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

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

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.

Study Overview

• Status: Completed
• Conditions: Cancer; Solid Tumor; Hepatic Impairment
• Intervention / Treatment: Drug: Tivantinib; Drug: Tivantinib; Drug: Tivantinib; Drug: Tivantinib

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90033
      • USC/Norris Comprehensive Cancer Center
  • New Jersey
    • Hackensack, New Jersey, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 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
2. Male or female ≥18 years of age
3. Life expectancy of >12 weeks
4. Women of childbearing potential (WOCBP) must have a negative pregnancy test performed prior to the start of study drug
5. 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
6. Subjects with impaired hepatic function will be grouped according to Child-Pugh classification score
7. 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
8. Eastern Cooperative Oncology Group (ECOG) performance status ≥2
9. Adequate bone marrow and renal function
10. 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
11. 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:

1. History of liver transplant
2. Any major surgical procedure within 3 weeks prior to the first dose of study drug;
3. Active, clinically serious infections defined as ≥Grade 2 according to NCI Common Toxicity Criteria for Adverse Effects (CTCAE), version 4.0
4. 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

5. 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
6. 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
7. Significant gastrointestinal disorders, in the opinion of the Investigator
8. Pregnant or breastfeeding
9. Received Tivantinib as prior therapy
10. 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
11. Any other investigational drug/medical device within 3 weeks prior to the first dose
12. 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
13. Subjects receiving Coumadin anticoagulants
14. Inability to swallow oral medications
15. 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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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]

Collaborators and Investigators

• Sponsor: Daiichi Sankyo, Inc.
• Collaborators: Medpace, Inc.
• Investigators: Study Director: Masaya Tachibana, PhD, Daiichi Sankyo, Inc.

Study record dates

Study Major Dates

• Study Start: April 1, 2014
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): July 1, 2016

Study Registration Dates

• First Submitted: May 20, 2014
• First Submitted That Met QC Criteria: May 27, 2014
• First Posted (Estimate): May 30, 2014

Study Record Updates

• Last Update Posted (Actual): February 12, 2019
• Last Update Submitted That Met QC Criteria: February 8, 2019
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases
• Other Study ID Numbers: ARQ197-A-U160

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
• IPD Sharing Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
• IPD Sharing Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR