ARQ197-A-U303 A PHASE 3, RANDOMIZED, DOUBLE-BLIND STUDY OF TIVANTINIB (ARQ 197)IN SUBJECTS WITH MET DIAGNOSTIC-HIGH INOPERABLE HEPATOCELLULAR CARCINOMA (HCC) TREATED WITH ONE PRIOR SYSTEMIC THERAPY

Study ID
STU 102012-059

Cancer Related
Yes

Healthy Volunteers
No

Study Sites

Contact
Tyson Dudley
214-648-7031
tyson.dudley@utsouthwestern.edu

Principal Investigator
Muhammad Beg

Summary

Global, multi-center, randomized, placebo-controlled,double-blind Phase 3 study designed to compare treatment
of tivantinib versus placebo in subjects with MeT Diagnostic-High (MeT-High) ([GreaterThanorequalTo] 50% of tumor cells with a staining intensity of [GreaterThanorequalTo] 2+ for MeT as assessed by immunohistochemistry in a central lab) inoperable HCC (where surgery is not indicated due to disease extension, co-morbidities, or other technical reasons). Subjects must have had radiographic disease progression after onesorafenib containing systemic first line therapy or were unable to tolerate sorafenib. Subjects are randomized to receive either tivantinib or placebo in a 2:1 ratio and are stratified based on vascular invasion (present or not), extra-hepatic spread including distant metastasis and/or involved regional ([?] peri-hepatic, must be [GreaterThanorequalTo]20 mm in shortest diameter) or distant lymph nodes (present or not), and alpha fetoprotein (aFP) (less/equal or greater than 200 ng/mL).

approximately 350 subjects randomized in a 2:1 ratio to either tivantinib (~234 subjects) or placebo (~116 subjects)

The investigational drug tivantinib and its matching placebo are supplied as tablets. a dose of 120 mg (1 tablet of 120 mg) of tivantinib will be administered by mouth twice daily (BiD), once in the morning and once in the evening with meals, for a total daily dose of 240 mg.

a tivantinib tablet dose of 240 mg BiD (a total daily dose of 480 mg) was selected for this Phase 3 study on the basis of efficacy and tolerability established in Phase 1 and Phase 2 studies with capsules. in august 2013, following a higher than expected incidence of neutropenia-related toxicities, the study DMC evaluated all available data including preliminary pharmacokinetics. Based on this review, the DMC recommended the starting dose of 120 mg BiD (for a total daily dose of 240 mg).

Study endpoints:

Primary:
* overall survival (oS) in iTT population

Secondary:
* Progression free survival (PFS) by central,
independent radiology review
* Safety

exploratory:
* objective response rate (oRR), disease control rate
(DCR), time to progression (TTP), and type of
progression, by central, independent radiology
review
* Population pharmacokinetic (PK) parameters
* Functional assessment of Cancer Therapy-
Hepatobiliary (FaCT-Hep)-based FHSi-3 Pain
Score (pain, pain in back, pain/discomfort in
stomach); FaCT-Hepatobiliary Symptom index
(FHSi-8) score, emotional Well Being (eWB)
score, and the FaCT-Hep total score
* Time-to-hospitalization (all-cause) and time-tohospitalization
(HCC-related)

in august 2013, following a higher than expected incidence of neutropenia-related adverse events, the study DMC evaluated all available data including preliminary pharmacokinetics, and recommended the reduced starting
dose of 120 mg BiD. Therefore the 120 mg BiD regimen will be the intended dose regimen should marketing approval be granted. The subjects will need to be grouped to 2 cohorts: the 120 mg cohort (all subjects who are randomized to a starting dose of 120mg BiD versus Placebo) and the 240 mg cohort (all subjects who are randomized to a starting dose of 240mg BiD versus Placebo). Data from subjects in the 120 mg cohort will be used for the primary analysis of efficacy regarding potential marketing approval of the 120 mg BiD dose regimen.

Participant Eligibility

Subjects must satisfy all of the following criteria to be included in the study:
1. Written informed consent granted prior to initiation of any study-specific
screening procedures
2. 18 years of age or older
3. 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
4. MET Diagnostic-High tissue reported by the central authorized laboratory using
archival or recent biopsy tumor samples; (see the lab manual and Section 6.1 of
the protocol for tissue preparation details)
5. 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. For the
purpose of this study, intolerance to sorafenib is determined as follows:

* The subject must have tried to take sorafenib for a period of at least
28 days (even intermittently)

* The subject must have tried to dose reduce sorafenib at <=50% of the full
dose for a period of at least 14 days (even intermittently) and still have a
documented Grade >= 2 toxicity

* A period of even less than 14 days on sorafenib is acceptable in case of:
i. Uncontrolled Grade 3-4 arterial hypertension
ii. Pancreatitis, cardiac event, encephalopathy related to sorafenib
iii. >= Grade 2 Hand-foot syndrome triggered even at 50% of the
sorafenib dose
6. 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
7. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) <= 1 (see
Appendix 17.2)
8. 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
9. Measurable disease as defined by the Response Evaluation Criteria in Solid
Tumors (RECIST) version 1.1. 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. Baseline
radiographic assessment needs to be done within 21 days prior to randomization.
10. Adequate bone marrow, liver, and renal functions at Screening Visit, defined as:
platelet count >= 60 x 109/L; hemoglobin >= 9.0 g/dL; absolute neutrophil count
(ANC) >= 1.5 x 109/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
11. 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)
12. 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
13. Life expectancy of at least 12 weeks