Sunitinib and Chemoembolization in Treating Patients With Liver Cancer That Cannot Be Removed by Surgery

Study Overview
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Brief Summary
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RATIONALE: Sunitinib 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. Chemoembolization kills tumor cells by blocking the blood flow to the tumor and keeping chemotherapy drugs, such as doxorubicin, near the tumor. Giving sunitinib together with chemoembolization may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving sunitinib together with chemoembolization works in treating patients with liver cancer that cannot be removed by surgery.

Detailed Description
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OBJECTIVES: Primary To determine the progression-free survival at 4 months of patients treated with this regimen. Secondary To determine overall survival of these patients. To determine if dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can be used to measure decrease in tumor perfusion and vascular permeability as a result of treatment with sunitinib malate in combination with TACE, and if it can be useful in prognosis. To examine the safety and tolerability of this regimen. To determine if a change in circulating endothelial precursor cell number and total monocyte count on days 3, 8, 10, and 35 of therapy (as compared with levels at baseline) and decrease in soluble vascular endothelial growth factor receptor-2 in serum on days 8 (before TACE), 10, and 35 of therapy (as compared with baseline) correlate with improved response and survival. To determine the effect of this therapy on quality of life as measured by the FACT-HEP scale prior to each course of therapy. OUTLINE: This is a multicenter study. Patients receive oral sunitinib malate once daily on days 1-7 and 15-35 in course 1 and on days 1-28 in all subsequent courses. Patients undergo hepatic artery chemoembolization with doxorubicin hydrochloride on day 8 of course 1 only. Treatment with sunitinib malate repeats every 6 weeks* in the absence of disease progression or unacceptable toxicity. NOTE: *Course 1 is 7 weeks in duration; all subsequent courses are 6 weeks in duration. Blood samples are collected at baseline and periodically during study to measure circulating endothelial precursor cell levels, total monocyte count, and soluble vascular endothelial growth factor receptor-2. Quality of life is assessed by the FACT-HEP scale at baseline, prior to each course of treatment, and then at the completion of treatment. After completion of study treatment, patients are followed every 6 months.

Official Title
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A Phase II Study of SUNITINIB MALATE (Sutent) and Chemoembolization in Patients With Unresectable Hepatocellular Cancer

Conditions
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Liver Cancer

Intervention / Treatment
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* Drug: doxorubicin hydrochloride
* Drug: sunitinib malate
* Other: laboratory biomarker analysis
* Procedure: hepatic artery embolization
* Procedure: quality-of-life assessment


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically, cytologically, or serologically* confirmed hepatocellular carcinoma meeting the following criteria: 1-4 lesions Involvement of 1 or both liver lobes NOTE: *Alpha-fetoprotein (AFP) > 500 mcg/L in high-risk patients Measurable disease by CT scan or MRI Disease does not exceed 50% of the liver parenchyma At least 1 lesion ≥ 3 cm in longest diameter Tumor burden involves < 50% of the liver Refused surgery OR unresectable disease due to any of the following: Multifocality Advanced cirrhosis Comorbid illness Candidate for chemoembolization No fibrolamellar histology No ascites No known brain metastases PATIENT CHARACTERISTICS: ECOG performance status 0-2 Life expectancy ≥ 12 weeks WBC ≥ 3,000/mm³ ANC ≥ 1,500/mm³ Hemoglobin ≥ 8.5 g/dL (transfusion allowed) Platelet count ≥ 100,000/mm³ Bilirubin ≤ 2 mg/dL AST ≤ 5 times upper limit of normal (ULN) INR < 1.5 Creatinine ≤ 2.0 mg/dL OR creatinine clearance ≥ 30 mL/min No bleeding diathesis or coagulopathy No active congestive heart failure No uncontrolled angina No myocardial infarction within the past 12 months No cardiac arrhythmia Ejection fraction ≥ 45% (in patients with known coronary artery disease and in patients > 50 years of age) Child-Pugh class A or B cirrhosis No impedance of hepatopedal blood flow (portal vein thrombosis) No thrombosis of the main portal vein No encephalopathy No biliary obstruction No variceal bleed within the past 6 months No history of allergic reactions attributed to compounds of similar chemical or biologic composition to sunitinib malate No absolute contraindication to doxorubicin, iodinated contrast material, microfibrillar collage hemostat, or dexamethasone No other concurrent uncontrolled illness including, but not limited to, any of the following: Ongoing or active infection Psychiatric illness or social situation that would limit compliance with study requirements No other active malignancies within the past year except nonmelanoma skin cancer or carcinoma in situ No significant traumatic injury within the past 4 weeks No QTc prolongation (i.e., QTc interval ≥ 500 msec) or other significant ECG abnormalities Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 6 months after the completion of study treatment PRIOR CONCURRENT THERAPY: Recovered from prior therapy Prior liver-directed therapy, such as chemoembolization, radiofrequency ablation, cryoablation, or ethanol injection allowed if the following criteria are met: Treated lesion remains inactive by CT scan or MRI and new lesion being embolized is distinct from the previously treated lesion Radiographic progression of previously treated lesion requiring re-embolization Prior liver resection allowed Prior immunotherapy allowed No prior antiangiogenesis therapy No prior liver transplantation Patients awaiting a cadaveric or orthotopic liver transplantation are eligible provided they have end-stage liver disease with a priority score of < 20 points More than 4 weeks since prior radiotherapy or chemotherapy (6 weeks for nitrosoureas or mitomycin C) More than 4 weeks since prior major surgery or open biopsy At least 1 week since prior fine needle biopsy No concurrent immunotherapy No concurrent radiotherapy No concurrent combination antiretroviral therapy for HIV-positive patients No concurrent therapeutic doses of coumarin-derivative anticoagulants (e.g., warfarin) Doses of ≤ 1 mg/day are allowed for prophylaxis of thrombosis as long as INR ≤ 1.5 Both full dose and prophylactic dose low molecular weight heparin allowed as long as PT INR ≤ 1.5 No anticipated major surgery during and for 3 months after completion of study treatment No other concurrent investigational agents No other concurrent anticancer therapy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sunitinib<br>oral sunitinib malate once daily on days 1-7 and 15-35 in course 1 and on days 1-28 in all subsequent courses | Drug: doxorubicin hydrochloride<br>* Transarterial chemoembolization<br>Drug: sunitinib malate<br>* Given Orally<br>Other: laboratory biomarker analysis<br>* Correlative Study<br>Procedure: hepatic artery embolization<br>* Surgical procedure<br>Procedure: quality-of-life assessment<br>* Correlative Study<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | median progression free survival in months | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | median survival in months | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months | 
| Tissue Perfusion, Ktrans, IAUC, and Percent Viable Tumor as Measured by DCE-MRI at Baseline and on Days 8 (Before Transarterial Chemoembolization), 10, and 35 |  | Baseline, day 8, day 10, day 28 and day 35 | 
| Safety and Tolerability | Number of participants with adverse advent. Please refer to adverse event reporting for more detail. | Daily while on treatment through study completion, an average of 1 year | 
| Assess the Change in the Quality of Life Among Patients Using the FACTHep (Version 4) for Hepatobiliary Cancers. | We utilized the FACT-HEP TOTAL SCORE (version 4) quality-of-life scale, which is a 45 item scale ranging from 96-178. Higher scores reflect better quality of life. No subscales were analyzed. | Baseline and Cycle 2 | 
| Tumor Marker Response (AFP) | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | Baseline, week 7 and every 6 weeks after | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult primary hepatocellular carcinoma, advanced adult primary liver cancer, localized unresectable adult primary liver cancer, recurrent adult primary liver cancer