEASE CHARACTERISTICS:

• Histologically confirmed hepatocellular carcinoma or liver tumor responding to the Barcelona criteria
• Child-Pugh score of 5-6 (Class A)
• Tumor suitable for transarterial chemoembolization (one or more planned courses allowed)
• Tumor not suitable for surgical resection
• No extrahepatic metastases, including cerebral metastases

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Absolute neutrophil count ≥ 1.5 x 10^9/L
• Platelet count ≥ 100 x 10^9/L
• Hemoglobin ≥ 10 g/dL
• PT ≥ 50%
• Creatinine ≤ 120 μmol/L
• Bilirubin normal
• ALT/AST ≤ 3.5 times upper limit of normal (ULN)
• Alkaline phosphatases ≤ 4 times ULN
• Fibrinogen ≥ 1.5 g/L
• Not pregnant or nursing
• Fertile patients must use effective contraception
• No portal vein thrombosis
• Able to comply with scheduled follow-up and management of toxicity
• No uncontrolled hypertension or requiring ≥ 2 classes of antihypertensive drugs
• No concomitant disease or uncontrolled severe disease
• No contraindications to the vascular occlusion procedure
• No prior or concurrent malignancy within the past 5 years, except adequately treated cone-biopsied carcinoma in situ of the cervix or basal cell carcinoma of the skin
• No psychiatric disability or social, family, or geographic reason for which the patient may not be followed regularly

PRIOR CONCURRENT THERAPY:

• At least 7 days since prior CYP3A4 inhibitors or inducers
• At least 3 months since prior radiofrequency ablation
• No prior chemotherapy
• No prior sunitinib, sorafenib, or any other inhibitors of angiogenesis
• No concurrent participation in another trial