PK and Safety of Midostaurin in Subjects With Impaired Hepatic Function and Subjects With Normal Hepatic Function

This is an interventional basic science trial for Hepatic Impairment focused on measuring Pharmacokinetics, Hepatic impaired patients, Healthy volunteers, Varying degrees of hepatic impairment Read More

Key Inclusion Criteria:

• Adult male or female subjects age 18-70 years
• Negative serum beta-hCG pregnancy test for all women prior to starting treatment
• Normal vital signs, body weight, BMI and laboratory test results
• Willing to comply with dietary, fluid and lifestyle restrictions
• Able to communicate well with the Investigator and comply with the requirements of the study.

Additional Inclusion Criteria for hepatic impaired subjects

• Physical signs consistent with hepatic impairment
• CPC score consistent with degree of hepatic impairment
• Serum creatinine <=2xULN
• ANC >1000cells/mm3, hemaglobin >9g/dL, platelet count > 50,000/mm3 (group 2-3 only)

Key Exclusion Criteria:

• Significant neurologic or psychiatric disorder which could compromise participation in the study.
• History of: seizures requiring anti-convulsant therapy; unstable COPD; GI or rectal bleeding 3 weeks prior to study start; Myocardial Infarction within 12 months; unstable or poorly controlled angina or other clinically significant heart disease; clinically significant urinary obstruction or difficulty voiding; clinically significant ECG abnormalities or long QT-interval syndrome; pancreatic injury or pancreatitis
• Concurrent severe / uncontrolled medical conditions
• Significant illness within 2 weeks prior to dosing or hospitalisation within 4 weeks prior to dosing
• Any surgical or medical condition that may significantly affect absorption, distribution, metabolism or excretion of drugs
• Clinically significant ECG abnormalities at screening
• Cotinine levels greater than 500ng/mL (group 1-3) or smokers not willing to limit tobacco or nicotine products equivalent to 10 cigarettes per day (group 4 and 5) for 1 week prior to dosing and throughout hospital confinement
• Consumption of alcohol within 3 days (group 1-3) or within 2 days (groups 4 and 5) prior to dosing or during the study.
• Administration of CYP3A4/5 or P-gp inducing or inhibiting drugs within 14 days prior to dosing or during the study
• Sexually active males unless they use condom during intercourse while taking midostaurin and for at least 3 months after the last exposure to drug.
• Use of any prescription drug within 2 weeks or over the counter medication within 72 hours prior to dosing
• Consumption of grapefruit, grapefruit juice, Seville oranges, start fruit / juice within 72 hours prior to dosing

Additional exclusion criteria for healthy controls

• Clinical evidence of liver disease or liver injury
• Positive HBsAg or Hep C test result

Additional exclusion criteria for hepatic impairment subjects

• Symptoms or history of >=G3 hepatic encephalopathy; surgical portosystemic shunt
• PTT >2.5xULN; INR >3; Total bilirubin >6mg/dL
• Evidence of progressive liver disease within 4 weeks prior to starting study
• Clinical evidence of severe >=G3 ascites (groups 2 and 3)