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

• Status: Completed
• Trial end date: 2020-05-09
• Target enrollment: 0
• Participant gender: All

Summary

The purpose of this international study was to assess the effect of varying degrees of impaired hepatic function compared to a normal hepatic function (Child-Pugh classification) on the pharmacokinetics and safety of midostaurin.

• Phase: Phase 1
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: Novartis Pharmaceuticals
• Treatments: 4'-N-benzoylstaurosporine; Midostaurin; Staurosporine

Criteria

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)