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

Neoplasms Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01853046
• Other study ID #: 16653
• Status: Completed
• Phase: Phase 1
• First received: May 10, 2013
• Last updated: August 7, 2015
• Start date: June 2013
• Est. completion date: July 2015

Study information

• Verified date: August 2015
• Source: Bayer
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Health CanadaUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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)

Recruitment information / eligibility

• Status: Completed
• Enrollment: 24
• Est. completion date: July 2015
• Est. primary completion date: July 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Neoplasms
• Renal Insufficiency

Intervention

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)

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Bayer

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	based on non-compartmental PK evaluation	Days 1-5: Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 24, 48 and 96 hours post-dose	No
Primary	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		Days 1-2: 0-24 hours	No
Secondary	Tumor response assessment for measurable lesions according to RECIST, v1.1 (Response Evaluation Criteria in Solid Tumors)		Up to 6 months	No
Secondary	Assessment of bone metastases by scintigraphy (bone scan)		Up to 6 months	No
Secondary	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	based on non-compartmental PK evaluation	Days 1-5: Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 24, 48 and 96 hours post-dose	No
Secondary	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	based on non-compartmental PK evaluation	Days 1-5: Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 24, 48 and 96 hours post-dose	No
Secondary	Cmax (maximum drug concentration in plasma after first dose administration) for regorafenib and its pharmacologically active metabolites M-2 and M-5	based on non-compartmental PK evaluation	Days 1-5: Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 24, 48 and 96 hours post-dose	No
Secondary	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	based on non-compartmental PK evaluation	Days 1-5: Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 24, 48 and 96 hours post-dose	No
Secondary	tlast (time of last data point >LLOQ) after single dose for regorafenib and its pharmacologically active metabolites M-2 and M-5	based on non-compartmental PK evaluation	Days 1-5: Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 24, 48 and 96 hours post-dose	No
Secondary	t1/2 (half-life associated with the terminal slope) after single dose for regorafenib and its pharmacologically active metabolites M-2 and M-5	based on non-compartmental PK evaluation	Days 1-5: Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 24, 48 and 96 hours post-dose	No
Secondary	CL/F (total body clearance of drug after extravascular administration) after single dose for regorafenib and its pharmacologically active metabolites M-2 and M-5	based on non-compartmental PK evaluation	Days 1-5: Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 24, 48 and 96 hours post-dose	No
Secondary	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	based on non-compartmental PK evaluation	Days 1-5: Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 24, 48 and 96 hours post-dose	No
Secondary	AUC(0-24)md ((AUC(0-24) after multiple-dose administration) for regorafenib and its pharmacologically active metabolites M-2 and M-5	based on non-compartmental PK evaluation	Days 21-25: Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 24 hours post-dose	No
Secondary	Cmax,md (Cmax after multiple-dose administration) for regorafenib and its pharmacologically active metabolites M-2 and M-5	based on non-compartmental PK evaluation	Days 21-25: Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 24 hours post-dose	No
Secondary	AUC(0-tlast)md (AUC(0-tlast) after multiple-dose administration) for regorafenib and its pharmacologically active metabolites M-2 and M-5	based on non-compartmental PK evaluation	Days 21-25: Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 24 hours post-dose	No
Secondary	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	based on non-compartmental PK evaluation	Days 21-25: Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 24 hours post-dose	No
Secondary	tlast,md (tlast after multiple-dose administration) for regorafenib and its pharmacologically active metabolites M-2 and M-5	based on non-compartmental PK evaluation	Days 21-25: Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 24 hours post-dose	No
Secondary	AUC(0-24)md ((AUC(0-24) after multiple-dose administration) for regorafenib and its pharmacologically active metabolites M-2 and M-5	based on population PK model	Days 21-25: Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 24 hours post-dose	No
Secondary	AUC(0-tlast)md ((AUC (0-tlast) after multiple-dose administration) for regorafenib and its pharmacologically active metabolites M-2 and M-5	based on population PK model evaluation and on the nominal dosing schedule	Days 21-25: Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 24 hours post-dose	No
Secondary	RACmax (Accumulation ratio calculated from Cmax,md and Cmax) for regorafenib and its pharmacologically active metabolites M-2 and M-5	based on non-compartmental PK evaluation	Up to 21 days	No
Secondary	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	based on non-compartmental PK evaluation	Up to 21 days	No
Secondary	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	based on non-compartmental PK evaluation	Up to 21 days	No
Secondary	AE,ur(0-24)md (AE,ur(0-24) after multiple-dose administration) for metabolites M-7 and M-8	based on non-compartmental PK evaluation	Days 21-22: 0-24 hours	No
Secondary	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	based on non-compartmental PK evaluation	Days 1-2: 0-10 hours	No
Secondary	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	based on non-compartmental PK evaluation	Days 1-2: 10-24 hours	No
Secondary	AE,ur(0-10) Stage 2 for metabolites M-7 and M-8	based on non-compartmental PK evaluation	Days 21-22: 0-10 hours	No
Secondary	AE,ur(10-24) Stage 2 for metabolites M-7 and M-8	based on non-compartmental PK evaluation	Days 21-22: 10-24 hours	No

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