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

Study Overview
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Brief Summary
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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

Official Title
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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

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: Digoxin
* Drug: Rosuvastatin
* Drug: Regorafenib (Stivarga, BAY73-4506)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer, Probe substrates, Pharmacokinetics, Safety, Regorafenib, Advanced solid malignant tumors