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A Phase 3, Randomized, Double-Blind Study of Tivantinib (ARQ 197) in Subjects With MET Diagnostic-High Inoperable Hepatocellular Carcinoma Treated With One Prior Systemic Therapy

Phase 3
18 Years
Open (Enrolling)
Hepatocellular Carcinoma

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Trial Information

A Phase 3, Randomized, Double-Blind Study of Tivantinib (ARQ 197) in Subjects With MET Diagnostic-High Inoperable Hepatocellular Carcinoma Treated With One Prior Systemic Therapy

Expression of c-Met in tumors correlates with aggressive hepatocellular carcinoma (HCC)
features. Overexpression of the receptor in tumor samples or high level of blood HGF in
subjects is related to higher recurrence rate after surgery for HCC, while high c-Met
expression correlates with shorter survival in HCC subjects. In summary, c-Met holds an
important prognostic role in the natural history of HCC. This Phase 3 study in MET
Diagnostic-High inoperable HCC subjects has been designed based on the results from the
randomized, controlled Phase 2 study conducted by ArQule, Inc. with tivantinib versus
placebo in subjects with MET Diagnostic-High inoperable HCC who have failed one prior
systemic therapy, mentioned above. The purpose of this study is to confirm the efficacy of
tivantinib in MET Diagnostic-High HCC subjects who were previously treated with one systemic
therapy, and to further evaluate the safety profile of the experimental drug in this subject

Inclusion Criteria:

- Histologically confirmed HCC that is inoperable (where surgery is not indicated due
to disease extension, co-morbidities, or other technical reasons), and not eligible
for local therapy

- MET Diagnostic-High tissue reported by the central authorized laboratory using
archival or recent biopsy tumor samples

- Received at least 4 weeks of one prior sorafenib containing systemic therapy and then
experienced documented radiographic disease progression; or inability to tolerate
prior therapy received for at least a minimum period of time.

- Discontinued prior systemic treatment or any investigational drug for at least 2
weeks (14 days) or for at least 3 weeks for IV anti-cancer drugs, prior to the study

- ECOG Performance Status (PS) of <= equal to 1

- Local or loco-regional therapy (i.e., surgery, radiation therapy, hepatic arterial
embolization, chemoembolization, radiofrequency ablation, percutaneous ethanol
injection, or cryoablation) must have been completed >= 4 weeks prior to

- Measurable disease as defined by the RECIST v1.1. Tumor lesions previously treated
with local therapy should demonstrate clear dimensional increase by radiographic
assessment in order to be selected as target lesion(s) at baseline.

- Adequate bone marrow, liver, and renal functions at Screening Visit, defined as:

platelet count greater than or equal to 60 x 10^9/L; hemoglobin greater than or equal to
9.0 g/dL; absolute neutrophil count (ANC) <= 1.5 x 10^9/L; total bilirubin <= 2 mg/dL;
Alanine transaminase (ALT) and aspartate aminotransferase (AST) <= 5 x upper limit of
normal (ULN); serum creatinine <= 1.5 x ULN; albumin <= 2.8 g/dL; international normalized
ratio (INR) 0.8 to ULN or <= 3 for subjects receiving anticoagulant such as coumadin or
heparin. Subjects who are therapeutically anticoagulated are allowed to participate
provided that prior to anticoagulant therapy no evidence of underlying defect in
coagulation exists

- Women of childbearing potential must have a negative serum pregnancy test performed
within 14 days prior to the randomization (where demanded by local regulations, test
may be required within 72 hours prior to randomization)

- Male and female subjects of child-bearing potential must agree to use doublebarrier
contraceptive measures, oral contraception, or avoidance of intercourse during the
study and for 90 days after last investigational drug dose received

- Life expectancy of at least 12 weeks

Exclusion Criteria:

- More than 1 prior systemic regimen (prior MET inhibitors/antibodies are not allowed;
experimental systemic therapy for inoperable HCC given before or after sorafenib
counts as separate regimen and is not allowed)

- Child-Pugh B-C cirrhotic status based on clinical findings and laboratory results

- Previous or concurrent cancer that is distinct from HCC in primary site or histology,
EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, and superficial
bladder tumors. Any cancer curatively treated more than 3 years prior to enrollment
is permitted.

- History of congestive heart failure defined as Class II to IV per New York Heart
Association (NYHA) classification within 6 months prior to study entry; active
coronary artery disease (CAD); clinically significant bradycardia or other
uncontrolled, cardiac arrhythmia defined as greater than or equal to Grade 3
according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse
Events (CTCAE), or uncontrolled hypertension; myocardial infarction occurring within
6 months prior to study entry (myocardial infarction occurring more than 6 months
prior to study entry is permitted)

- Active clinically serious infections defined as >= Grade 3 according to NCI CTCAE

- Any medical, psychological, or social conditions, particularly if unstable, including
substance abuse, that may, in the opinion of the Investigator, interfere with the
subject's safety or participation in the study, protocol compliance, or evaluation of
the study results

- Known human immunodeficiency virus (HIV) infection

- Blood or albumin transfusion within 5 days prior to the blood draw being used to
confirm eligibility

- Concomitant interferon therapy or therapies for active HCV infection

- Pregnancy or breast-feeding

- History of liver transplant

- Inability to swallow oral medications

- Clinically significant gastrointestinal bleeding occurring <= 4 weeks prior to

Type of Study:


Study Design:

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

Outcome Measure:

Overall survival (OS) in Intent to Treat (ITT) population

Outcome Description:

Patients will be contacted every 12 weeks to track overall survival

Outcome Time Frame:

Every 12 weeks

Safety Issue:


Principal Investigator

Giovanni Abbadessa, MD

Investigator Role:

Study Director

Investigator Affiliation:

ArQule, Inc


United States: Food and Drug Administration

Study ID:




Start Date:

December 2012

Completion Date:

December 2015

Related Keywords:

  • Hepatocellular Carcinoma
  • MET diagnostic-high
  • Unresectable
  • Hepatocellular
  • Carcinoma
  • c-Met inhibitor
  • Carcinoma
  • Carcinoma, Hepatocellular



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