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

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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:
Information provided by (Responsible Party):
Bayer

Tracking Information
First Submitted Date  ICMJE May 10, 2013
First Posted Date  ICMJE May 14, 2013
Results First Submitted Date  ICMJE July 12, 2016
Results First Posted Date  ICMJE February 20, 2017
Last Update Posted Date February 20, 2017
Study Start Date  ICMJE June 2013
Actual Primary Completion Date July 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 23, 2016)
  • 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.
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: May 10, 2013)
  • AUC(0-tlast) [area under the concentration-time curve after single 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
  • AUC(0-24)md [Area under the concentration-time curve after multiple dose from time zero to 24 hours 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 population PK model evaluation
  • 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: 0-10 and 10-24 hours ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 23, 2016)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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
  • 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.
  • 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).
  • 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.
  • 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
  • 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
  • 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
  • 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
  • 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
Original Secondary Outcome Measures  ICMJE
 (submitted: May 10, 2013)
  • Tumor response assessment for measurable lesions according to RECIST, v1.1 (Response Evaluation Criteria in Solid Tumors) [ Time Frame: Up to 6 months ]
  • Assessment of bone metastases by scintigraphy (bone scan) [ Time Frame: Up to 6 months ]
  • 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(0-24) (AUC from time zero to 24 hours p.a. after 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 (maximum drug concentration in plasma after 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
  • 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
  • tlast (time of last data point >LLOQ) 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 (half-life associated with the terminal slope) 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
  • CL/F (total body clearance of drug after extravascular 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
  • Vz/F (apparent volume of distribution during terminal phase after single 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
  • 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
  • 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 population PK model evaluation
  • 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, and 24 hours post-dose ]
    based on non-compartmental PK evaluation
  • 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, and 24 hours post-dose ]
    based on non-compartmental PK evaluation
  • 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, and 24 hours post-dose ]
    based on population PK model evaluation and on actual individual dosing schedule
  • 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, and 24 hours post-dose ]
    based on population PK model evaluation and on the nominal dosing schedule
  • 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, and 24 hours post-dose ]
    based on non-compartmental PK evaluation
  • 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, and 24 hours post-dose ]
    based on non-compartmental PK evaluation
Current Other Pre-specified Outcome Measures
 (submitted: December 23, 2016)
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.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Pharmacokinetics and Safety of Regorafenib (BAY73-4506) in Cancer Subjects With Severe Renal Impairment
Official Title  ICMJE 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
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)
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Neoplasms
Intervention  ICMJE 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)
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Regorafenib (Stivarga, BAY73-4506)
  • 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.
    Intervention: Drug: Regorafenib (Stivarga, BAY73-4506)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 10, 2013)
24
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE November 2015
Actual Primary Completion Date July 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01853046
Other Study ID Numbers  ICMJE 16653
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Bayer
Study Sponsor  ICMJE Bayer
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Bayer Study Director Bayer
PRS Account Bayer
Verification Date December 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP