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

• ClinicalTrials.gov Identifier: NCT01004978
• Recruitment Status: Active, not recruiting
• First Posted: October 30, 2009
• Results First Posted: February 17, 2023
• Last Update Posted: February 17, 2023
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Tracking Information

• First Submitted Date: October 29, 2009
• First Posted Date: October 30, 2009
• Results First Submitted Date: January 19, 2023
• Results First Posted Date: February 17, 2023
• Last Update Posted Date: February 17, 2023
• Actual Study Start Date: October 28, 2009
• Actual Primary Completion Date: February 11, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 19, 2023)

Progression-free Survival (PFS) [ Time Frame: Assessed 4 months after first chemoembolization, 8 months after first chemoembolization, then every 8 weeks, up to 4 years ]

PFS is defined to be the time from randomization to progression or death without evidence of progression. For cases without documentation of progression, follow-up will be censored at the date of last disease assessment without progression, unless death occurs within 4 months following the date last known progression-free, in which case the death will be counted as an event. Progression is assessed per Solid Tumor Response Criteria (RECIST) and defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, or the appearance of one or more new lesion(s), and/or unequivocal progression of existing nontarget lesions.

• Original Primary Outcome Measures (submitted: October 29, 2009): Progression-free survival

Current Secondary Outcome Measures (submitted: January 19, 2023)

• Overall Survival (OS) [ Time Frame: Assessed every 3 months for 2 years and then every 6 months for 2 years ]
  Overall survival (OS) is defined as time from randomization to death from any cause, censoring cases who had not died at the date last known alive.
• Progression-free Survival (PFS) Among Patients With Extra-hepatic Progression [ Time Frame: Assessed 4 months after first chemoembolization, 8 months after first chemoembolization, then every 8 weeks, up to 4 years ]
  PFS is defined to be the time from randomization to progression or death without evidence of progression. Progression is assessed per Solid Tumor Response Criteria (RECIST) and defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, or the appearance of one or more new lesion(s), and/or unequivocal progression of existing nontarget lesions. For patients with progressive disease, the progression was classified as either intra- or extra-hepatic or both intra- and extra-hepatic. Patients with both intra- and extra-hepatic progression were considered as having extra-hepatic progression. This analysis was performed among patients with extra-hepatic progression.
• Progression-free Survival (PFS) Among Patients With Intra-hepatic Progression [ Time Frame: Assessed 4 months after first chemoembolization, 8 months after first chemoembolization, then every 8 weeks, up to 4 years ]
  PFS is defined to be the time from randomization to progression or death without evidence of progression. Progression is assessed per Solid Tumor Response Criteria (RECIST) and defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, or the appearance of one or more new lesion(s), and/or unequivocal progression of existing nontarget lesions. For patients with progressive disease, the progression was classified as either intra- or extra-hepatic or both intra- and extra-hepatic. This analysis was performed among patients with intra-hepatic progression.

Original Secondary Outcome Measures (submitted: October 29, 2009)

• Overall survival
• Toxicity

Current Other Pre-specified Outcome Measures (submitted: January 19, 2023)

• Pharmacogenetic and Pharmacokinetic Properties of Sorafenib Including Angiogenesis, Monooxygenases, Polymorphisms and Multidrug Resistance Mutation (MDR) [ Time Frame: Assessed at baseline, days 1, 8 and 15 of cycle 1 sorafenib, 3-5 days prior to 2nd and 3rd TACE ]
  This analysis will be performed across a few ECOG-ACRIN studies of sorafenib to evaluate the association between genotypes that are related with sorafenib activity and clinical outcomes.
• Inter-reader Concordance for Response by EASL (European Association for the Study of the Liver) Criteria [ Time Frame: at 4 months and 8 months Assessed at 4 months and 8 months following initial chemoembolization ]
  Response was determined using the European Association for the Study of the Liver (EASL) criteria, which was recommended as an alternative to RECIST for grading therapeutic response of advanced hepatocellular carcinoma (HCC). The EASL criteria use the longest dimension of enhancing tumor as the primary metric for gauging tumor response. The Kappa statistics will be applied to assess agreement between readers.
• Association Between Objective Tumor Response by EASL Criteria and PFS as Well as OS [ Time Frame: Assessed 4 months after first chemoembolization, 8 months after first chemoembolization, then every 8 weeks, up to 4 years ]
  PFS is defined to be the time from randomization to progression or death without evidence of progression. For cases without documentation of progression, follow-up will be censored at the date of last disease assessment without progression, unless death occurs within 4 months following the date last known progression-free, in which case the death will be counted as an event. Progression is assessed per Solid Tumor Response Criteria (RECIST) and defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, or the appearance of one or more new lesion(s), and/or unequivocal progression of existing nontarget lesions. OS is defined as time from randomization to death or date last known alive. Response is assessed at 4 and 8 months by EASL criteria.
• To Evaluate the Effects of Intra-hepatic vs. Extra-hepatic Progression on OS. [ Time Frame: Assessed 4 months after first chemoembolization, 8 months after first chemoembolization, then every 8 weeks, up to 4 years ]
  Progression is assessed per Solid Tumor Response Criteria (RECIST) and defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, or the appearance of one or more new lesion(s), and/or unequivocal progression of existing nontarget lesions. For patients with progressive disease, the progression was classified as either intra- or extra-hepatic or both intra- and extra-hepatic. OS is defined as the time from randomization to death or date last known alive.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Chemoembolization With or Without Sorafenib Tosylate in Treating Patients With Liver Cancer That Cannot Be Removed by Surgery
• 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
• Brief Summary: 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.

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. 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 versus (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 A: Patients receive sorafenib tosylate at 400 mg 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 B: 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 A.

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

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

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment

Condition

• Hepatocellular Carcinoma
• Unresectable Hepatocellular Carcinoma

Intervention

• Drug: Cisplatin
  Given IV; undergo trans arterial chemoembolisation (TACE)
  Other Names:

  • CDDP
  • Cis-diaminedichloroplatinum (II)
  • Cis-diaminedichloroplatinum
  • diaminedichloroplatinum
  • cis-platinum
  • platinum
  • DDP
  • Platinol
  • Platinol-AQ
  • DACP
  • NSC 119875
• Drug: Doxorubicin
  Given IV; undergo TACE
  Other Names:

  • Doxorubicin Hydrochloride
  • ADR
  • Adriamycin
  • Adriamycin RDF
  • Adriamycin PFS
  • hydroxydaunorubicin
• Drug: LC bead
  Given IV; undergo TACE
• Drug: Mitomycin
  Given IV; undergo TACE
  Other Names:

  • Mitomycin C
  • Mutamycin
• Other: Placebo Administration
  Given PO
• Drug: Sorafenib
  Given PO
  Other Names:

  • BAY 43-9006 Tosylate
  • BAY 54-9085
  • Nexavar
  • Sorafenib Tosylate

Study Arms

• Experimental: Arm A (sorafenib and TACE)
  Patients receive sorafenib tosylate at 400mg 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 (this option may only be utilized for patients registered prior to addendum #3); conventional chemoembolization comprising doxorubicin hydrochloride only; or chemoembolization comprising LC bead and doxorubicin. Treatment with TACE repeats approximately every 4 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: Cisplatin
  • Drug: Doxorubicin
  • Drug: LC bead
  • Drug: Mitomycin
  • Drug: Sorafenib
• Active Comparator: Arm B (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 A.
  Interventions:

  • Drug: Cisplatin
  • Drug: Doxorubicin
  • Drug: LC bead
  • Drug: Mitomycin
  • Other: Placebo Administration

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: February 18, 2021): 235
• Original Estimated Enrollment (submitted: October 29, 2009): 400
• Estimated Study Completion Date: June 2023
• Actual Primary Completion Date: February 11, 2021 (Final data collection date for primary outcome measure)

Eligibility 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
• 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 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
• Branch portal vein invasion by tumor is permitted
• 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 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
• Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception
• Patient must be able to swallow pills, as study medications cannot be crushed

Exclusion Criteria:

• Clinical or radiographic evidence of extrahepatic HCC
• Ascites detectable on physical examination
• Candidates for curative resection, orthotopic liver transplantation, or radiofrequency ablation (RFA)
• Prior brachytherapy such as yttrium-90 microsphere
• Prior sorafenib, chemoembolization, or systemic chemotherapy including cytotoxic agents or molecularly targeted agents
• Patients with main portal vein invasion by tumor
• Evidence of bleeding diathesis or active gastrointestinal bleeding
• Clinical signs of heart failure
• Human immunodeficiency virus (HIV) positive

• 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
• Allergy to iodine or gadolinium contrast that cannot be safely controlled with premedication

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01004978
• Other Study ID Numbers: NCI-2011-01981; NCI-2011-01981 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); CDR0000657952; E1208 ( Other Identifier: ECOG-ACRIN Cancer Research Group ); E1208 ( Other Identifier: CTEP ); U10CA180820 ( U.S. NIH Grant/Contract ); U10CA021115 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Individual participant data may be made available upon request as per the ECOG-ACRIN Data Sharing Policy.

• Current Responsible Party: National Cancer Institute (NCI)
• Original Responsible Party: Robert L. Comis, ECOG Group Chair's Office
• Current Study Sponsor: National Cancer Institute (NCI)
• Original Study Sponsor: Eastern Cooperative Oncology Group
• Collaborators: Not Provided

Investigators

• Study Chair: Jean-Francois Geschwind, M.D.; Johns Hopkins University/Sidney Kimmel Cancer Center

• PRS Account: National Cancer Institute (NCI)
• Verification Date: January 2023