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
• Last Update Posted: September 26, 2022
• 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
• Last Update Posted Date: September 26, 2022
• 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: April 26, 2018)

Progression free survival (PFS) [ Time Frame: Time from randomization to progression or death without evidence of progression, assessed up to 16 months ]

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.

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

Current Secondary Outcome Measures (submitted: March 2, 2018)

• Overall survival [ Time Frame: Time from randomization to death from any cause, or last known date of survival, assessed up to 4 years ]
  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 ]

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

• Overall survival
• Toxicity

• Current Other Pre-specified Outcome Measures: Not Provided
• 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 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.

• 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
  Undergo TACE
  Other Names:

  • Abiplatin
  • Blastolem
  • Briplatin
  • CDDP
  • Cis-diammine-dichloroplatinum
  • Cis-diamminedichloridoplatinum
  • Cis-diamminedichloro Platinum (II)
  • Cis-diamminedichloroplatinum
  • Cis-dichloroammine Platinum (II)
  • Cis-platinous Diamine Dichloride
  • Cis-platinum
  • Cis-platinum II
  • Cis-platinum II Diamine Dichloride
  • Cismaplat
  • Cisplatina
  • Cisplatinum
  • Cisplatyl
  • Citoplatino
  • Citosin
  • Cysplatyna
  • DDP
  • Lederplatin
  • Metaplatin
  • Neoplatin
  • Peyrone's Chloride
  • Peyrone's Salt
  • Placis
  • Plastistil
  • Platamine
  • Platiblastin
  • Platiblastin-S
  • Platinex
  • Platinol
  • Platinol- AQ
  • Platinol-AQ
  • Platinol-AQ VHA Plus
  • Platinoxan
  • Platinum
  • Platinum Diamminodichloride
  • Platiran
  • Platistin
  • Platosin
• Drug: Doxorubicin Hydrochloride
  Undergo TACE
  Other Names:

  • 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI)
  • ADM
  • Adriacin
  • Adriamycin
  • Adriamycin Hydrochloride
  • Adriamycin PFS
  • Adriamycin RDF
  • ADRIAMYCIN, HYDROCHLORIDE
  • Adriamycine
  • Adriblastina
  • Adriblastine
  • Adrimedac
  • Chloridrato de Doxorrubicina
  • DOX
  • DOXO-CELL
  • Doxolem
  • Doxorubicin HCl
  • Doxorubicin.HCl
  • Doxorubin
  • Farmiblastina
  • FI 106
  • FI-106
  • hydroxydaunorubicin
  • Rubex
• Drug: Doxorubicin-Eluting Beads
  Undergo TACE
• Other: Laboratory Biomarker Analysis
  Correlative studies
• Drug: Mitomycin
  Undergo TACE
  Other Names:

  • Ametycine
  • Jelmyto
  • MITO
  • Mito-C
  • Mito-Medac
  • Mitocin
  • Mitocin-C
  • Mitolem
  • Mitomycin C
  • Mitomycin-C
  • Mitomycin-X
  • Mitomycine C
  • Mitosol
  • Mitozytrex
  • Mutamycin
  • Mutamycine
  • NCI-C04706
• Other: Pharmacological Study
  Correlative studies
• Other: Placebo Administration
  Given PO
• Drug: Sorafenib Tosylate
  Given PO
  Other Names:

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

Study Arms

• 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: Cisplatin
  • Drug: Doxorubicin Hydrochloride
  • Drug: Doxorubicin-Eluting Beads
  • Other: Laboratory Biomarker Analysis
  • Drug: Mitomycin
  • Other: Pharmacological Study
  • Drug: Sorafenib Tosylate
• 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:

  • Drug: Cisplatin
  • Drug: Doxorubicin Hydrochloride
  • Drug: Doxorubicin-Eluting Beads
  • Other: Laboratory Biomarker Analysis
  • Drug: Mitomycin
  • Other: Pharmacological Study
  • 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
• Study Completion Date: Not Provided
• 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; 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

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) ); ECOG-E1208; 10-00544; 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: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• 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

• Principal Investigator: Al B Benson; ECOG-ACRIN Cancer Research Group

• PRS Account: National Cancer Institute (NCI)
• Verification Date: September 2022