BAY73-4506 Probe Substrate Study

Inclusion Criteria:

• Histological or cytological documentation of confirmed advanced solid tumors. Subjects should have measurable or non-measurable disease according to RECIST
• Life Expectancy of at least 3 months

• Adequate bone marrow, liver, and renal functions as assessed by the following laboratory requirements conducted within 14 days prior to the first study treatment:

  • Hemoglobin ≥ 9.0 g/dL
  • Absolute neutrophil count (ANC) ≥1,500/mm3
  • Platelet count ≥ 100,000/ mm3
  • Total bilirubin ≤ 1.5 times the upper limit of normal (ULN)
  • Alkaline phosphatase ≤ 2 times ULN
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN (≤ 5.0 x ULN for subjects with cancer involving the liver)
  • Serum creatinine ≤ 1.5 times ULN and glomerular filtration rate (GFR) ≥ 30 ml/min/1.73 m2, according to the MDRD (Modified Diet in Renal Disease) abbreviated formula
  • Lipase ≤ 1.5 ULN
  • International normalized ratio (INR) and partial thromboplastin time (PTT) ≤ 1.5 ULN
• Subjects who are therapeutically treated with warfarin, heparin or other anticoagulants are not eligible for study participation in Group A. Subjects who are therapeutically treated with warfarin, heparin or other anticoagulants, will be allowed to participate in Group B of the study provided they meet all eligibility criteria. Close monitoring of at least weekly evaluations will be performed until INR or PTT are stable by the local standard of care.

Exclusion Criteria:

• History of cardiac disease: Congestive heart failure (New York Heart Association, NYHA, Class III or IV) or active coronary artery disease (unstable angina [angina symptoms at rest] or new-onset angina [began within the last 3 months] or myocardial infarction within the past 6 months). Treatment with Type 1A or 3 anti-arrhythmics, such as Quinidine, Procainamide, Amiodarone, or Sotalol are not permitted. β-Blockers and digoxin are permitted.
• Uncontrolled hypertension (failure of diastolic blood pressure to fall to or below 90 mmHg or systolic blood pressure to fall to or below 140 mmHg with or without the use of antihypertensive drugs). At screening, subjects with history of hypertension should be on a stable anti-hypertensive treatment for at least 7 days prior to the first dose of study drug.
• Patients with known allergy to any of the study drug(s) to be administered, including known severe allergies, non-allergic drug reactions, or multiple drug allergies to any of the study drug(s) to be administered. This is also includes hypersensitivity to any of the compounds or excipients that will be administered to the study subject, specifically regorafenib, and warfarin, omeprazole and midazolam for subjects in Group A, or rosiglitazone for subjects in Group B.
• Subjects with evidence or history of disorders of coagulation
• Known history of HIV or positive screening test for HIV infection or active hepatitis B or C
• Subjects unable to swallow PO (per os) medications
• Active serious infection (> Grade 2 according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4)
• Interstitial lung disease with ongoing signs and symptoms at the time of screening
• Autologous bone marrow transplant or stem cell rescue within 4 months prior to Day 1