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

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.