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

NCT01429337 | Completed Phase 1 FDA Drug

• 2 other identifiers: CPKC412A21162010-020694-16
• Study Type: interventional
• Target: 43
• Locations: 6 countries
• Sites: 7

Brief 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.

Conditions

Hepatic Impairment

Keywords

Pharmacokinetics; Hepatic impaired patients; Healthy volunteers; Varying degrees of hepatic impairment

Outcome Measures

Primary Outcomes (1)

• Peak Plasma Concentrations (Cmax) for midostaurin and its metabolites, CGP52421 and CGP62221

  In subjects with Child Pugh A, Child Pugh B (and matching healthy volunteers) Cmax will be measured at Day 1 and Day 7. In subjects with Child Pugh C (and matching healthy volunteers) Cmax will be measured at Day 1

  at different timepoints from Day 1 to Day 7

Secondary Outcomes (8)

• Incidence of treatment emergent adverse events (AEs)

  During the study and until 28 days follow-up period

• CYP3A4 induction by midostaurin in the hepatic impaired population

  At different timepoints from Day 3 to Day 11

• Protein binding (free fraction) of midostaurin and it's metabolites

  Day 1 and Day 7

• Apparent volume of distribution (Vz/F) of midostaurin

  Day 1 and Day 7

• Total body apparent clearance of drug (CL/F) of midostaurin

  Day 1 and Day 7

Study Arms (5)

Normal hepatic function - group 1

EXPERIMENTAL

Matched control for group 2 and 3 - healthy volunteers matched with respect to age, body weight, BMI and gender to subjects in mild and moderate hepatic function groups. Subjects will be treated with midostaurin 50mg b.i.d from days 1-6 and 50mg o.d on day 7.

Drug: Midostaurin

Mild hepatic impairment - group 2

EXPERIMENTAL

Subjects with mild impaired hepatic function - Child Pugh A classification score 5-6. Subjects will be treated with midostaurin 50mg b.i.d from days 1-6 and 50mg o.d on day 7.

Drug: Midostaurin

Moderate hepatic impairment - group 3

EXPERIMENTAL

Subjects with moderate hepatic function - Child Pugh B classification score 7-9. Subjects will be treated with midostaurin 50mg b.i.d from days 1-6 and 50mg o.d on day 7.

Drug: Midostaurin

Severe hepatic impairment - group 4

EXPERIMENTAL

Subjects with severe hepatic impairment function - Child Pugh C classification score 10-15. Subjects will be treated with a single dose of midostaurin of 50mg on day 1.

Drug: Midostaurin

Normal hepatic function - group 5

EXPERIMENTAL

Matched control for group 4 - healthy volunteers matched with respect to age, body weight, BMI and gender to subjects in severe hepatic function group. Subjects will be treated with a single dose of midostaurin of 50mg on day 1.

Drug: Midostaurin

Interventions

Midostaurin DRUG

Midostaurin 25 mg soft gelatin capsules (2 capsules). The midostaurin capsules will be administered orally with 240 mL of non-carbonated water in the morning (between 8-10 AM), and in the evening (after a 12 hour break) from Day 1 to Day 6. On Day 7, midostaurin will be administered in the morning only (between 8-10 AM).

Also known as: PKC412

Mild hepatic impairment - group 2; Moderate hepatic impairment - group 3; Normal hepatic function - group 1

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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)

You may not qualify if:

• 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
• Clinical evidence of liver disease or liver injury
• Positive HBsAg or Hep C test result
• Symptoms or history of \>=G3 hepatic encephalopathy; surgical portosystemic shunt

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (7)

American Research Corporation Inc

San Antonio, Texas, 78215, United States

Location

Novartis Investigative Site

Brussels, 1200, Belgium

Location

Novartis Investigative Site

Sofia, 1618, Bulgaria

Location

Novartis Investigative Site

Berlin, 14050, Germany

Location

Novartis Investigative Site

Frankfurt, 60590, Germany

Location

Novartis Investigative Site

Kaunas, LTU, LT 50161, Lithuania

Location

Novartis Investigative Site

Cluj-Napoca, Napoca, 400006, Romania

Location

Related Links

• Novartis clinical trials results database

MeSH Terms

Interventions

midostaurin

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 12, 2011
• First Posted: September 7, 2011
• Study Start: March 7, 2011
• Primary Completion: April 13, 2020
• Study Completion: May 9, 2020
• Last Updated: May 12, 2021

Record last verified: 2021-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1); BU (1); RO (1); BE (1); DE (2); LI (1)