Study of Tivantinib in Subjects With Inoperable Hepatocellular Carcinoma (HCC) Who Have Been Treated With One Prior Therapy (METIV-HCC)

• ClinicalTrials.gov Identifier: NCT01755767
• Recruitment Status: Completed
• First Posted: December 24, 2012
• Results First Posted: July 15, 2020
• Last Update Posted: April 6, 2021
• Sponsor: Daiichi Sankyo
• Collaborator: ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA)
• Information provided by (Responsible Party): Daiichi Sankyo

Tracking Information

• First Submitted Date: December 19, 2012
• First Posted Date: December 24, 2012
• Results First Submitted Date: June 10, 2020
• Results First Posted Date: July 15, 2020
• Last Update Posted Date: April 6, 2021
• Actual Study Start Date: December 27, 2012
• Actual Primary Completion Date: March 28, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 30, 2020)

• Median Overall Survival (OS) Following Treatment With Tivantinib 120 mg BID Compared to Placebo Group in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy [ Time Frame: within 36 months ]
  Overall survival (OS) is defined as the time from randomization to the date of death. The rate of OS (percentage of participants still alive) was determined only in the tivantinib 120 mg BID cohort.
• Overall Survival (OS) Rate At Different Time Points Following Treatment With Tivantinib 120 mg BID Compared to Placebo Group in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy [ Time Frame: within 36 months ]
  Overall survival (OS) is defined as the time from randomization to the date of death. The rate of OS (percentage of participants still alive) was determined only in the tivantinib 120 mg BID cohort.

Original Primary Outcome Measures (submitted: December 19, 2012)

Overall survival (OS) in Intent to Treat (ITT) population [ Time Frame: Every 12 weeks ]

Patients will be contacted every 12 weeks to track overall survival

Current Secondary Outcome Measures (submitted: June 30, 2020)

• Progression-free Survival Following Treatment With Tivantinib 120 mg BID Compared to Placebo Group in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy (ITT Population) [ Time Frame: within 10 months ]
  Progression-free survival (PFS) is defined as the time from the date of randomization to the date of the first radiographic disease progression or death due to any cause. The rate of PFS (percentage of participants still alive without disease progression) was determined only in the tivantinib 120 mg BID cohort.
• Treatment-Emergent Adverse Events Reported (>20% in Tivantinib Cohort) Following Treatment With Tivantinib Compared With Placebo in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy [ Time Frame: Baseline to 30 days after last dose, up to approximately 4 years ]
  Treatment-emergent adverse events (TEAEs) are reported for the tivantinib 120 mg BID cohort group.
• Treatment-Emergent Adverse Events Reported (>20% in Tivantinib Cohort) Following Treatment With Tivantinib Compared With Placebo in Participants With MET Diagnostic-High Inoperable Hepatocellular Carcinoma (HCC) Treated With One Prior Systemic Therapy [ Time Frame: Baseline to 30 days after last dose, up to approximately 4 years ]
  Treatment-emergent adverse events (TEAEs) are reported for the tivantinib 240 mg BID cohort group.

Original Secondary Outcome Measures (submitted: December 19, 2012)

• Progression free survival (PFS) [ Time Frame: Every 8 weeks ]
  Patients will be evaluated for these endpoints every 8 weeks. Progression free survival (PFS) by central, independent radiology review
• Safety [ Time Frame: Weekly for first 4 weeks, bi-wekkly thereafter ]
  Further characterize the safety of ARQ 197 in patients with unresectable HCC.

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

Descriptive Information

• Brief Title: Study of Tivantinib in Subjects With Inoperable Hepatocellular Carcinoma (HCC) Who Have Been Treated With One Prior Therapy
• Official Title: 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
• Brief Summary: The purpose of this study is to determine if tivantinib (ARQ 197) is effective in treating patients with MET diagnostic-high hepatocellular carcinoma (liver cancer) who have already been treated once with another therapy.
• Detailed Description: 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.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Hepatocellular Carcinoma

Intervention

• Drug: Tivantinib
  Tivantinib tablets
  Other Name: ARQ197
• Drug: Placebo
  Matching placebo tablets
  Other Name: Placebo comparator

Study Arms

• Experimental: Tivantinib 240 mg BID Cohort
  The tivantinib dosage of 240 mg tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food, for a total daily dose of 480 mg.
  Intervention: Drug: Tivantinib
• Experimental: Tivantinib 120 mg BID Cohort
  Tivantinib 120 mg is administered by oral tablet BID, once in the morning and once in the evening, with food, for a total daily dose of 240 mg (amended dosing group; primary analysis group).
  Intervention: Drug: Tivantinib
• Placebo Comparator: Placebo Matching 240 mg BID Cohort
  Matching placebo is administered by oral tablet(s) BID, once in the morning and once in the evening, with food.
  Intervention: Drug: Placebo
• Placebo Comparator: Placebo Matching 120 mg BID Cohort
  Matching placebo is administered by oral tablet(s) BID, once in the morning and once in the evening, with food.
  Intervention: Drug: Placebo

• Publications *: Rimassa L, Assenat E, Peck-Radosavljevic M, Pracht M, Zagonel V, Mathurin P, Rota Caremoli E, Porta C, Daniele B, Bolondi L, Mazzaferro V, Harris W, Damjanov N, Pastorelli D, Reig M, Knox J, Negri F, Trojan J, Lopez Lopez C, Personeni N, Decaens T, Dupuy M, Sieghart W, Abbadessa G, Schwartz B, Lamar M, Goldberg T, Shuster D, Santoro A, Bruix J. Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): a final analysis of a phase 3, randomised, placebo-controlled study. Lancet Oncol. 2018 May;19(5):682-693. doi: 10.1016/S1470-2045(18)30146-3. Epub 2018 Apr 3.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 7, 2017): 383
• Original Estimated Enrollment (submitted: December 19, 2012): 303
• Actual Study Completion Date: July 31, 2017
• Actual Primary Completion Date: March 28, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

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: Argentina, Australia, Austria, Belgium, Brazil, Canada, France, Germany, Italy, Netherlands, New Zealand, Portugal, Spain, Sweden, Switzerland, United States

Administrative Information

• NCT Number: NCT01755767
• Other Study ID Numbers: ARQ197-A-U303; 2012-003308-10 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Daiichi Sankyo
• Original Responsible Party: Same as current
• Current Study Sponsor: Daiichi Sankyo
• Original Study Sponsor: Same as current
• Collaborators: ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA)

Investigators

• Study Director: Global Clinical Leader; Daiichi Sankyo

• PRS Account: Daiichi Sankyo
• Verification Date: March 2021