BAY73-4506 Probe Substrate Study

This study is ongoing, but not recruiting participants.
Information provided by (Responsible Party):
Bayer Identifier:
First received: January 31, 2011
Last updated: September 30, 2014
Last verified: September 2014

In vitro studies have shown that regorafenib may have a clinically relevant inhibitory effect on substrates of CYP2C19, CYP3A4, CYP2C9 and CYP2C8. This CYP probe substrate study will be performed to evaluate the effect of regorafenib on the pharmacokinetics (PK) of CYP substrates and provide information about potential changes in exposure of these substrates when administered with regorafenib.

Condition Intervention Phase
Drug: Regorafenib (Stivarga, BAY73-4506) + warfarin + omeprazole + midazolam
Drug: Regorafenib (Stivarga, BAY73-4506) + rosiglitazone
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I, Non-randomized Open-label Study to Evaluate the Effect of BAY73-4506 (Regorafenib) on Probe Substrates of CYP 2C9 (Warfarin), 2C19 (Omeprazole) and 3A4 (Midazolam) in a Cocktail Approach (Group A) and on a Probe Substrate of CYP 2C8 (Rosiglitazone, Group B) in Patients With Advanced Solid Tumors

Resource links provided by NLM:

Further study details as provided by Bayer:

Primary Outcome Measures:
  • Pharmacokinetics of probe substrates (AUC, Cmax, etc.) [ Time Frame: Approximately 6 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Tumor Response evaluation measured by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) [ Time Frame: Up to 3 years or longer if indicated ] [ Designated as safety issue: Yes ]
  • Adverse event collection [ Time Frame: Up to 3 years or longer if indicated ] [ Designated as safety issue: Yes ]

Enrollment: 40
Study Start Date: August 2011
Estimated Study Completion Date: April 2015
Estimated Primary Completion Date: April 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm 1 Drug: Regorafenib (Stivarga, BAY73-4506) + warfarin + omeprazole + midazolam
BAY73-4506 administered orally twice a day (bid) in a 21-day on / 7-day off schedule Group A: CYP 2C9 (warfarin), 2C19 (omeprazole) and 3A4 (midazolam) at Cycle 1
Experimental: Arm 2 Drug: Regorafenib (Stivarga, BAY73-4506) + rosiglitazone
BAY73-4506 administered orally twice a day (bid) in a 21-day on / 7-day off schedule Group B: CYP2C8 (rosiglitazone) at Cycle 1


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

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01287598

Canada, Alberta
Edmonton, Alberta, Canada, T6G 1Z2
Canada, British Columbia
Vancouver, British Columbia, Canada, V5Z 4E6
Canada, Ontario
Hamilton, Ontario, Canada, L8V 5C2
Canada, Quebec
Montreal, Quebec, Canada, H3T 1E2
Sponsors and Collaborators
Study Director: Bayer Study Director Bayer
  More Information

Additional Information:
No publications provided

Responsible Party: Bayer Identifier: NCT01287598     History of Changes
Other Study ID Numbers: 12434
Study First Received: January 31, 2011
Last Updated: September 30, 2014
Health Authority: Canada: Health Canada
United States: Food and Drug Administration

Keywords provided by Bayer:
Phase I
Probe substrate
target therapy
small molecule

Additional relevant MeSH terms:
Adjuvants, Anesthesia
Anesthetics, General
Anesthetics, Intravenous
Anti-Anxiety Agents
Anti-Ulcer Agents
Central Nervous System Agents
Central Nervous System Depressants
Enzyme Inhibitors
GABA Agents
GABA Modulators
Gastrointestinal Agents
Hematologic Agents
Hypnotics and Sedatives
Hypoglycemic Agents
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Pharmacologic Actions
Physiological Effects of Drugs
Proton Pump Inhibitors
Psychotropic Drugs
Therapeutic Uses
Tranquilizing Agents processed this record on October 20, 2014