Pharmacokinetics of Tivantinib in Subjects With Advanced Solid Tumors and Hepatic Impairment

Study Overview
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Brief Summary
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This is a multi-center, open-label, Phase 1 study to evaluate the impact of hepatic impairment on the pharmacokinetics of Tivantinib in cancer subjects with varying degrees of hepatic function, from normal to severely impaired.

Official Title
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A Phase 1, Open-Label Study Assessing the Impact of Hepatic Impairment on the Pharmacokinetics of Tivantinib in Subjects With Advanced Solid Tumors

Conditions
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Hepatic Impairment, Solid Tumor, Cancer

Intervention / Treatment
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* Drug: Tivantinib
* Drug: Tivantinib
* Drug: Tivantinib
* Drug: Tivantinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must have histologically or cytologically confirmed advanced solid tumor. However, Hepatocellular Carcinoma (HCC) subjects are allowed without histological confirmation as long as there is radiological diagnosis as per standard criteria Male or female ≥18 years of age Life expectancy of >12 weeks Women of childbearing potential (WOCBP) must have a negative pregnancy test performed prior to the start of study drug Male subjects and WOCBP must agree to use double barrier contraceptive measures or avoid intercourse during the study and for 90 days after the last dose of study drug Subjects with impaired hepatic function will be grouped according to Child-Pugh classification score Subjects with biliary obstruction for whom a biliary drain or stent has been placed are eligible, provided that the drain or stent has been in place for at least 10 days prior to the first dose of Tivantinib, and the subject's liver function has stabilized as defined by 2 measurements at least 5 days apart that put the subject in the same hepatic impairment group Eastern Cooperative Oncology Group (ECOG) performance status ≥2 Adequate bone marrow and renal function Ability to provide written informed consent, comply with protocol visits and procedures, take oral medication, and not have any active infection or chronic comorbidity that would interfere with therapy Fully informed about their illness and the investigational nature of the study protocol and must sign and date an Institutional Review Board-approved Informed Consent Form Exclusion Criteria: History of liver transplant Any major surgical procedure within 3 weeks prior to the first dose of study drug; Active, clinically serious infections defined as ≥Grade 2 according to NCI Common Toxicity Criteria for Adverse Effects (CTCAE), version 4.0 Known metastatic brain or meningeal tumors, unless the subject is >3 months from definitive therapy and clinically stable (supportive therapy with steroids or anticonvulsant medications is allowed) with respect to the tumor at the time of the first dose of study drug History of cardiac disease Active coronary artery disease, defined as myocardial infarction, unstable angina, coronary bypass graft, or stenting within 6 months prior to study entry Evidence of uncontrolled bradycardia or other cardiac arrhythmia defined as ≥Grade 2 according to NCI CTCAE, version 4.0, or uncontrolled hypertension Any condition that is unstable or that could jeopardize the safety of the subject and the subject's protocol compliance, including known infection with human immunodeficiency virus Significant gastrointestinal disorders, in the opinion of the Investigator Pregnant or breastfeeding Received Tivantinib as prior therapy Received anti-cancer therapy, including antibody, retinoid, or hormonal treatment (except megestrol acetate as supportive care), and radiation, within 3 weeks before dosing. Prior and concurrent use of hormone replacement therapy, the use of gonadotropin-releasing hormone modulators for prostate cancer, and the use of somatostatin and analogs for neuroendocrine tumors are permitted Any other investigational drug/medical device within 3 weeks prior to the first dose Substance abuse or medical, psychological, or social conditions that, in the opinion of the Investigator, may interfere with the subject's participation in the clinical study or evaluation of the clinical study results Subjects receiving Coumadin anticoagulants Inability to swallow oral medications Administration or possibility of initiating or continuing any treatment with any known Cytochrome P450 3A4 (CYP3A4) and CYP2C19 enzyme and P-glycoprotein altering drugs (inducer or inhibitor) or non drug agents within 14 days prior to dosing and during the primary objective phase

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 - Normal hepatic function<br>Subjects with normal hepatic function | Drug: Tivantinib<br>* Single oral administration of Tivantinib 120 mg on Day 1 followed by Tivantinib 360 mg twice daily in the extension phase.<br>|
| Experimental: Group 2 - Mild hepatic impairment<br>Subjects with mild hepatic impairment by Child-Pugh classification scores | Drug: Tivantinib<br>* Single oral administration of Tivantinib 120 mg on Day 1 followed by Tivantinib 120 mg twice daily in the extension phase<br>|
| Experimental: Group 3 - Moderate hepatic impairment<br>Subjects with moderate hepatic impairment by Child-Pugh classification scores | Drug: Tivantinib<br>* Single oral administration of Tivantinib 120 mg on Day 1 followed by Tivantinib 120 mg once daily in the extension phase<br>|
| Experimental: Group 4 - Severe hepatic impairment<br>Subjects with severe hepatic impairment by Child-Pugh classification scores | Drug: Tivantinib<br>* Single oral administration of Tivantinib 120 mg on Day 1 followed by Tivantinib 120 mg once every other day in the extension phase<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite of plasma pharmacokinetic parameters of Tivantinib | The following pharmacokinetic parameters will be determined: population estimates of apparent total clearance (CL/F), apparent volume of distribution (V/F), area under the concentration-time curve during the dosing interval (AUCtau), and maximum concentration (Cmax) during the dosing interval. | 0 (predose), 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours after a single dose and 0 (predose), 1, 2, 3, 4, 6, 8, 12, 24, and 48 hours after Cycle 1 Day 11 dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite of plasma pharmacokinetic parameters of Tivantinib | The following pharmacokinetic parameters will be determined: area under the concentration-time curve from time zero to the last quantifiable concentration (AUClast) and Cmax after single dose, time to maximum plasma concentration (Tmax) | 0 (predose), 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours after a single dose and 0 (predose), 1, 2, 3, 4, 6, 8, 12, 24, and 48 hours after Cycle 1 Day 11 dose | 
| Composite of plasma pharmacokinetic parameters of Tivantinib metabolites | The following pharmacokinetic parameters will be determined: Cmax and AUClast, AUCtau, Tmax, and metabolite ratios for Cmax, AUClast, and AUCtau. | 0 (predose), 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours after a single dose and 0 (predose), 1, 2, 3, 4, 6, 8, 12, 24, and 48 hours after Cycle 1 Day 11 dose] |