Chemoembolization With or Without Sorafenib Tosylate in Treating Patients With Liver Cancer That Cannot Be Removed By Surgery

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01004978
First received: October 29, 2009
Last updated: June 23, 2014
Last verified: June 2014
  Purpose

This randomized phase III trial studies chemoembolization and sorafenib tosylate to see how well they work compared with chemoembolization alone in treating patients with liver cancer that cannot be removed by surgery. Drugs used in chemotherapy, such as doxorubicin hydrochloride, mitomycin, and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Chemoembolization kills tumor cells by carrying drugs directly into blood vessels near and then blocking the blood flow to allow a higher concentration of the drug to reach the tumor for a longer period of time. Sorafenib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving chemoembolization together with sorafenib tosylate is more effective than chemoembolization alone in treating patients with liver cancer.


Condition Intervention Phase
Adult Primary Hepatocellular Carcinoma
Localized Unresectable Adult Primary Liver Cancer
Recurrent Adult Primary Liver Cancer
Drug: sorafenib tosylate
Other: placebo
Drug: doxorubicin hydrochloride
Drug: doxorubicin-eluting beads
Drug: cisplatin
Drug: mitomycin C
Other: pharmacological study
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Phase III Randomized, Double-Blind Trial of Chemoembolization With or Without Sorafenib in Unresectable Hepatocellular Carcinoma (HCC) in Patients With and Without Vascular Invasion

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Progression-free survival [ Time Frame: Time from randomization to progression or death without evidence of progression, assessed up to 4 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Overall survival [ Time Frame: Time from randomization to death from any cause, or last known date of survival, assessed up to 4 years ] [ Designated as safety issue: No ]
  • Incidence of adverse events, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 4 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 400
Study Start Date: October 2009
Estimated Primary Completion Date: February 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (sorafenib tosylate and TACE)
Patients receive sorafenib tosylate PO BID in the absence of disease progression or unacceptable toxicity. Beginning within 2 weeks after a stable dose of sorafenib tosylate is reached, patients undergo TACE comprising doxorubicin hydrochloride, mitomycin C, and cisplatin (closed to accrual as of 10/1/2010); conventional chemoembolization comprising doxorubicin hydrochloride only; or chemoembolization comprising doxorubicin-eluting beads. Treatment with TACE repeats approximately every 4 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.
Drug: sorafenib tosylate
Given PO
Other Names:
  • BAY 43-9006
  • BAY 43-9006 Tosylate Salt
  • BAY 54-9085
  • Nexavar
  • SFN
Drug: doxorubicin hydrochloride
Undergo TACE
Other Names:
  • ADM
  • ADR
  • Adria
  • Adriamycin PFS
  • Adriamycin RDF
Drug: doxorubicin-eluting beads
Undergo TACE
Drug: cisplatin
Undergo TACE
Other Names:
  • CACP
  • CDDP
  • CPDD
  • DDP
Drug: mitomycin C
Undergo TACE
Other Names:
  • MITC
  • MITO
  • MITO-C
  • Mitocin-C
  • MTC
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Placebo Comparator: Arm II (placebo and TACE)
Patients receive placebo PO BID in the absence of disease progression or unacceptable toxicity. Beginning within 2 weeks after a stable dose of placebo is reached, patients undergo TACE as in Arm I.
Other: placebo
Given PO
Other Name: PLCB
Drug: doxorubicin hydrochloride
Undergo TACE
Other Names:
  • ADM
  • ADR
  • Adria
  • Adriamycin PFS
  • Adriamycin RDF
Drug: doxorubicin-eluting beads
Undergo TACE
Drug: cisplatin
Undergo TACE
Other Names:
  • CACP
  • CDDP
  • CPDD
  • DDP
Drug: mitomycin C
Undergo TACE
Other Names:
  • MITC
  • MITO
  • MITO-C
  • Mitocin-C
  • MTC
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

Detailed Description:

PRIMARY OBJECTIVE:

I. To compare progression-free survival (PFS) of chemoembolization alone to sorafenib (sorafenib tosylate) in combination with chemoembolization.

SECONDARY OBJECTIVES:

I. To compare overall survival (OS) of chemoembolization alone to sorafenib in combination with chemoembolization.

II. To evaluate extra-hepatic versus intra-hepatic patterns of failure. III. To determine the rates of toxicity related to sorafenib in combination with chemoembolization.

TERTIARY OBJECTIVES:

I. Pharmacogenetic and pharmacokinetic ancillary (PG0107) objective: To analyze the pharmacogenetic and pharmacokinetic properties of sorafenib including angiogenesis, monooxygenases, polymorphisms and multidrug resistance (MDR).

II. Eastern Cooperative Oncology Group (ECOG)-American College of Radiology Imaging Network (ACRIN) secondary imaging objective: site vs. central evaluation of PFS.

III. Correlative imaging science objective: to determine the inter-reader concordance for response characterization at four and eight months by the European Association for the Study of Liver (EASL) criteria.

IV. Correlative imaging science objective: to determine the value of objective tumor response at four and eight months by the EASL criteria to predict PFS (by Response Evaluation Criteria in Solid Tumors [RECIST]) and OS.

V. Correlative imaging science objective: to evaluate the effects of intra-hepatic vs. extra-hepatic progression on OS.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive sorafenib tosylate orally (PO) twice daily (BID) in the absence of disease progression or unacceptable toxicity. Beginning within 2 weeks after a stable dose of sorafenib tosylate is reached, patients undergo transarterial chemoembolization (TACE) comprising doxorubicin hydrochloride, mitomycin C, and cisplatin (closed to accrual as of 10/1/2010); conventional chemoembolization comprising doxorubicin hydrochloride only; or chemoembolization comprising doxorubicin-eluting beads. Treatment with TACE repeats approximately every 4 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive placebo PO BID in the absence of disease progression or unacceptable toxicity. Beginning within 2 weeks after a stable dose of placebo is reached, patients undergo TACE as in Arm I.

MAINTENANCE THERAPY: After completion of chemoembolization, patients receive sorafenib tosylate or placebo as in Arm I and II in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 years.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have a diagnosis of hepatocellular carcinoma by at least one criterion listed below:

    • Histologically confirmed
    • Magnetic resonance imaging (MRI) or computerized tomography (CT) consistent with liver cirrhosis AND at least one solid liver lesion > 2 cm with early enhancement and delayed enhancement washout regardless of alpha-feto protein levels (AFP)
    • AFP > 400 ng/mL AND evidence of at least one solid liver lesion > 2 cm regardless of specific imaging characteristics on CT or MRI
  • Patients must have hepatocellular carcinoma (HCC) limited to the liver; there must be no clinical or radiographic evidence of extrahepatic HCC
  • Portal lymphadenopathy IS permitted for patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) - as lymphadenopathy is commonly associated with hepatitis unrelated to malignancy
  • Staging CT of the chest and CT or MRI of the abdomen and pelvis must have been completed within 4 weeks of study registration
  • Patients must have measurable disease constituting < 50% of liver parenchyma within 4 weeks of registration
  • Patients may not have ascites detectable on physical examination
  • Patients must not be candidates for curative resection, orthotopic liver transplantation, or radiofrequency ablation (RFA)
  • Patients may have been treated with RFA in the past, but no sooner than 4 weeks before study registration
  • Patients may have undergone previously attempted curative liver resection
  • Patients may NOT have been previously treated with brachytherapy such as Yttrium-90 microsphere
  • Patients may NOT have been previously treated with sorafenib, chemoembolization, or systemic chemotherapy including cytotoxic agents or molecularly targeted agents
  • Branch portal vein invasion by tumor is permitted but patients with main portal vein invasion by tumor are not eligible
  • Patients must have Child-Pugh score of A or B7 within 4 weeks prior to study registration
  • Serum total bilirubin =< 2.0 mg/dL
  • Alkaline phosphatase < 5 X upper limit of normal (ULN)
  • Aspartate aminotransferase (AST), alanine aminotransferase (ALT) < 5 X ULN
  • Serum creatinine =< 1.5 mg/dL
  • Platelet count >= 50,000/mm^3
  • Patients must not have any evidence of bleeding diathesis or active gastrointestinal bleeding
  • Patients must have no clinical signs of heart failure and meet New York Heart Association functional classification I or II defined as:

    • Class I - patients with no limitation of activities; they suffer no symptoms from ordinary activities
    • Class II - patients with slight, mild limitation of activity; they are comfortable with rest or with mild exertion
  • Patients must have an ECOG performance status of 0 or 1
  • Patients must have a life expectancy of at least 3 months
  • Patients must not be known to be human immunodeficiency virus (HIV) positive
  • Patients must not have other uncontrolled intercurrent illnesses excluding HBV or HCV, including, but not limited to: uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia or psychiatric illness/addictive disorders that would limit compliance with study requirements

    • Uncontrolled hypertension is defined as optimally treated baseline blood pressure that exceeds 150/90 mm Hg
  • Patients must not be taking cytochrome P450 enzyme inducing drugs
  • Women must not be pregnant or breast-feeding; all females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy
  • Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception
  • Patients must not have an allergy to iodine or gadolinium contrast that can not be safely controlled with premedication
  • Patient must be able to swallow pills, as study medications can not be crushed
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01004978

  Show 278 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: Jean-Francois (Jeff) Geschwind ECOG-ACRIN Cancer Research Group
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01004978     History of Changes
Other Study ID Numbers: NCI-2011-01981, NCI-2011-01981, ECOG-E1208, CDR0000657952, E1208, E1208, U10CA180820, U10CA021115
Study First Received: October 29, 2009
Last Updated: June 23, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Carcinoma
Liver Neoplasms
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Adenocarcinoma
Mitomycins
Mitomycin
Doxorubicin
Sorafenib
Cisplatin
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Alkylating Agents
Radiation-Sensitizing Agents
Physiological Effects of Drugs
Protein Kinase Inhibitors

ClinicalTrials.gov processed this record on July 26, 2014