Effect of Regorafenib on Digoxin and Rosuvastatin in Patients With Advanced Solid Malignant Tumors.

Sponsor

Bayer (Industry)

Overall Status

Completed

CT.gov ID

NCT02106845

Collaborator

(none)

Enrollment

Locations

Arms

49.7

Actual Duration (Months)

8.4

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Evaluate the effect of regorafenib on the pharmacokinetics of digoxin (P-gp substrate :

P-glycoprotein) and rosuvastatin (BCRP substrate: Breast cancer resistant protein) by comparing their Area under time curve (AUC(0-24)) and maximum drug concentration (Cmax) on Day -7 and Cycle 1 or Cycle 2 Day 15 of regorafenib in cancer patients

Condition or Disease	Intervention/Treatment	Phase
Neoplasms	Drug: Digoxin Drug: Rosuvastatin Drug: Regorafenib (Stivarga, BAY73-4506)	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

42 participants

Allocation:

Non-Randomized

Intervention Model:

Crossover Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I, Multi-center, Non-randomized, Open Label, Drug-drug-interaction Study to Determine the Effect of Multiple Doses of Regorafenib (BAY 73-4506) on the Pharmacokinetics of Probe Substrates of Transport Proteins P-gp (Digoxin; Group A) and BCRP (Rosuvastatin; Group B) in Patients With Advanced Solid Malignant Tumors

Actual Study Start Date :

Apr 22, 2014

Actual Primary Completion Date :

Apr 27, 2015

Actual Study Completion Date :

Jun 12, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: P-gp probe substrate(digoxin)+regorafenib	Drug: Digoxin Single dose of digoxin 0.5 mg (2 tablets 0.25 mg) orally without and with regorafenib Drug: Regorafenib (Stivarga, BAY73-4506) Once daily orally 160 mg (4 tablets 40 mg)
Experimental: Group B: BCRP probe substrate (rosuvastatin) + regorafenib	Drug: Rosuvastatin Single dose of rosuvastatin 5mg (1 tablet 5 mg) without and with regorafenib 160 mg q.d. (4 tablets 40 mg) Drug: Regorafenib (Stivarga, BAY73-4506) Once daily orally 160 mg (4 tablets 40 mg)

Arm

Intervention/Treatment

Experimental: P-gp probe substrate(digoxin)+regorafenib

Drug: Digoxin

Single dose of digoxin 0.5 mg (2 tablets 0.25 mg) orally without and with regorafenib

Drug: Regorafenib (Stivarga, BAY73-4506)

Once daily orally 160 mg (4 tablets 40 mg)

Experimental: Group B: BCRP probe substrate (rosuvastatin) + regorafenib

Drug: Rosuvastatin

Single dose of rosuvastatin 5mg (1 tablet 5 mg) without and with regorafenib 160 mg q.d. (4 tablets 40 mg)

Drug: Regorafenib (Stivarga, BAY73-4506)

Once daily orally 160 mg (4 tablets 40 mg)

Outcome Measures

Primary Outcome Measures

Area under the plasma concentration-time curve from time zero to 24 hours (AUC(0-24)) for Digoxin [On Pre-Cycle Day -7 and on Cycle 1 Day15 or Cycle 2 Day 15]
Maximum drug concentration (Cmax) in plasma for Digoxin [On Pre-Cycle Day -7 and on Cycle 1 Day15 or Cycle 2 Day 15]
Area under the plasma concentration-time curve from time zero to 24 hours (AUC(0-24)) for rosuvastatin [On Pre-Cycle Day -7 and on Cycle 1 Day15 or Cycle 2 Day 15]
Maximum drug concentration (Cmax) in plasma for rosuvastatin [On Pre-Cycle Day -7 and on Cycle 1 Day15 or Cycle 2 Day 15]

Secondary Outcome Measures

Tumor Response following RECIST criteria [From first dose up to 3 months after end of treatment]
Number of participants with adverse events as a measure of safety and tolerability [Up to 30 days after last dose]
Number of participants with drug related adverse events as a measure of safety and tolerability [Up to 30 days after last dose]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:
The following criteria apply to ALL patients starting the study treatment:
Patients with histologically confirmed, locally advanced or metastatic solid tumors refractory to standard therapy or in whom regorafenib is considered a standard treatment.
Male or Female Caucasian patients >/= 18 years of age
Women of childbearing potential and men must agree to use adequate contraception before entering the program until at least 8 weeks after the last study drug administration.
Life expectancy of at leat 12 weeks
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
Adequate bone marrow and liver function
Estimated creatinine clearance (CLcr) ≥ 30 mL/min as calculated using the Cockroft-Gault (C-G) equation.
Thyroid Stimulating Hormone(TSH) within normal ranges.
The following inclusion criteria apply to Group A (digoxin + regorafenib) patients

ONLY:

Potassium, magnesium and calcium blood levels within normal range according to the local laboratory.
The following inclusion criteria apply to Group B (rosuvastatin + regorafenib) patients ONLY:
Signed genetic informed consent. Patients must be able to understand and willing to sign the written informed consent intended to screen for BCRP and OATP1B1 polymorphisms.
Exclusion Criteria:
For ALL patients
Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study medication.
Non-healing wound, skin ulcer, or bone fracture.
Ongoing or active infection.
Other anticancer treatment.
Patients unable to swallow oral medications
For Group A (digoxin + regorafenib):
Family history of sudden cardiac death.
For Group B (rosuvastatin + regorafenib):
Patients with porphyria.
Patients with intestinal or urinary obstructions.