Trial record 1 of 1 for:    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
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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 October 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: October 17, 2014
Last verified: October 2014

October 29, 2009
October 17, 2014
October 2009
February 2018   (final data collection date for primary outcome measure)
PFS [ Time Frame: Time from randomization to progression or death without evidence of progression, assessed up to 16 months ] [ Designated as safety issue: No ]
All PFS analyses will use the multi-time point (for the vascular invasion at 4, 8 and 12 months, and the non-vascular invasion group at 8, 12 and 16 months) Cochran-Mantel-Haenszel (CMH) test of Freidlin, et al. with an overall one-sided 0.025 type I error. The p-value from the one-sided multi-time point CMH test will be compared to the truncated O'Brien-Fleming boundary.
Progression-free survival [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01004978 on ClinicalTrials.gov Archive Site
  • 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 ]
    Analyses will use a one-sided logrank test stratified on vascular invasion (yes vs. no) and Child-Pugh Score (A vs. B7), using a one-sided overall type I error of 0.025. Critical values at interim analyses will be determined using a truncated version of the Lan-Demets error spending rate function corresponding to the O'Brien-Fleming boundary.
  • 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 ]
  • Overall survival [ Designated as safety issue: No ]
  • Toxicity [ Designated as safety issue: Yes ]
Not Provided
Not Provided
 
Chemoembolization With or Without Sorafenib Tosylate in Treating Patients With Liver Cancer That Cannot Be Removed by Surgery
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

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 the tumor 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.

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. 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. 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. 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. 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.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
  • Adult Primary Hepatocellular Carcinoma
  • Localized Unresectable Adult Primary Liver Cancer
  • Recurrent Adult Primary Liver Cancer
  • Drug: sorafenib tosylate
    Given PO
    Other Names:
    • BAY 43-9006
    • BAY 43-9006 Tosylate Salt
    • BAY 54-9085
    • Nexavar
    • SFN
  • Other: placebo
    Given PO
    Other Name: PLCB
  • Drug: doxorubicin hydrochloride
    Undergo TACE
    Other Names:
    • ADM
    • ADR
    • Adria
  • 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
  • Other: laboratory biomarker analysis
    Correlative studies
  • 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.
    Interventions:
    • Drug: sorafenib tosylate
    • Drug: doxorubicin hydrochloride
    • Drug: doxorubicin-eluting beads
    • Drug: cisplatin
    • Drug: mitomycin C
    • Other: pharmacological study
    • Other: laboratory biomarker analysis
  • Active 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.
    Interventions:
    • Other: placebo
    • Drug: doxorubicin hydrochloride
    • Drug: doxorubicin-eluting beads
    • Drug: cisplatin
    • Drug: mitomycin C
    • Other: pharmacological study
    • Other: laboratory biomarker analysis
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
400
Not Provided
February 2018   (final data collection date for primary outcome measure)

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 cannot be safely controlled with premedication
  • Patient must be able to swallow pills, as study medications cannot be crushed
Both
18 Years and older
No
United States
 
NCT01004978
NCI-2011-01981, NCI-2011-01981, ECOG-E1208, CDR0000657952, E1208, E1208, U10CA021115, U10CA180820
Yes
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Jean-Francois (Jeff) Geschwind ECOG-ACRIN Cancer Research Group
National Cancer Institute (NCI)
October 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP