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

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

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.

Study Overview

• Status: Terminated
• Conditions: Liver Cancer
• Intervention / Treatment: Other: laboratory biomarker analysis; Procedure: quality-of-life assessment; Drug: doxorubicin hydrochloride; Drug: sunitinib malate; Procedure: hepatic artery embolization

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • Buffalo, New York, United States, 14263-0001
      • Roswell Park Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Roswell Park Cancer Institute
• Investigators: Principal Investigator: Renuka Iyer, MD, Roswell Park Cancer Institute

Study record dates

Study Major Dates

• Study Start: April 1, 2007
• Primary Completion (Actual): December 1, 2010
• Study Completion (Actual): May 1, 2014

Study Registration Dates

• First Submitted: August 31, 2007
• First Submitted That Met QC Criteria: August 31, 2007
• First Posted (Estimate): September 3, 2007

Study Record Updates

• Last Update Posted (Actual): May 9, 2017
• Last Update Submitted That Met QC Criteria: March 31, 2017
• Last Verified: March 1, 2017

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; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Antibiotics, Antineoplastic; Sunitinib; Doxorubicin; Liposomal doxorubicin
• Other Study ID Numbers: CDR0000563261; RPCI-I-82706