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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: tivantinib
* Drug: omeprazole
* Drug: s-warfarin
* Drug: caffeine
* Dietary Supplement: vitamin K
* Drug: digoxin
* Drug: midazolam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have a histologically or cytologically confirmed advanced solid tumor at screening; Male or female ≥ 18 years of age; 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; An Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2; 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; 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 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: 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; Active, clinically serious infection(s) defined as ≥ Grade 2 according to NCI CTCAE, version 4; Family or personal history of coagulopathy; History of hypersensitivity or adverse reactions to omeprazole, digoxin, warfarin, caffeine, midazolam, or vitamin K; 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; Pregnant or breastfeeding; Any major surgical procedure within 3 weeks prior to first dose of study drug; Significant gastrointestinal disorder(s), in the opinion of the Investigator (eg, Crohn's disease, ulcerative colitis, extensive gastric resection); 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; Received any other investigational drug within 3 weeks prior to dosing; Received tivantinib as prior therapy; 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; 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; Inability to swallow oral medications that could interfere with the absorption of tivantinib; 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 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.

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: Other
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Test drug administration<br>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<br>* three oral 120 mg tablets administered twice a day<br>* Other names: ARQ 197;Drug: omeprazole<br>* One 40 mg oral capsule once alone and once again with tivantinib<br>Drug: s-warfarin<br>* One 10 mg oral tablet once alone and once again with tivantinib<br>Drug: caffeine<br>* One 200 mg oral tablet once alone and once again with tivantinib<br>Dietary Supplement: vitamin K<br>* One oral 5 mg tablet on multiple days when and around warfarin administration<br>Drug: digoxin<br>* One oral 0.25 mg tablet once alone and once again with tivantinib<br>Drug: midazolam<br>* Intravenous 1.5 mg dose once alone and once again with tivantinib<br>|

What is the study measuring?
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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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Oncology, pharmacokinetics, PK interaction in advanced solid tumors with our drug and other drugs