Pharmacokinetics and Safety of Regorafenib (BAY73-4506) in Cancer Subjects With Severe Renal Impairment

• ClinicalTrials.gov Identifier: NCT01853046
• Recruitment Status: Completed
• First Posted: May 14, 2013
• Results First Posted: February 20, 2017
• Last Update Posted: February 20, 2017
• Sponsor: Bayer
• Information provided by (Responsible Party): Bayer

Study Description

Brief Summary:

To characterize the pharmacokinetics and safety of regorafenib in cancer subjects with severe renal impairment when compared to the Control group (cancer subjects with normal or mildly impaired renal function)

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 24 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I, Multi-center, Non-randomized, Open Label, Parallel-group Study Evaluating the Pharmacokinetics and Safety of Regorafenib (BAY73-4506) in Cancer Subjects With Severe Renal Impairment Compared to a Control Group
• Study Start Date: June 2013
• Actual Primary Completion Date: July 2015
• Actual Study Completion Date: November 2015

Arms and Interventions

Arm	Intervention/treatment
Experimental: Regorafenib(Stivarga, BAY73-4506)-Normal/Mild Renal Impairment; Participants with normal/mild renal impairment received Regorafenib 160 mg o.d.as a single dose in Stage 1, Day 1 with a washout of at least 5 days, followed by multiple dosing in an intermittent administration schedule (3 week on / 1 week off) over 2 cycles in Stage 2 (56 days). Cycle 2 started immediately after Cycle 1. A Cycle for this study is defined as 28 days.	Drug: Regorafenib (Stivarga, BAY73-4506); Regorafenib 160 mg o.d. will be administered as a single dose on Day 1 of Stage 1 followed by multiple dosing in an intermittent administration schedule (3 week-on/1 week-off) over 2 cycles in Stage 2 (56 days, cycle defined as 28 days)
Experimental: Regorafenib (Stivarga, BAY73-4506)-Severe Renal Impairment; Participants with severe renal impairment received Regorafenib 160 mg o.d. as a single dose in Stage 1, Day 1 with a washout of at least 5 days, followed by multiple dosing in an intermittent administration schedule (3 week on / 1 week off) over 2 cycles in Stage 2 (56 days). Cycle 2 started immediately after Cycle 1. A Cycle for this study is defined as 28 days.	Drug: Regorafenib (Stivarga, BAY73-4506); Regorafenib 160 mg o.d. will be administered as a single dose on Day 1 of Stage 1 followed by multiple dosing in an intermittent administration schedule (3 week-on/1 week-off) over 2 cycles in Stage 2 (56 days, cycle defined as 28 days)

Outcome Measures

Primary Outcome Measures :

1. AUC(0-tlast) [Area Under the Concentration-time Curve After Single (First) Dose From Time Zero to the Last Data Point >LLOQ (Lower Limit of Quantification)] for Regorafenib and Its Pharmacologically Active Metabolites M-2 and M-5 [ Time Frame: Days 1-5: Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 24, 48 and 96 hours post-dose ]
   Based on non-compartmental PK evaluation. The AUC(0-tlast) [Area Under the Concentration-time Curve After Single (First) Dose From Time Zero to the Last Data Point >LLOQ (Lower Limit of Quantification)] is a measure of systemic drug exposure from time 0 up to the time point at which the last measurable drug could be detectable, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample.
2. AE,ur(0-24) (Amount of Drug Excreted Via Urine During the Collection Interval 0-24 Hours Post Administration) for Metabolites M-7 and M-8 [ Time Frame: Days 1-2: 0-24 hours ]
   Amount of drug excreted into urine during the collection interval 0-24 hours post dose was expressed as percentage of administered dose.

Secondary Outcome Measures :

1. AUC (Area Under the Plasma Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose) for Regorafenib and Its Pharmacologically Active Metabolites M-2 and M-5 [ Time Frame: Days 1-5: Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 24, 48 and 96 hours post-dose ]
   Based on non-compartmental PK evaluation. AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption.
2. AUC(0-24) (AUC From Time Zero to 24 Hours p.a. After Single (First) Dose Administration) for Regorafenib and Its Pharmacologically Active Metabolites M-2 and M-5 [ Time Frame: Days 1-5: Pre-dose, 0.5, 1, 2, 4, 6, 8, 10 and 24 hours post-dose ]
   Based on non-compartmental PK evaluation. The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample; AUC(0-24) is defined as AUC divided from zero to 24 hours after single (first) dose.
3. Cmax (Maximum Drug Concentration in Plasma After Single (First) Dose Administration) for Regorafenib and Its Pharmacologically Active Metabolites M-2 and M-5 [ Time Frame: Days 1-5: Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 24, 48 and 96 hours post-dose ]
   Based on non-compartmental PK evaluation.Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample.
4. Tmax (Time to Reach Maximum Drug Concentration in Plasma After Single (First) Dose) for Regorafenib and Its Pharmacologically Active Metabolites M-2 and M-5 [ Time Frame: Days 1-5: Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 24, 48 and 96 hours post-dose ]
   Based on non-compartmental PK evaluation.Tmax refers to the time after dosing when a drug attains its highest measurable concentration (Cmax). It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content.
5. Tlast (Time of Last Data Point >LLOQ) After Single (First) Dose for Regorafenib and Its Pharmacologically Active Metabolites M-2 and M-5 [ Time Frame: Days 1-5: Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 24, 48 and 96 hours post-dose ]
   based on non-compartmental PK evaluation.
6. t1/2 (Half-life Associated With the Terminal Slope) After Single (First) Dose for Regorafenib and Its Pharmacologically Active Metabolites M-2 and M-5 [ Time Frame: Days 1-5: Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 24, 48 and 96 hours post-dose ]
   Based on non-compartmental PK evaluation. t1/2 refers to the elimination of the drug. It is the time taken for the blood plasma concentration to reach half the concentration in the terminal phase of elimination. It is expressed in hours (h) and derived from the terminal slope of the concentration versus time curve.
7. CL/F (Total Body Clearance of Drug After Extravascular Administration) After Single (First) Dose for Regorafenib and Its Pharmacologically Active Metabolites M-2 and M-5 [ Time Frame: Days 1-5: Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 24, 48 and 96 hours post-dose ]
   Based on non-compartmental PK evaluation.Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
8. Vz/F (Apparent Volume of Distribution During Terminal Phase After Single (First) Oral Administration) for Regorafenib and Its Pharmacologically Active Metabolites M-2 and M-5 [ Time Frame: Days 1-5: Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 24, 48 and 96 hours post-dose ]
   Based on non-compartmental PK evaluation.Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.
9. AUC(0-24)md ((AUC(0-24) After Multiple-dose Administration) for Regorafenib and Its Pharmacologically Active Metabolites M-2 and M-5 [ Time Frame: Days 21-25: Pre-dose, 0.5, 1, 2, 4, 6, 8, 10 and 24 hours post-dose ]
   Based on non-compartmental PK evaluation.
10. Cmax,md (Cmax After Multiple-dose Administration) for Regorafenib and Its Pharmacologically Active Metabolites M-2 and M-5 [ Time Frame: Days 21-25: Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 24, 48 and 96 hours post-dose ]
    Based on non-compartmental PK evaluation.Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample.
11. AUC(0-tlast)md (AUC(0-tlast) After Multiple-dose Administration) for Regorafenib and Its Pharmacologically Active Metabolites M-2 and M-5 [ Time Frame: Days 21-25: Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 24, 48 and 96 hours post-dose ]
    based on non-compartmental PK evaluation.
12. Tmax,md (Time to Reach Maximum Drug Concentration in Plasma After Multiple-dose Administration) for Regorafenib and Its Pharmacologically Active Metabolites M-2 and M-5 [ Time Frame: Days 21-25: Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 24, 48 and 96 hours post-dose ]
    based on non-compartmental PK evaluation
13. Tlast,md (Tlast After Multiple-dose Administration) for Regorafenib and Its Pharmacologically Active Metabolites M-2 and M-5 [ Time Frame: Days 21-25: Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 24, 48 and 96 hours post-dose ]
    based on non-compartmental PK evaluation
14. RACmax (Accumulation Ratio Calculated From Cmax,md and Cmax) for Regorafenib and Its Pharmacologically Active Metabolites M-2 and M-5 [ Time Frame: Up to 25 days ]
    Based on non-compartmental PK evaluation. Accumulation ratio based on maximum plasma concentration (Cmax) was calculated as ratio of Cmax,md and Cmax.
15. RAAUC (Accumulation Ratio Calculated From AUC(0-24)md and AUC(0-24)) for Regorafenib and Its Pharmacologically Active Metabolites M-2 and M-5 [ Time Frame: Up to 25 days ]
    Based on non-compartmental PK evaluation. RAAUC calculated as ratio of AUC(0-24)md and AUC(0-24).
16. RLin (Linearity Factor Calculated as Ratio From AUC(0-24)md and AUC) for Regorafenib and Its Pharmacologically Active Metabolites M-2 and M-5 [ Time Frame: Up to 25 days ]
    Based on non-compartmental PK evaluation. RLin is the linearity factor of PK after multiple administrations of identical doses calculated as ratio of AUC(0-24)md and AUC.
17. AE,ur(0-24)md (AE,ur(0-24) After Multiple-dose Administration) for Metabolites M-7 and M-8 [ Time Frame: Days 21-22: 0-24 hours ]
    based on non-compartmental PK evaluation
18. AE,ur(0-10) Stage 1 (Amount of Drug Excreted Via Urine During the Collection Interval 0-10 Hours Post Administration) for Metabolites M-7 and M-8 [ Time Frame: Days 1-2: 0-10 hours ]
    based on non-compartmental PK evaluation
19. AE,ur(10-24) Stage 1 ((Amount of Drug Excreted Via Urine During the Collection Interval 10-24 Hours Post Administration) for Metabolites M-7 and M-8 [ Time Frame: Days 1-2: 10-24 hours ]
    based on non-compartmental PK evaluation
20. AE,ur(0-10) Stage 2 for Metabolites M-7 and M-8 [ Time Frame: Days 21-22: 0-10 hours ]
    based on non-compartmental PK evaluation
21. AE,ur(10-24) Stage 2 for Metabolites M-7 and M-8 [ Time Frame: Days 21-22: 10-24 hours ]
    based on non-compartmental PK evaluation

Other Outcome Measures:

1. Tumor Response Assessment for Measurable Lesions According to RECIST, v1.1 (Response Evaluation Criteria in Solid Tumors) [ Time Frame: Up to 6 months ]
   Positron emission tomography - computed tomography (ET-CT), CT, or magnetic resonance imaging (MRI) scans of all anatomic regions involved with the disease were performed to assess tumor response using the Response Evaluation Criteria in Solid Tumors, Version 1.1. (RECIST v1.1). Bone metastases were assessed by bone scintigraphy (bone scan). Tumor measurements and evaluation of tumor response were performed at baseline and within the last 7 days of Cycle 2. Thereafter, if subjects continued regorafenib treatment, tumor assessments were performed after every third cycle and at the end-of-treatment (EOT) visit. In addition, outcome of "Assessment of Bone Metastases by Scintigraphy if Applicable (Bone Scan)" was registered, the results of which has been reported as tumor response in this outcome as well.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Subjects with histologically confirmed, locally advanced or metastatic, refractory solid tumors who are not candidates for standard therapy
• Male or female subject ≥ 18 years of age
• Women of childbearing potential must have a negative urine pregnancy test performed within 7 days before start of study treatment
• Life expectancy at least 8 weeks
• Adequate bone marrow, and liver function as assessed by the following laboratory requirements conducted within 7 days of starting the study treatment
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 or 2

• For subjects with NORMAL OR MILDLY IMPAIRED RENAL FUNCTION (Control group); to be tested within 7 days of starting the study treatment:

  • Estimated creatinine clearance (CLcr) ≥ 60 mL/min as calculated using the Cockcroft-Gault equation

• For subjects with SEVERELY IMPAIRED renal function; to be tested within 7 days of starting the study treatment:

  • CLcr 15-29 mL/min as calculated using the Cockcroft-Gault equation

Exclusion Criteria:

• Symptomatic metastatic brain or meningeal tumors
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study medication
• History of organ allograft
• Non-healing wound, skin ulcer, or bone fracture
• Pheochromocytoma
• Uncontrolled concurrent medical illness including uncontrolled hypertension
• History of cardiac disease
• Pleural effusion or ascites that causes respiratory compromise
• Interstitial lung disease with ongoing signs and symptoms at the time of screening
• Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 months before the start of study medication
• Subjects with evidence or history of bleeding diathesis; any hemorrhage or bleeding event NCI-CTCAE Grade ≥ 3 or higher within 4 weeks of start of investigational treatment
• Dehydration NCI-CTCAEversion 4.0 Grade ≥ 1
• Unresolved toxicity higher than NCI-CTCAE version 4.0 Grade 1 attributed to any prior therapy/procedure (excluding alopecia or anemia or grade 2 neuropathy that is not reversible due to oxaliplatin)
• Seizure disorder requiring anticonvulsant therapy (such as steroids or anti-epileptics)

• For subjects with SEVERELY IMPAIRED renal function:

  • Renal failure requiring hemo- or peritoneal dialysis
  • Acute renal failure
  • Acute nephritis
  • Nephrotic syndrome

Contacts and Locations

Locations

United States, California

Los Angeles, California, United States, 90033

United States, Colorado

Aurora, Colorado, United States, 80045

United States, Missouri

St. Louis, Missouri, United States, 63110

United States, New Hampshire

Lebanon, New Hampshire, United States, 03756

United States, New York

Buffalo, New York, United States, 14263-0001

Canada, Alberta

Edmonton, Alberta, Canada, T6G 1Z2

Canada, British Columbia

Vancouver, British Columbia, Canada, V5Z 4E6

Canada, Ontario

Hamilton, Ontario, Canada, L8V 5C2

Canada, Quebec

Montreal, Quebec, Canada, H2L 4M1

Sponsors and Collaborators

Bayer

Investigators

• Study Director: Bayer Study Director; Bayer

More Information

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT01853046
• Other Study ID Numbers: 16653
• First Posted: May 14, 2013
• Results First Posted: February 20, 2017
• Last Update Posted: February 20, 2017
• Last Verified: December 2016

Keywords provided by Bayer:

Regorafenib; pharmacokinetics; safety; severe renal impairment; Solid tumors

Additional relevant MeSH terms:

Renal Insufficiency; Kidney Diseases; Urologic Diseases