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

Continuous Sunitinib Treatment in Patients With Unresectable Hepatocellular Carcinoma A Multicenter Phase II Trial

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.

Study Overview

• Status: Completed
• Conditions: Liver Cancer
• Intervention / Treatment: Drug: sunitinib malate

Detailed Description

OBJECTIVES:

Primary

• Demonstrate the antitumor activity of continuous sunitinib malate treatment in patients with unresectable hepatocellular carcinoma.

Secondary

• 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 deficiency.
• 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 years.

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 2

Contacts and Locations

Study Locations

• Switzerland
  • St. Gallen, Switzerland, CH-9007
    • Kantonsspital - St. Gallen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

Inclusion criteria:

• 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

Exclusion criteria:

• Clinical ascites of any grade
• Clinical symptoms or history of CNS metastases or leptomeningeal disease
• Known fibrolamellar HCC or mixed cholangiocarcinoma and HCC

PATIENT CHARACTERISTICS:

Inclusion criteria:

• 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

Exclusion criteria:

• Pregnant or nursing
• Encephalopathy
• 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 syndrome
• 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:

Inclusion criteria:

• 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 present study
• Low-dose anticoagulants for maintenance of patency of central venous access or prevention of deep vein thrombosis allowed

Exclusion criteria:

• 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 John's wort)

  • 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Continuous sunitinib treatment	Drug: sunitinib malate; Starting dose: 37.5 mg 3 x 12.5 mg capsule; Reduced dose: 25 mg 2 x 12.5 mg capsule; Other Names: Sutent

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Progression-free survival	at 12 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Objective response	Objective response (CR+PR) to treatment will be determined. CR or PR is to be confirmed after a minimum of 4 weeks
Disease stabilization (DS)	Disease stabilization (CR, PR or SD) under sunitinib treatment will be determined
Duration of DS	Duration of DS (CR, PR or SD) will be calculated from the time that measurement criteria are met for the first time until documented tumor progression
Progression-free survival	PFS will be calculated from registration until documented tumor progression or death, whichever occurs first.
Time to progression	TTP will be calculated from registration until documented tumor progression or death due to tumor.
Overall survival	OS will be calculated from registration until death
Adverse events as assessed by NCI CTCAE v3.0	All AEs will be assessed according to NCI CTCAE v3.0.
Serum alpha fetoprotein level	Serum AFP levels will be measured during the therapy, if AFP is ≥ 1.5 x ULN at baseline.

Collaborators and Investigators

• Sponsor: Swiss Group for Clinical Cancer Research

Publications and helpful links

General Publications

• Koeberle D, Montemurro M, Samaras P, Majno P, Simcock M, Limacher A, Lerch S, Kovacs K, Inauen R, Hess V, Saletti P, Borner M, Roth A, Bodoky G. Continuous Sunitinib treatment in patients with advanced hepatocellular carcinoma: a Swiss Group for Clinical Cancer Research (SAKK) and Swiss Association for the Study of the Liver (SASL) multicenter phase II trial (SAKK 77/06). Oncologist. 2010;15(3):285-92. doi: 10.1634/theoncologist.2009-0316. Epub 2010 Mar 4.

Study record dates

Study Major Dates

• Study Start: July 1, 2007
• Primary Completion (ACTUAL): August 1, 2008
• Study Completion (ACTUAL): February 1, 2009

Study Registration Dates

• First Submitted: August 8, 2007
• First Submitted That Met QC Criteria: August 8, 2007
• First Posted (ESTIMATE): August 9, 2007

Study Record Updates

• Last Update Posted (ESTIMATE): June 26, 2012
• Last Update Submitted That Met QC Criteria: June 25, 2012
• Last Verified: June 1, 2012

More Information

Terms related to this study

• Keywords: advanced adult primary liver cancer; recurrent adult primary liver cancer; localized unresectable adult primary liver cancer; adult primary hepatocellular carcinoma
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Sunitinib
• Other Study ID Numbers: SAKK 77/06; SWS-SAKK-77/06; EU-20750; EUDRACT-2007-003977-22; CDR0000560441