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

NCT01517399 | Completed Phase 1

• 1 other identifier: ARQ197-A-U158
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Solid Tumors

Keywords

Oncology; pharmacokinetics; PK interaction in advanced solid tumors with our drug and other drugs

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (8)

• Maximum observed concentration in plasma [Cmax] - Omeprazole, S-warfarin, Caffeine, Midazolam, Digoxin and the metabolite 5-hydroxyomeprazole

  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

  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

  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

  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)

Study Arms (1)

Test drug administration

OTHER

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; Drug: omeprazole; Drug: s-warfarin; Drug: caffeine; Dietary Supplement: vitamin K; Drug: digoxin; Drug: midazolam

Interventions

tivantinib DRUG

three oral 120 mg tablets administered twice a day

Also known as: ARQ 197

Test drug administration

omeprazole DRUG

One 40 mg oral capsule once alone and once again with tivantinib

Test drug administration

s-warfarin DRUG

One 10 mg oral tablet once alone and once again with tivantinib

Test drug administration

caffeine DRUG

One 200 mg oral tablet once alone and once again with tivantinib

Test drug administration

vitamin K DIETARY_SUPPLEMENT

One oral 5 mg tablet on multiple days when and around warfarin administration

Test drug administration

digoxin DRUG

One oral 0.25 mg tablet once alone and once again with tivantinib

Test drug administration

midazolam DRUG

Intravenous 1.5 mg dose once alone and once again with tivantinib

Test drug administration

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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;

Sponsors & Collaborators

• Daiichi Sankyo: lead
• Medpace, Inc.: collaborator

Study Sites (1)

START - South Texas Accelerated Research Therapeutics, LLC

San Antonio, Texas, 78229, United States

Location

MeSH Terms

Conditions

Neoplasms

Interventions

ARQ 197; Omeprazole; Warfarin; Caffeine; Vitamin K; Digoxin; Midazolam

Intervention Hierarchy (Ancestors)

2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Sulfur Compounds; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; 4-Hydroxycoumarins; Coumarins; Benzopyrans; Pyrans; Xanthines; Alkaloids; Purinones; Purines; Naphthoquinones; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Phytol; Diterpenes; Terpenes; Polycyclic Compounds; Digitalis Glycosides; Cardenolides; Cardiac Glycosides; Cardanolides; Steroids; Fused-Ring Compounds; Glycosides; Carbohydrates; Benzodiazepines; Benzazepines

Study Officials

• Hamim Zahir, BPharm, PhD

  Daiichi Sankyo UK Ltd.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 4, 2012
• First Posted: January 25, 2012
• Study Start: December 1, 2011
• Primary Completion: August 1, 2013
• Study Completion: September 1, 2013
• Last Updated: February 12, 2019

Record last verified: 2018-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• 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.
• 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.

Locations

US (1)