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

This study is currently recruiting participants.
Verified December 2012 by Daiichi Sankyo Inc.
Sponsor:
Collaborator:
Medpace, Inc.
Information provided by (Responsible Party):
Daiichi Sankyo Inc.
ClinicalTrials.gov Identifier:
NCT01517399
First received: January 4, 2012
Last updated: December 10, 2012
Last verified: December 2012
History of Changes
  Purpose

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.


Condition Intervention Phase
Solid Tumors
 Drug: tivantinib
Drug: omeprazole
Drug: s-warfarin
Drug: caffeine
Dietary Supplement: vitamin K
Drug: digoxin
Drug: midazolam
 Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics Study
Intervention Model: Crossover Assignment
Masking: Open Label
Official Title: 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

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by Daiichi Sankyo Inc.:

Primary Outcome Measures:
  • Area under the plasma concentration versus time curve (AUC) for S-Warfarin, Caffeine, Midazolam and Digoxin [ Time Frame: 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) ] [ Designated as safety issue: No ]
    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

  • Area under the plasma concentration versus time curve (AUC) for Omeprazole [ Time Frame: 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) ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Maximum observed concentration in plasma [Cmax] - Omeprazole, S-warfarin, Caffeine, Midazolam, Digoxin and the metabolite 5-hydroxyomeprazole [ Time Frame: 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) ] [ Designated as safety issue: No ]
    Maximum observed concentration in plasma [Cmax] when omeprazole, warfarin, caffeine, midazolam and digoxin are administered alone or in combination with tivantinib.

  • Time to Maximum Plasma Concentration (Tmax) - Omeprazole, S-warfarin, Caffeine, Midazolam, Digoxin and the metabolite 5-hydroxyomeprazole [ Time Frame: 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) ] [ Designated as safety issue: No ]
    Maximum observed concentration in plasma [Tmax] when omeprazole, warfarin, caffeine, midazolam and digoxin are administered alone or in combination with tivantinib.

  • Apparent oral clearance [CL/F] - Omeprazole, S-warfarin, Caffeine, Midazolam, Digoxin and the metabolite 5-hydroxyomeprazole [ Time Frame: 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) ] [ Designated as safety issue: No ]
    Apparent oral clearance [CL/F] when omeprazole, warfarin, caffeine, midazolam and digoxin are administered alone or in combination with tivantinib.

  • Apparent volume of distribution [V/F] - Omeprazole, S-warfarin, Caffeine, Midazolam, Digoxin and the metabolite 5-hydroxyomeprazole [ Time Frame: 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) ] [ Designated as safety issue: No ]
    Apparent volume of distribution [V/F] when omeprazole, warfarin, caffeine, midazolam and digoxin are administered alone or in combination with tivantinib.

  • Maximum observed concentration in plasma [Cmax] for Tivantinib and its major metabolites, HPM4, HPM5, HPM6, and HPM8 [ Time Frame: Pharmacokinetic sampling will be done on Days 6, 10, and 16 (designated as days 1, 5, and 11 in the study protocol) ] [ Designated as safety issue: No ]
  • Time to Maximum Plasma Concentration (Tmax) for Tivantinib and its major metabolites, HPM4, HPM5, HPM6, and HPM8 [ Time Frame: Pharmacokinetic sampling will be done on Days 6, 10, and 16 (designated as days 1, 5, and 11 in the study protocol) ] [ Designated as safety issue: No ]
  • Apparent oral clearance [CL/F] for Tivantinib and its major metabolites, HPM4, HPM5, HPM6, and HPM8 [ Time Frame: Pharmacokinetic sampling will be done on Days 6, 10, and 16 (designated as days 1, 5, and 11 in the study protocol) ] [ Designated as safety issue: No ]
  • Apparent volume of distribution [V/F] for Tivantinib and its major metabolites, HPM4, HPM5, HPM6, and HPM8 [ Time Frame: Pharmacokinetic sampling will be done on Days 6, 10, and 16 (designated as days 1, 5, and 11 in the study protocol) ] [ Designated as safety issue: No ]

Estimated Enrollment: 30
Study Start Date: December 2011
Estimated Study Completion Date: May 2013
Estimated Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01517399

Contacts
Contact: Jennifer Cutter, Ph. D. 1-513-579-9911 ext 2526 j.cutter@medpace.com
Contact: Brandy Hampton 1-513-579-9911 ext 2186 b.hampton@medpace.com

Locations
United States, Texas
START - South Texas Accelerated Research Therapeutics, LLC Recruiting
San Antonio, Texas, United States, 78229
Contact: Isabel Jimenez     210-593-5265     Isabel.Jimenez@start.stoh.com    
Principal Investigator: Kyriakos Papadopoulos, MD            
Sponsors and Collaborators
Daiichi Sankyo Inc.
Medpace, Inc.
Investigators
Study Director: Hamim Zahir, BPharm, PhD Daiichi-Sankyo Pharma Development
  More Information

No publications provided

Responsible Party: Daiichi Sankyo Inc.
ClinicalTrials.gov Identifier: NCT01517399     History of Changes
Other Study ID Numbers: ARQ197-A-U158
Study First Received: January 4, 2012
Last Updated: December 10, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Daiichi Sankyo Inc.:
Oncology
pharmacokinetics
PK interaction in advanced solid tumors with our drug and other drugs

Additional relevant MeSH terms:
Caffeine
Midazolam
Digoxin
Omeprazole
Vitamin K
Vitamins
Warfarin
Central Nervous System Stimulants
Physiological Effects of Drugs
Pharmacologic Actions
Central Nervous System Agents
Therapeutic Uses
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
 Purinergic P1 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents
Cardiotonic Agents
Cardiovascular Agents
Anti-Arrhythmia Agents
Protective Agents
Adjuvants, Anesthesia
Anti-Anxiety Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Hypnotics and Sedatives
Anesthetics, Intravenous

ClinicalTrials.gov processed this record on May 19, 2013