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

Study Overview
=================
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.

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.

Conditions
-----------------
Hepatic Impairment

Intervention / Treatment
-----------------
* Drug: Midostaurin
* Drug: Midostaurin


Participation Criteria
=================
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)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Normal hepatic function - group 1<br>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<br>* 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).<br>* Other names: PKC412;|
| Experimental: Mild hepatic impairment - group 2<br>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<br>* 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).<br>* Other names: PKC412;|
| Experimental: Moderate hepatic impairment - group 3<br>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<br>* 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).<br>* Other names: PKC412;|
| Experimental: Severe hepatic impairment - group 4<br>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<br>* 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) on Day 1 only.<br>* Other names: PKC412;|
| Experimental: Normal hepatic function - group 5<br>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<br>* 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) on Day 1 only.<br>* Other names: PKC412;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment emergent adverse events (AEs) | Safety and tolerability of midostaurin measured by the number of treatment emergent adverse events in subjects with hepatic impairment (and matching healthy volunteers) | During the study and until 28 days follow-up period | 
| CYP3A4 induction by midostaurin in the hepatic impaired population | CYP3A4 induction will be measured by assessing endogenous biomarkers (6beta-hydroxycortisol to cortisol ratio) applicable to multiple dosing Child Pugh A and Child Pugh B subjects and matching healthy volunteers) | At different timepoints from Day 3 to Day 11 | 
| Protein binding (free fraction) of midostaurin and it's metabolites | Free fraction of midostaurin and it's metabolites, CGP62221 and CGP52421, will be assessed by measuring their unbound concentration in plasma samples 3 hours post last dose on Day 1 (group 4 and 5) and Day 7 (group 1-3). | Day 1 and Day 7 | 
| Apparent volume of distribution (Vz/F) of midostaurin | In subjects with Child Pugh A and Child Pugh B (and matching healthy volunteers), volume of distribution will be measured on Day 7. In subjects with Child Pugh C (and healthy volunteers), volume of distribution will be measured at Day 1. | Day 1 and Day 7 | 
| Total body apparent clearance of drug (CL/F) of midostaurin | In subjects with Child Pugh A and Child Pugh B (and matching healthy volunteers), total body clearance will be measured on Day 7. In subjects with Child Pugh C (and healthy volunteers), total body clearance will be measured at Day 1. | Day 1 and Day 7 | 
| Elimination half life (t½) of midostaurin and its metabolites, CGP52421 and CGP62221 | In subjects with Child Pugh A and Child Pugh B (and matching healthy volunteers), elimination half life will be measured on Day 7. In subjects with Child Pugh C (and healthy volunteers), elimination half life will be measured at Day 1. | Day 1 and Day 7 | 
| Time to maximum plasma concentration (tmax) for midostaurin and its metabolites, CGP52421 and CGP62221 | In subjects with Child Pugh A and Child Pugh B (and matching healthy volunteers), tmax will be measured at Day 1 and Day 7. In subjects with Child Pugh C (and healthy volunteers), tmax will be measured at Day 1. | Day 1 and Day 7 | 
| Area under the plasma concentration versus time curves (AUCs) for midostaurin and its metabolites, CGP52421 and CGP62221 | In subjects with Child Pugh A and Child Pugh B (and matching healthy volunteers), AUC will be measured at Day 1 and Day 7. In subjects with Child Pugh C (and healthy volunteers), AUC will be measured at Day 1. | Day 1 and Day 7 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Pharmacokinetics, Hepatic impaired patients, Healthy volunteers, Varying degrees of hepatic impairment