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.
PURPOSE: This phase II trial is studying how well sunitinib works in treating patients with
liver cancer that cannot be removed by surgery.
- Demonstrate the antitumor activity of continuous sunitinib malate treatment in patients
with unresectable hepatocellular carcinoma.
- Evaluate the safety of sunitinib malate treatment.
- Measure serum cobalamin (i. e., vitamin B12) level during sunitinib malate treatment in
order to investigate the relationship between sunitinib malate treatment and cobalamin
- Control the cobalamin deficiency by cobalamin replacement.
- Investigate whether changes in tumor density could be used as a criterion for tumor
response in future trials.
OUTLINE: This is a multicenter study.
Patients receive oral sunitinib malate once daily. Treatment continues in the absence of
disease progression or unacceptable toxicity.
Patients undergo blood sample collection on day 1 of each course to assess serum cobalamin
levels and correlation with sunitinib malate treatment. Patients are also assessed for
changes in tumor density and correlation with response. Baseline CT scans are compared with
scans performed at 6 and 12 weeks to evaluate changes in CT-scan density due to tumor
necrosis and response.
After completion of study therapy, patients are followed at least every 3 months for up to 3
Minimum age: 18 Years.
Maximum age: N/A.
- Histologically, cytologically, or radiologically confirmed hepatocellular carcinoma
(HCC) meeting 1 of the following criteria:
- Localized, surgically unresectable disease
- Candidates for radical surgery for locally advanced disease are excluded
- Metastatic disease
- Measurable disease, defined as ≥ 1 lesion, outside of pretreated areas, that can be
measured in ≥ 1 dimension as ≥ 10 mm by spiral or multi-slice CT scan or MRI
- Child-Pugh class A or mildly decompensated Child-Pugh class B liver dysfunction
- Clinical ascites of any grade
- Clinical symptoms or history of CNS metastases or leptomeningeal disease
- Known fibrolamellar HCC or mixed cholangiocarcinoma and HCC
- WHO performance status 0-1
- Hemoglobin ≥ 9. 0 g/dL
- Absolute neutrophil count ≥ 1,500/mm³
- Platelet count ≥ 75,000/mm³
- Bilirubin ≤ 2 times upper limit of normal (ULN)
- ALT ≤ 7 times ULN
- Albumin ≥ 2. 5 g/dL
- Creatinine clearance ≥ 40 mL/min
- Quick test ≥ 50% (adequate coagulation)
- Urine dipstick for proteinuria < 2+ OR ≤ 1 g of protein in 24-hour urine collection
- Negative pregnancy test
- Fertile patients must use effective contraception during and for 12 months after
completion of study therapy
- Pregnant or nursing
- Malignancy within the past 5 years except for adequately treated cervical carcinoma in
situ or localized nonmelanoma skin cancer
- Hemorrhagic or thrombotic cerebrovascular event in the past 12 months
- Documented variceal hemorrhage within the past 3 months
- History or presence of clinically significant acute or unstable cardiovascular,
cerebrovascular, renal, gastrointestinal, pulmonary, immunological (except for the
presence of hepatitis B virus, hepatitis C virus, or cirrhosis), endocrine, or central
nervous system disorders
- Known HIV infection
- Active infection requiring IV antibiotics
- Arterial hypertension ≥ 150/100 mm Hg, despite therapy
- Ongoing cardiac dysrhythmias ≥ grade 2
- Atrial fibrillation of any grade
- Prolongation of QTc > 500 msec in screening ECG or history of familial long QT
- Inability to take oral medications
- Psychiatric disorder precluding understanding of information of study-related topics,
giving informed consent, or interfering with compliance for oral drug intake
PRIOR CONCURRENT THERAPY:
- At least 4 weeks since prior surgery or liver-directed therapy (e. g., transarterial
embolization/chemoembolization [limited to 5 treatments], radiofrequency ablation,
cryoablation, radiotherapy, or percutaneous ethanol injection)
- Previously treated lesions must remain separate from those to be measured in the
- Low-dose anticoagulants for maintenance of patency of central venous access or
prevention of deep vein thrombosis allowed
- Prior systemic anticancer treatment for hepatocellular carcinoma
- Prior organ transplantation
- Treatment in a clinical study within the past 30 days
- Concurrent full-dose anticoagulant or requirement for anticoagulant therapy
- Concurrent experimental drugs or other anticancer therapy
- Concurrent use or anticipated need for CYP3A4 inhibitors (e. g., ketoconazole,
itraconazole, voriconazole, erythromycin, clarithromycin, and protease inhibitors)
- Concurrent CYP3A4 inducers (e. g., carbamazepine, continuous treatment with
dexamethasone [> 2 mg/day for > 7 days], phenobarbital, phenytoin, rifampicin, and St
- Concurrent antacids allowed provided they are administered > 1 hour before or > 1
hour after study drug
- Concurrent elective major surgery
- Concurrent radiotherapy
- Concurrent analgesic radiotherapy of nontarget lesions allowed