Pharmacokinetics and Safety of Midostaurin in Subjects With Impaired Hepatic Function and Subjects With Normal Hepatic Function - Full Text View

Purpose

The purpose of this international study is 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.

Condition	Intervention	Phase
Hepatic Impairment	Drug: Midostaurin	Phase 1

Study Type:	Interventional
Study Design:	Allocation: Randomized Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Basic Science
Official Title:	An Open-label, Multiple Dose, 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

Further study details as provided by Novartis:

Primary Outcome Measures:

composite of pharmacokinetics (PK) of midostaurin in subjects with mild, moderate, and severely impaired hepatic function relative to healthy controls by analyzing plasma samples [ Time Frame: at different timepoints from Day 1 to Day 11 ] [ Designated as safety issue: Yes ]
The following PK parameters for midostaurin and its major metabolites will be assessed at Day 1 and Day 7: For PKC412: tmax, Cmax, AUC(0-τ), t½*, CL/F*, and Vz/F*. For CGP52421: tmax, Cmax, AUC(0-τ), and if applicable t½* For CGP62221: tmax, Cmax, AUC(0-τ), and t½*. *on Day 7 only

Secondary Outcome Measures:

the safety and tolerability of midostaurin in subjects with hepatic impairment by assessing the AEs, SAEs, including abnormalities of laboratory parameters [ Time Frame: During the study and until 28 days follow-up period ] [ Designated as safety issue: Yes ]
the relationship between pharmacokinetics and hepatic function parameters by assessing total bilirubin, prothrombin time and albumin [ Time Frame: At different timepoints from Day 1 to Day 11 ] [ Designated as safety issue: Yes ]
potential CYP3A4 induction by midostaurin in the hepatic impaired population by assessing endogenous biomarkers (6beta-hydroxycortisol to cortisol ratio) [ Time Frame: At different timepoints from Day 3 to Day 11 ] [ Designated as safety issue: Yes ]
protein binding by assessing the level of α1-acid glycoprotein (AAG) in plasma samples [ Time Frame: At baseline (day -1) for the protein binding and Day 1 + Day 7 for the free fraction ] [ Designated as safety issue: Yes ]
will also determine the free fraction of midostaurin and its metabolites CGP62221 and CGP52421 by assessing the concentration of PKC412 and its metabolites in blood samples.

Estimated Enrollment:	42
Study Start Date:	March 2011
Estimated Study Completion Date:	November 2013
Estimated Primary Completion Date:	November 2013 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Normal hepatic function group	Drug: Midostaurin Midostaurin 25 mg soft gelatin 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, midostaurine will be administered only in the morning. Other Name: PKC412
Experimental: Mild hepatic impairment group	Drug: Midostaurin Midostaurin 25 mg soft gelatin 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, midostaurine will be administered only in the morning. Other Name: PKC412
Experimental: Moderate hepatic impairment group	Drug: Midostaurin Midostaurin 25 mg soft gelatin 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, midostaurine will be administered only in the morning. Other Name: PKC412
Experimental: Severe hepatic impairment group	Drug: Midostaurin Midostaurin 25 mg soft gelatin 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, midostaurine will be administered only in the morning. Other Name: PKC412

Eligibility

Ages Eligible for Study:	18 Years to 70 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

• Subjects must be able to communicate well with the Investigator and comply with the requirements of the study.

Exclusion Criteria:

Significant neurologic or psychiatric disorder which could compromise participation in the study.
Subjects with known ongoing alcohol and/or drug abuse within 1 month prior to dosing or evidence of such abuse.
Use of tobacco or products containing nicotine within 7 days prior to dosing or during the study.
Consumption of alcohol within 3 days prior to dosing or during the study.
Women of childbearing potential unless they are using a highly effective contraception method the length of the study and for at least for at least 3 months after the last exposure to midostaurin. Highly effective methods include: Total abstinence, female sterilization or male partner sterilization. Or use a combination of (a+b): a) Placement of an intrauterine device or intrauterine system , b)barrier method of contraception
Sexually active males unless they use condom during intercourse while taking midostaurin and for at least 3 months after the last exposure to drug. A condom is required to be used also by vasectomized men.

Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01429337

Contacts

Contact: Novartis Pharmaceuticals	+41613241111	clinicaltrial.enquiries@novartis.com
Contact: Novartis Pharmaceuticals

Locations

Belgium
Novartis Investigative Site	Recruiting
Bruxelles, Belgium, 1200
Bulgaria
Novartis Investigative Site	Recruiting
Sofia, Bulgaria, 1618
Germany
Novartis Investigative Site	Recruiting
Berlin, Germany, 14050
Novartis Investigative Site	Terminated
Frankfurt, Germany, 60590
Novartis Investigative Site	Withdrawn
Mainz, Germany, D-55101
Romania
Novartis Investigative Site	Not yet recruiting
Bucharest, Bucuresti, Romania, 022328
Novartis Investigative Site	Not yet recruiting
Cluj, Napoca, Romania, 400006
South Africa
Novartis Investigative Site	Withdrawn
Bloemfontein, Free State, South Africa, 9300
Novartis Investigative Site	Withdrawn
George, South Africa, 6529
Novartis Investigative Site	Withdrawn
Port Elizabeth, South Africa, 6045

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

Study Director:

Novartis Pharmaceuticals

More Information

No publications provided

Responsible Party:	Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:	NCT01429337 History of Changes
Other Study ID Numbers:	CPKC412A2116, 2010-020694-16
Study First Received:	July 12, 2011
Last Updated:	April 15, 2013
Health Authority:	United States: Food and Drug Administration Germany: BfArM (Bundesinstitut für Arzneimittel und Medizinprodukte) Belgium: FAMPH (Federal Agency for Medicines and Health Products) Bulgaria: Bulgarian Drug Agency South Africa: MCC (Medicines Control Council)

Keywords provided by Novartis:

Pharmacokinetics
Hepatic impaired patients
Healthy volunteers
Varying degrees of hepatic impairment

Additional relevant MeSH terms:

Liver Diseases
Digestive System Diseases
4'-N-benzoylstaurosporine
Staurosporine
Antineoplastic Agents

Therapeutic Uses
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on June 18, 2013