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BAY73-4506 Probe Substrate Study

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01287598
Recruitment Status : Completed
First Posted : February 1, 2011
Last Update Posted : July 10, 2019
Information provided by (Responsible Party):

Brief Summary:
  • To evaluate the effect of BAY73-4506 on the pharmacokinetics of probe substrates of CYP 2C9 (warfarin), 2C19 (omeprazole) and 3A4 (midazolam) administered in a cocktail approach and on the pharmacokinetics of a probe substrate of CYP 2C8 (rosiglitazone)
  • To evaluate safety, anti-tumor activity, pharmacokinetics, and pharmacodynamics of BAY73-4506 in patients with advanced solid tumors

Condition or disease Intervention/treatment Phase
Neoplasms Drug: Regorafenib (Stivarga, BAY73-4506) Drug: Warfarin Drug: Omeprazole Drug: Midazolam Drug: Rosiglitazone Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 41 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (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
Actual Study Start Date : August 2, 2011
Actual Primary Completion Date : July 3, 2018
Actual Study Completion Date : July 30, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Blood Thinners

Arm Intervention/treatment
Experimental: Arm 1
Regorafenib (Stivarga, BAY73-4506) + warfarin + omeprazole + midazolam
Drug: Regorafenib (Stivarga, BAY73-4506)
BAY73-4506 administered once a daily (od) in a 21-day on / 7-day off schedule

Drug: Warfarin
CYP 2C9 (warfarin) at Cycle 1

Drug: Omeprazole
CYP 2C19 (omeprazole) at Cycle 1

Drug: Midazolam
CYP 3A4 (midazolam) at Cycle 1

Experimental: Arm 2
Regorafenib (Stivarga, BAY73-4506) + rosiglitazone
Drug: Regorafenib (Stivarga, BAY73-4506)
BAY73-4506 administered once a daily (od) in a 21-day on / 7-day off schedule

Drug: Rosiglitazone
CYP2C8 (rosiglitazone) at Cycle 1

Primary Outcome Measures :
  1. Pharmacokinetics of probe substrates (AUC, Cmax, etc.) [ Time Frame: Approximately 6 weeks ]

Secondary Outcome Measures :
  1. Tumor Response evaluation measured by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) [ Time Frame: Up to 3 years or longer if indicated ]
  2. Adverse event collection [ Time Frame: Up to 3 years or longer if indicated ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Female and male subjects must be ≥ 18 years at the first screening examination / visit
  • ECOG Performance Status of ≤ 2
  • 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
    • ALT and 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
    • INR and 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.
  • Recovery from previous drug/procedure-related toxicities to CTC Grade 0 or 1 levels (except for alopecia), or to baseline preceding the prior treatment. Preexisting chemotherapy induced sensory neuropathy of CTC Grade ≤2 is not an exclusion criteria.
  • Negative serum pregnancy test must be obtained within 7 days prior to the start of treatment in women of childbearing potential. Negative results must be available prior to study treatment.
  • Subjects enrolled in this study must use adequate barrier birth control measures prior to, during the course of the study, and 3 months after the last administration of regorafenib.
  • An adequate contraception includes the use of condoms or a vasectomy, hormonal contraception with implants or combined PO contraceptives, certain intrauterine devices, bilateral tubal ligation, or hysterectomy. In addition, adequate birth control measures for the subject's partner is required, such as a hormonal contraception with implants or combined PO contraceptives, certain intrauterine devices, bilateral tubal ligation, or hysterectomy, use of condoms or a vasectomy.

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.
  • Left ventricular ejection fraction (LVEF) < 50% or below the LLN for the institution (whichever is higher).
  • Subjects with pheochromocytoma
  • Dehydration NCI-CTCAE, version 4, Grade > 1
  • 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 arterial or venous thrombotic or embolic events, such as cerebrovascular accident (including transient ischemic attack), deep vein thrombosis, or pulmonary embolism within 6 months before the start of study medication.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01287598

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Canada, Alberta
Cross Cancer Institute
Edmonton, Alberta, Canada, T6G 1Z2
Canada, British Columbia
British Columbia Cancer Agency-Vancouver Centre
Vancouver, British Columbia, Canada, V5Z 4E6
Canada, Ontario
Juravinski Cancer Centre
Hamilton, Ontario, Canada, L8V 5C2
Canada, Quebec
Sir Mortimer B. Davis Jewish General Hospital
Montreal, Quebec, Canada, H3T 1E2
Sponsors and Collaborators
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Study Director: Bayer Study Director Bayer

Additional Information:
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Responsible Party: Bayer Identifier: NCT01287598     History of Changes
Other Study ID Numbers: 12434
First Posted: February 1, 2011    Key Record Dates
Last Update Posted: July 10, 2019
Last Verified: July 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Bayer:
Phase I
Probe substrate
target therapy
small molecule
Additional relevant MeSH terms:
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Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Anti-Ulcer Agents
Gastrointestinal Agents
Proton Pump Inhibitors
Enzyme Inhibitors
Hypoglycemic Agents