Clinical trial NCT01429337: PK and Safety of Midostaurin in Subjects With Impaired Hepatic Function and Subjects With Normal Hepatic Function
Official title: An Open-label, Parallel Group, Phase I Study to Assess the Pharmacokinetics and Safety of Midostaurin in Subjects With Impaired Hepatic Function and Subjects With Normal Hepatic Function.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hepatic Impairment
Keywords: Pharmacokinetics
Hepatic impaired patients
Healthy volunteers
Varying degrees of hepatic impairment
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2011-09-07
Enrollment: 43
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

Detailed description: Midostaurin was developed for the treatment of patients with hematological and nonhematological malignancies. However, disease complications and various co-medications made it difficult to perform a hepatic impairment study in the targeted patient population.

Metabolism and elimination of midostaurin predominantly occurs in the liver. Patients with impaired hepatic function may have a higher risk to have a decreased elimination or metabolism of midostaurin which may lead to increased systemic exposure or toxicity, hence understanding the impact of an impaired hepatic function on midostaurin PK is important.

Cumulative safety data from over 900 subjects exposed to midostaurin showed that the drug was well tolerated in patients and in healthy subjects, thus, it was appropriate and justifiable to study midostaurin in subjects with varying degrees of hepatic impairment.

Due to the difficulty in enrolling subjects with severe hepatic impairment, an interim analysis was performed when all mild and moderate hepatic impaired subjects, and the respective control subjects, had completed the trial, in order to obtain interim results on the PK and safety of midostaurin in patients with mild and moderate hepatic impairment. The protocol was amended in April 2018 to make the inclusion / exclusion criteria more fitting with enrolling the severe hepatic impairment group. The final study analysis was performed when all severe hepatic impaired subjects, and the matching controls, had completed the study.

Eligibility 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)

Primary outcomes:
measure: Peak Plasma Concentrations (Cmax) for midostaurin and its metabolites, CGP52421 and CGP62221
timeFrame: at different timepoints from Day 1 to Day 7
Secondary outcomes:
measure: Incidence of treatment emergent adverse events (AEs)
timeFrame: During the study and until 28 days follow-up period
measure: CYP3A4 induction by midostaurin in the hepatic impaired population
timeFrame: At different timepoints from Day 3 to Day 11
measure: Protein binding (free fraction) of midostaurin and it's metabolites
timeFrame: Day 1 and Day 7
measure: Apparent volume of distribution (Vz/F) of midostaurin
timeFrame: Day 1 and Day 7
measure: Total body apparent clearance of drug (CL/F) of midostaurin
timeFrame: Day 1 and Day 7
measure: Elimination half life (t½) of midostaurin and its metabolites, CGP52421 and CGP62221
timeFrame: Day 1 and Day 7
measure: Time to maximum plasma concentration (tmax) for midostaurin and its metabolites, CGP52421 and CGP62221
timeFrame: Day 1 and Day 7
measure: Area under the plasma concentration versus time curves (AUCs) for midostaurin and its metabolites, CGP52421 and CGP62221
timeFrame: Day 1 and Day 7
Other outcomes:
Locations:
city: San Antonio
country: United States
facility: American Research Corporation Inc
state: Texas
city: Bruxelles
country: Belgium
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Frankfurt
country: Germany
facility: Novartis Investigative Site
city: Kaunas
country: Lithuania
facility: Novartis Investigative Site
state: LTU
city: Cluj
country: Romania
facility: Novartis Investigative Site
state: Napoca
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: