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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


Phase 3
18 Years
N/A
Open (Enrolling)
Both
Adult Primary Hepatocellular Carcinoma, Localized Unresectable Adult Primary Liver Cancer, Recurrent Adult Primary Liver Cancer

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Trial Information

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


PRIMARY OBJECTIVE:

I. To compare Progression-Free Survival (PFS) of chemoembolization alone to sorafenib 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 MDR.

II. ECOG 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 RECIST) and OS.

V. To evaluate the effects of intra-hepatic vs. extra-hepatic progression on OS.

OUTLINE: This is a multicenter study. Patients are stratified according to macrovascular
intrahepatic portal vein invasion (present vs absent), Child Pugh score (A vs B7), and
chemoembolization method (doxorubicin-eluting bead vs conventional). Patients are randomized
to 1 of 2 treatment arms.

ARM I: Patients receive sorafenib tosylate orally (PO) twice daily 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 twice daily 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. Patients undergo chest, abdomen, and/or pelvis CT scans or MRI at baseline, at 4
and 8 months, and every 2 months thereafter.

Blood and tissue samples may be collected at baseline and periodically during study for
pharmacogenetic and pharmacokinetic studies. After completion of study therapy, patients are
followed up periodically for 4 years.


Inclusion Criteria:



- Diagnosis of hepatocellular carcinoma (HCC) according to 1 of the following criteria:

- Histologically confirmed disease

- Liver cirrhosis AND ≥ 1 solid liver lesion > 2 cm with early enhancement and
delayed enhancement washout on CT scan or MRI regardless of alpha-fetoprotein
levels (AFP)

- AFP > 400 ng/mL AND ≥ 1 solid liver lesion > 2 cm regardless of specific imaging
characteristics on CT scan or MRI

- Disease must be limited to the liver

- No clinical or radiographic evidence of extra hepatic HCC

- Portal vein lymphadenopathy is allowed for patients with hepatitis B or C

- Branch portal vein invasion by tumor allowed

- No main portal vein invasion by tumor

- Measurable disease constituting < 50% of liver parenchyma within the past 4 weeks

- Child Pugh score of A or B7 within the past 4 weeks

- No ascites detectable on physical evaluation

- Not a candidate for curative resection, orthotopic liver transplantation, or
radiofrequency ablation (RFA)

- ECOG performance status 0-1

- Life expectancy ≥ 3 months

- Platelet count ≥ 50,000/μL

- Total bilirubin ≤ 2.0 mg/dL

- Alkaline phosphatase < 5 times upper limit of normal (ULN)

- AST and ALT < 5 times ULN

- Serum creatinine ≤ 1.5 mg/dL

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Able to swallow pills

- No clinical signs of heart failure

- No NYHA class III or IV heart disease

- No evidence of bleeding diathesis or active gastrointestinal bleeding

- No known HIV positivity

- No other concurrent uncontrolled illness (except hepatitis B or C) including, but not
limited to, any of the following:

- Uncontrolled hypertension (i.e., optimally treated baseline BP > 150/90 mm Hg)

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness and/or addictive disorder that would limit compliance with
study requirements

- No allergy to iodine or gadolinium contrast that cannot be safely controlled with
premedication

- No prior brachytherapy (e.g., yttrium-90 microspheres)

- No prior sorafenib tosylate, chemoembolization, or systemic chemotherapy, including
cytotoxic agents or molecularly targeted agents

- Prior attempted curative liver resection allowed

- More than 4 weeks since prior RFA

- No concurrent cytochrome P450 enzyme-inducing drugs

- No concurrent prophylactic G-CSF or GM-CSF

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Outcome Measure:

Progression-free survival

Outcome Time Frame:

Time from randomization to progression or death without evidence of progression, assessed up to 4 years

Safety Issue:

No

Principal Investigator

John Kauh

Investigator Role:

Principal Investigator

Investigator Affiliation:

Eastern Cooperative Oncology Group

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2011-01981

NCT ID:

NCT01004978

Start Date:

October 2009

Completion Date:

Related Keywords:

  • Adult Primary Hepatocellular Carcinoma
  • Localized Unresectable Adult Primary Liver Cancer
  • Recurrent Adult Primary Liver Cancer
  • Carcinoma
  • Liver Neoplasms
  • Carcinoma, Hepatocellular

Name

Location

Eastern Cooperative Oncology GroupBoston, Massachusetts  02215