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

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

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

Study Overview

• Status: Completed
• Conditions: Neoplasms
• Intervention / Treatment: Drug: Digoxin; Drug: Regorafenib (Stivarga, BAY73-4506); Drug: Rosuvastatin

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Baden-Württemberg
    • Freiburg, Baden-Württemberg, Germany, 79106
  • Hessen
    • Frankfurt, Hessen, Germany, 60488
  • Nordrhein-Westfalen
    • Herne, Nordrhein-Westfalen, Germany, 44625
• Hungary
  • Budapest, Hungary, 1122
  • Budapest, Hungary, 1083

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / 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: Regorafenib (Stivarga, BAY73-4506); Once daily orally 160 mg (4 tablets 40 mg); Drug: Rosuvastatin; Single dose of rosuvastatin 5mg (1 tablet 5 mg) without and with regorafenib 160 mg q.d. (4 tablets 40 mg)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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

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

Collaborators and Investigators

• Sponsor: Bayer

Publications and helpful links

Helpful Links

• Click here to find results for studies related to Bayer products.

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 22, 2014
• Primary Completion (ACTUAL): April 27, 2015
• Study Completion (ACTUAL): June 12, 2018

Study Registration Dates

• First Submitted: April 4, 2014
• First Submitted That Met QC Criteria: April 7, 2014
• First Posted (ESTIMATE): April 8, 2014

Study Record Updates

• Last Update Posted (ACTUAL): June 7, 2019
• Last Update Submitted That Met QC Criteria: June 5, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Keywords: Safety; Cancer; Pharmacokinetics; Regorafenib; Probe substrates; Advanced solid malignant tumors
• Additional Relevant MeSH Terms: Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Enzyme Inhibitors; Antimetabolites; Protective Agents; Cardiotonic Agents; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Digoxin; Rosuvastatin Calcium
• Other Study ID Numbers: 16674; 2013-003613-18 (EUDRACT_NUMBER)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No