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Pharmacokinetic Study of Alpelisib in Subjects With Hepatic Impairment.

Primary Purpose

Hepatic Impairment

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Alpelisib
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Hepatic Impairment focused on measuring Hepatic impairment, Healthy volunteers, Clinical pharmacology study, BYL719, alpelisib

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

-Other then hepatic impairment, subjects should be in good health as determined by past medical history, physical examination, vital signs, electrocardiogram (except for additional inclusion criteria for hepatic impaired subjects). -Subjects must weigh at least 50 kg and no more than 120 kg and have a body mass index in the range 18.0-36.0 kg/m2.

Additional criteria for hepatic impaired subjects: -Subjects must have a score clinically determined and calculated as per the Child-Pugh classification and consistent with the degree of hepatic impairment in which study is currently enrolling. -Stable Child-Pugh status within 28 days prior to dosing.

Exclusion Criteria: All subjects:

  • Subject has received a liver transplant at any time in the past and is on immunosuppressant therapy.
  • Smokers not willing to limit the use of tobacco to 10 cigarettes per day. -Surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, or which may jeopardize the subject's safety in case of participation in the study. -Use of any herbal medications/supplements.

History of acute pancreatitis within 1 year of study entry.

Additional criteria for subjects with normal liver function:

-Use of any prescription or non-prescription medication. -Positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result.

Additional criteria for hepatic impaired subjects: -Use of any prescription or non-prescription medication, that has the potential to interact with alpelisb. Concomitant medications without potential to interact with alpelisib must be stable in dose. -Encephalopathy grade 3 or worse. -Total bilirubin > 6 mg/dl. Screening or baseline ECG: QTcF>480msec for both genders

Other protocol-defined inclusion/exclusion criteria may apply.

Sites / Locations

  • DaVita Clinical Research-Denver
  • University of Miami / Clinical Research Services, Inc.
  • Orlando Clinical Research Center
  • DaVita Clinical Research

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Moderate hepatic impairment group

Severe hepatic impairment group

Matching healthy control group

Arm Description

Subjects with moderate hepatic impairment with Child-Pugh score 7 - 9

Subjects with severe hepatic impairment with Child-Pugh score 10 - 15

Subjects with apparent normal liver function matched to the hepatic impairment subjects by sex, race, age, and weight.

Outcomes

Primary Outcome Measures

Plasma pharmacokinetic (PK) parameter Cmax
Measurement of effect of hepatic impairment on PK of alpelisib by assessment of the maximum plasma concentration (PK parameter Cmax). Cmax directly determined from the plasma concentration-time profile.
PK parameter AUClast
Measurement of effect of hepatic impairment on PK of alpelisib by assessment of the PK parameter AUClast (area under the concentration-time curve from time zero to the last measurable concentration sampling time). AUC determined from the plasma concentration-time profile using non-compartmental analysis.
PK parameter AUCinf
Measurement of effect of hepatic impairment on PK of alpelisib by assessment of the PK parameter AUCinf (area under the concentration-time curve from time zero to infinity ). AUC determined from the plasma concentration-time profile using non-compartmental analysis.

Secondary Outcome Measures

PK parameter AUC0-t
Measurement of effect of hepatic impairment on PK of alpelisib by assessment of the PK parameter AUC0-t (the partial area under the concentration-time curve from time zero to t hours post dose). AUC determined from the plasma concentration-time profile using non-compartmental analysis.
PK parameter tmax
Measurement of effect of hepatic impairment on PK of alpelisib by assessment of the PK parameter tmax (time to reach maximum plasma concentration), directly determined from the plasma concentration-time profile.
PK parameter Cl/F
Measurement of effect of hepatic impairment on PK of alpelisib by assessment of the PK parameter Cl/F (apparent oral total drug total plasma clearance calculated from steady-state exposure data ). Cl/F determined from the plasma concentration-time profile using non-compartmental analysis.
PK parameter Vz/F
Measurement of effect of hepatic impairment on PK of alpelisib by assessment of the PK parameter Vz/F (the apparent volume of distribution during terminal phase). Vz/F determined from the plasma concentration-time profile using non-compartmental analysis.
PK parameter T1/2
Measurement of effect of hepatic impairment on PK of alpelisib by assessment of the PK parameter T1/2 (elimination half-life associated with the terminal slope (lambda-z) of a semi logarithmic concentration-time curve). T1/2 determined from the plasma concentration-time profile using non-compartmental analysis.
Relationship between PK parameters Cmax, AUClast, AUCinf and hepatic function parameters
Determination of the relationship between the primary PK parameters Cmax, AUClast, AUCinf and baseline hepatic function parameters total bilirubin, INR and serum albumin.
Adverse events severity and frequency
Assessment of safety and tolerability of a single dose alpelisib in hepatic impaired subjects compared with healthy matching control subjects by assessing the frequency and severity of adverse events based on the CTCAE criteria.
Change from baseline in laboratory parameters
Assessment of safety and tolerability of a single dose alpelisib in hepatic impaired subjects compared with healthy matching control subjects by assessing the change from baseline in hematological and biochemical laboratory parameters.
Change from baseline in ECG parameters
Assessment of safety and tolerability of a single dose alpelisib in hepatic impaired subjects compared with healthy matching control subjects by assessing the change from baseline in ECG parameters.

Full Information

First Posted
December 3, 2015
Last Updated
December 6, 2020
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT02624557
Brief Title
Pharmacokinetic Study of Alpelisib in Subjects With Hepatic Impairment.
Official Title
A Phase 1, Open-label, Single-dose, Multicenter, Parallel Group Study to Assess the Pharmacokinetics and Safety of Alpelisib (BYL719) in Subjects With Hepatic Impairment Compared to Matched Healthy Control Subjects.
Study Type
Interventional

2. Study Status

Record Verification Date
May 2018
Overall Recruitment Status
Completed
Study Start Date
December 21, 2015 (Actual)
Primary Completion Date
October 1, 2017 (Actual)
Study Completion Date
October 1, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
To characterize the pharmacokinetics and safety of alpelisib in subjects with hepatic impairment compared to matched healthy control subjects.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatic Impairment
Keywords
Hepatic impairment, Healthy volunteers, Clinical pharmacology study, BYL719, alpelisib

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
23 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Moderate hepatic impairment group
Arm Type
Experimental
Arm Description
Subjects with moderate hepatic impairment with Child-Pugh score 7 - 9
Arm Title
Severe hepatic impairment group
Arm Type
Experimental
Arm Description
Subjects with severe hepatic impairment with Child-Pugh score 10 - 15
Arm Title
Matching healthy control group
Arm Type
Experimental
Arm Description
Subjects with apparent normal liver function matched to the hepatic impairment subjects by sex, race, age, and weight.
Intervention Type
Drug
Intervention Name(s)
Alpelisib
Intervention Description
Subjects will receive a single dose of 300 mg alpelisib.
Primary Outcome Measure Information:
Title
Plasma pharmacokinetic (PK) parameter Cmax
Description
Measurement of effect of hepatic impairment on PK of alpelisib by assessment of the maximum plasma concentration (PK parameter Cmax). Cmax directly determined from the plasma concentration-time profile.
Time Frame
predose, 30 min, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 144 hours post-dose
Title
PK parameter AUClast
Description
Measurement of effect of hepatic impairment on PK of alpelisib by assessment of the PK parameter AUClast (area under the concentration-time curve from time zero to the last measurable concentration sampling time). AUC determined from the plasma concentration-time profile using non-compartmental analysis.
Time Frame
predose, 30 min, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 144 hours post-dose
Title
PK parameter AUCinf
Description
Measurement of effect of hepatic impairment on PK of alpelisib by assessment of the PK parameter AUCinf (area under the concentration-time curve from time zero to infinity ). AUC determined from the plasma concentration-time profile using non-compartmental analysis.
Time Frame
predose, 30 min, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 144 hours post-dose
Secondary Outcome Measure Information:
Title
PK parameter AUC0-t
Description
Measurement of effect of hepatic impairment on PK of alpelisib by assessment of the PK parameter AUC0-t (the partial area under the concentration-time curve from time zero to t hours post dose). AUC determined from the plasma concentration-time profile using non-compartmental analysis.
Time Frame
predose, 30 min, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 144 hours post-dose
Title
PK parameter tmax
Description
Measurement of effect of hepatic impairment on PK of alpelisib by assessment of the PK parameter tmax (time to reach maximum plasma concentration), directly determined from the plasma concentration-time profile.
Time Frame
predose, 30 min, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 144 hours post-dose
Title
PK parameter Cl/F
Description
Measurement of effect of hepatic impairment on PK of alpelisib by assessment of the PK parameter Cl/F (apparent oral total drug total plasma clearance calculated from steady-state exposure data ). Cl/F determined from the plasma concentration-time profile using non-compartmental analysis.
Time Frame
predose, 30 min, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 144 hours post-dose
Title
PK parameter Vz/F
Description
Measurement of effect of hepatic impairment on PK of alpelisib by assessment of the PK parameter Vz/F (the apparent volume of distribution during terminal phase). Vz/F determined from the plasma concentration-time profile using non-compartmental analysis.
Time Frame
predose, 30 min, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 144 hours post-dose
Title
PK parameter T1/2
Description
Measurement of effect of hepatic impairment on PK of alpelisib by assessment of the PK parameter T1/2 (elimination half-life associated with the terminal slope (lambda-z) of a semi logarithmic concentration-time curve). T1/2 determined from the plasma concentration-time profile using non-compartmental analysis.
Time Frame
predose, 30 min, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 144 hours post-dose
Title
Relationship between PK parameters Cmax, AUClast, AUCinf and hepatic function parameters
Description
Determination of the relationship between the primary PK parameters Cmax, AUClast, AUCinf and baseline hepatic function parameters total bilirubin, INR and serum albumin.
Time Frame
predose, 30 min, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 144 hours post-dose
Title
Adverse events severity and frequency
Description
Assessment of safety and tolerability of a single dose alpelisib in hepatic impaired subjects compared with healthy matching control subjects by assessing the frequency and severity of adverse events based on the CTCAE criteria.
Time Frame
Baseline Day 1 to 30 days post-dose
Title
Change from baseline in laboratory parameters
Description
Assessment of safety and tolerability of a single dose alpelisib in hepatic impaired subjects compared with healthy matching control subjects by assessing the change from baseline in hematological and biochemical laboratory parameters.
Time Frame
Baseline Day 1 to 30 days post-dose
Title
Change from baseline in ECG parameters
Description
Assessment of safety and tolerability of a single dose alpelisib in hepatic impaired subjects compared with healthy matching control subjects by assessing the change from baseline in ECG parameters.
Time Frame
Baseline Day 1 to 30 days post-dose

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: -Other then hepatic impairment, subjects should be in good health as determined by past medical history, physical examination, vital signs, electrocardiogram (except for additional inclusion criteria for hepatic impaired subjects). -Subjects must weigh at least 50 kg and no more than 120 kg and have a body mass index in the range 18.0-36.0 kg/m2. Additional criteria for hepatic impaired subjects: -Subjects must have a score clinically determined and calculated as per the Child-Pugh classification and consistent with the degree of hepatic impairment in which study is currently enrolling. -Stable Child-Pugh status within 28 days prior to dosing. Exclusion Criteria: All subjects: Subject has received a liver transplant at any time in the past and is on immunosuppressant therapy. Smokers not willing to limit the use of tobacco to 10 cigarettes per day. -Surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, or which may jeopardize the subject's safety in case of participation in the study. -Use of any herbal medications/supplements. History of acute pancreatitis within 1 year of study entry. Additional criteria for subjects with normal liver function: -Use of any prescription or non-prescription medication. -Positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result. Additional criteria for hepatic impaired subjects: -Use of any prescription or non-prescription medication, that has the potential to interact with alpelisb. Concomitant medications without potential to interact with alpelisib must be stable in dose. -Encephalopathy grade 3 or worse. -Total bilirubin > 6 mg/dl. Screening or baseline ECG: QTcF>480msec for both genders Other protocol-defined inclusion/exclusion criteria may apply.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
DaVita Clinical Research-Denver
City
Lakewood
State/Province
Colorado
ZIP/Postal Code
80228
Country
United States
Facility Name
University of Miami / Clinical Research Services, Inc.
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
Orlando Clinical Research Center
City
Orlando
State/Province
Florida
ZIP/Postal Code
32809
Country
United States
Facility Name
DaVita Clinical Research
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55404
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Links:
URL
https://www.novctrd.com/ctrdweb/trialresult/trialresults/pdf?trialResultId=17198
Description
Results for CBYL719A2105 can be found on the Novartis Clinical Trial Results Website

Learn more about this trial

Pharmacokinetic Study of Alpelisib in Subjects With Hepatic Impairment.

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