Study of Tivantinib in Subjects With Inoperable Hepatocellular Carcinoma (HCC) Who Have Been Treated With One Prior 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
population.

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
randomization

- 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 randomization

- Measurable disease as defined by the RECIST v1.1.

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 Hepatitis C virus (HCV)
infection

- Pregnancy or breast-feeding

- History of liver transplant

- Inability to swallow oral medications

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

- Pleural effusion or clinically evident (visible or palpable) ascites