Drug-drug Interaction Study of Tivantinib (ARQ 197) With Omeprazole, S-warfarin, Caffeine, Midazolam, and Digoxin in Cancer Subjects

A Phase 1, Open-Label, Single-Sequence Crossover Study Assessing the Effect of Tivantinib (ARQ 197) on the Pharmacokinetics of Omeprazole/S-Warfarin/Caffeine/Midazolam and Digoxin in Cancer Subjects

The purpose of this study is to determine the effects of tivantinib on the pharmacokinetics of omeprazole, s-warfarin, caffein, midazolam, or digoxin in patients with cancer.

Study Overview

• Status: Completed
• Conditions: Solid Tumors
• Intervention / Treatment: Drug: tivantinib; Drug: omeprazole; Drug: s-warfarin; Drug: caffeine; Dietary supplement: vitamin K; Drug: digoxin; Drug: midazolam

Detailed Description

Nonclinical studies have indicated that tivantinib (parent molecule) has the potential to inhibit CYP3A4 ([I]/Ki=0.15, midazolam as substrate), CYP2C19 ([I]/Ki=0.98), CYP2C9 ([I]/Ki=0.44), and CYP1A ([I]/Ki=0.37), and the efflux transporter P glycoprotein (P-gp) (I2/IC50=82) at the clinical concentrations being studied in the Phase 3 development program. In addition, tivantinib has major circulating plasma metabolite(s) which also have been shown in nonclinical studies to exhibit similar CYP inhibition potential. The results of this study will evaluate the potential of tivantinib to influence the pharmacokinetics of CYP3A4/CYP2C19/CYP2C9/CYP1A and/or P-gp substrates, and help to provide the guidance to clinicians on co-administration of tivantinib with drugs metabolized by CYP3A4/CYP2C19/CYP2C9/ CYP1A and/or transported by P-gp.

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • San Antonio, Texas, United States, 78229
      • START - South Texas Accelerated Research Therapeutics, LLC

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. Have a histologically or cytologically confirmed advanced solid tumor at screening;
2. Male or female ≥ 18 years of age;
3. Subjects (male and female) of childbearing potential 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. In addition, all female subjects of childbearing potential must have a negative pregnancy test result before initiating study treatment;
4. An Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2;

5. Adequate bone marrow, liver, clotting, and renal function, defined as:

   Platelet count ≥ 100 x 10^9/L, Hemoglobin (Hb) ≥ 9.0 g/dL, ANC ≥ 1.5 × 109/L, Total bilirubin ≤ 1.5 x the upper limit of normal (ULN), Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN (≤ 5 x ULN for subjects with liver metastases), International normalized ratio ≤ 1.5, Serum creatinine ≤ 1.5 x ULN;

6. Able to provide written informed consent, comply with protocol visits and procedures, be able to take oral medication, and not have any active infection or chronic co-morbidity that would interfere with therapy; and
7. Subjects must be fully informed about their illness and the investigational nature of the study protocol (including foreseeable risks and possible side effects) and must sign and date an IRB approved ICF (including HIPAA authorization, if applicable) before performance of any study specific procedures or tests.

Exclusion Criteria:

1. History of cardiac disease:

   • Active coronary artery disease, defined as myocardial infarction (MI), unstable angina, coronary artery bypass graft, or stenting within 6 months prior to study entry (an MI that occurred > 6 months prior to study entry is permitted);
   • Evidence of uncontrolled symptomatic bradycardia or other cardiac arrhythmia defined as ≥ Grade 2 according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4, or uncontrolled hypertension;
2. Active, clinically serious infection(s) defined as ≥ Grade 2 according to NCI CTCAE, version 4;
3. Family or personal history of coagulopathy;
4. History of hypersensitivity or adverse reactions to omeprazole, digoxin, warfarin, caffeine, midazolam, or vitamin K;
5. 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 first dose of study drug;
6. Pregnant or breastfeeding;
7. Any major surgical procedure within 3 weeks prior to first dose of study drug;
8. Significant gastrointestinal disorder(s), in the opinion of the Investigator (eg, Crohn's disease, ulcerative colitis, extensive gastric resection);
9. 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 analogs for neuroendocrine tumors are permitted;
10. Received any other investigational drug within 3 weeks prior to dosing;
11. Received tivantinib as prior therapy;
12. Substance abuse or medical, psychological, or social conditions that may, in the opinion of the Investigator, interfere with the subject's participation in the clinical study or evaluation of the clinical study results;
13. Any condition that is unstable or that could jeopardize the safety of the subject and the subject's protocol compliance, including known human immunodeficiency virus, hepatitis B virus, or hepatitis C virus infection;
14. Inability to swallow oral medications that could interfere with the absorption of tivantinib;
15. Administration or possibility of initiating or continuing any treatment with any known Cytochrome P450 (CYP)3A4, CYP2C19, CYP1A2, CYP2C9, and P-glycoprotein enzyme-altering drugs (inducer or inhibitor) or non-drug agents or systemic gastric pH modifiers (ie, ranitidine, proton pump inhibitors etc) within the 14 days prior to dosing and/or during the primary objective phase after initiation of the study treatment; or
16. Clinical diagnosis of hepatic impairment from chronic liver cirrhosis with confirmation by either previous liver biopsy or imaging, regardless of liver function test results at screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: Test drug administration; All drugs except vitamin K will be administered as a single dose once by itself as a reference treatment and once with tivantinib

Drug: tivantinib; three oral 120 mg tablets administered twice a day; Other Names: ARQ 197; Drug: omeprazole; One 40 mg oral capsule once alone and once again with tivantinib; Drug: s-warfarin; One 10 mg oral tablet once alone and once again with tivantinib; Drug: caffeine; One 200 mg oral tablet once alone and once again with tivantinib; Dietary supplement: vitamin K; One oral 5 mg tablet on multiple days when and around warfarin administration; Drug: digoxin; One oral 0.25 mg tablet once alone and once again with tivantinib; Drug: midazolam; Intravenous 1.5 mg dose once alone and once again with tivantinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under the plasma concentration versus time curve (AUC) for S-Warfarin, Caffeine, Midazolam and Digoxin	Parameters of S-warfarin/caffeine/midazolam and digoxin (area under the concentration-time curve from time 0 to the last quantifiable concentration [AUC last] and area under the curve from time of dosing extrapolated to infinity [AUC 0-inf]) when warfarin/caffeine/midazolam and digoxin are administered alone or in combination with tivantinib	Pharmacokinetic sampling will be done on days 1, 4, 6, 10, 11, 14, 16 (designated as days -5, -2, 1, 5, 6, 9, 11 in the study protocol)
Area under the plasma concentration versus time curve (AUC) for Omeprazole	The ratios of omeprazole exposures vs. 5-hydroxyomeprazole exposures in terms of AUC last and AUC 0-inf when omeprazole is administered alone or in combination with tivantinib.	Pharmacokinetic sampling will be done on days 1, 4, 6, 10, 11, 14, 16 (designated as days -5, -2, 1, 5, 6, 9, 11 in the study protocol)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum observed concentration in plasma [Cmax] - Omeprazole, S-warfarin, Caffeine, Midazolam, Digoxin and the metabolite 5-hydroxyomeprazole	Maximum observed concentration in plasma [Cmax] when omeprazole, warfarin, caffeine, midazolam and digoxin are administered alone or in combination with tivantinib.	Pharmacokinetic sampling will be done on days 1, 4, 6, 10, 11, 14, 16 (designated as days -5, -2, 1, 5, 6, 9, 11 in the study protocol)
Time to Maximum Plasma Concentration (Tmax) - Omeprazole, S-warfarin, Caffeine, Midazolam, Digoxin and the metabolite 5-hydroxyomeprazole	Maximum observed concentration in plasma [Tmax] when omeprazole, warfarin, caffeine, midazolam and digoxin are administered alone or in combination with tivantinib.	Pharmacokinetic sampling will be done on days 1, 4, 6, 10, 11, 14, 16 (designated as days -5, -2, 1, 5, 6, 9, 11 in the study protocol)
Apparent oral clearance [CL/F] - Omeprazole, S-warfarin, Caffeine, Midazolam, Digoxin and the metabolite 5-hydroxyomeprazole	Apparent oral clearance [CL/F] when omeprazole, warfarin, caffeine, midazolam and digoxin are administered alone or in combination with tivantinib.	Pharmacokinetic sampling will be done on days 1, 4, 6, 10, 11, 14, 16 (designated as days -5, -2, 1, 5, 6, 9, 11 in the study protocol)
Apparent volume of distribution [V/F] - Omeprazole, S-warfarin, Caffeine, Midazolam, Digoxin and the metabolite 5-hydroxyomeprazole	Apparent volume of distribution [V/F] when omeprazole, warfarin, caffeine, midazolam and digoxin are administered alone or in combination with tivantinib.	Pharmacokinetic sampling will be done on days 1, 4, 6, 10, 11, 14, 16 (designated as days -5, -2, 1, 5, 6, 9, 11 in the study protocol)
Maximum observed concentration in plasma [Cmax] for Tivantinib and its major metabolites, HPM4, HPM5, HPM6, and HPM8		Pharmacokinetic sampling will be done on Days 6, 10, and 16 (designated as days 1, 5, and 11 in the study protocol)
Time to Maximum Plasma Concentration (Tmax) for Tivantinib and its major metabolites, HPM4, HPM5, HPM6, and HPM8		Pharmacokinetic sampling will be done on Days 6, 10, and 16 (designated as days 1, 5, and 11 in the study protocol)
Apparent oral clearance [CL/F] for Tivantinib and its major metabolites, HPM4, HPM5, HPM6, and HPM8		Pharmacokinetic sampling will be done on Days 6, 10, and 16 (designated as days 1, 5, and 11 in the study protocol)
Apparent volume of distribution [V/F] for Tivantinib and its major metabolites, HPM4, HPM5, HPM6, and HPM8		Pharmacokinetic sampling will be done on Days 6, 10, and 16 (designated as days 1, 5, and 11 in the study protocol)

Collaborators and Investigators

• Sponsor: Daiichi Sankyo, Inc.
• Collaborators: Medpace, Inc.

Study record dates

Study Major Dates

• Study Start: December 1, 2011
• Primary Completion (Actual): August 1, 2013
• Study Completion (Actual): September 1, 2013

Study Registration Dates

• First Submitted: January 4, 2012
• First Submitted That Met QC Criteria: January 20, 2012
• First Posted (Estimate): January 25, 2012

Study Record Updates

• Last Update Posted (Actual): February 12, 2019
• Last Update Submitted That Met QC Criteria: February 8, 2019
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Keywords: pharmacokinetics; Oncology; PK interaction in advanced solid tumors with our drug and other drugs
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Central Nervous System Depressants; Enzyme Inhibitors; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Fibrin Modulating Agents; Purinergic Antagonists; Purinergic Agents; Gastrointestinal Agents; Protective Agents; Cardiotonic Agents; Micronutrients; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Vitamins; Anticoagulants; Antifibrinolytic Agents; Hemostatics; Coagulants; Anti-Ulcer Agents; Proton Pump Inhibitors; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Central Nervous System Stimulants; Digoxin; Midazolam; Vitamin K; Warfarin; Caffeine; Omeprazole
• Other Study ID Numbers: ARQ197-A-U158

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