BAY73-4506 Probe Substrate Study

Sponsor

Bayer (Industry)

Overall Status

Completed

CT.gov ID

NCT01287598

Collaborator

(none)

Enrollment

Locations

Arms

83.9

Actual Duration (Months)

10.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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

Study Design

Study Type:

Interventional

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 :

Aug 2, 2011

Actual Primary Completion Date :

Jul 3, 2018

Actual Study Completion Date :

Jul 30, 2018

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Pharmacokinetics of probe substrates (AUC, Cmax, etc.) [Approximately 6 weeks]

Secondary Outcome Measures

Tumor Response evaluation measured by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) [Up to 3 years or longer if indicated]
Adverse event collection [Up to 3 years or longer if indicated]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cross Cancer Institute	Edmonton	Alberta	Canada	T6G 1Z2
2	British Columbia Cancer Agency-Vancouver Centre	Vancouver	British Columbia	Canada	V5Z 4E6
3	Juravinski Cancer Centre	Hamilton	Ontario	Canada	L8V 5C2
4	Sir Mortimer B. Davis Jewish General Hospital	Montreal	Quebec	Canada	H3T 1E2