Pharmacokinetic Study of BKM120 in Subjects With Hepatic Impairment

A Phase I, Multicenter, Open-label, Single-dose, Parallel Group Study to Assess the Pharmacokinetics of BKM120 in Subjects With Mild, Moderate and Severe Hepatic Impairmen

To assess pharamcokinetics, safety and tolerability of a single oral dose of BKM120 in subjects with mild, moderate and severe hepatic impairment

Study Overview

• Status: Completed
• Conditions: Hepatic Impairment
• Intervention / Treatment: Drug: BKM120

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 1

Contacts and Locations

Study Locations

• Bulgaria
  • Sofia, Bulgaria, 1618
    • Novartis Investigative Site
• Germany
  • Berlin, Germany, 14050
    • Novartis Investigative Site
• Russian Federation
  • Moscow, Russian Federation, 117198
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subjects should be in good health (except for additional/ specific inclusion criteria related to hepatic impaired subjects) as determined by past medical history, physical examination, vital signs, electrocardiogram, and laboratory tests of no significance at screening
• Subjects must weigh at least 45 kg to participate in this study, and must have a body mass index (BMI) from (18.5-35.0 kg/m2)

• Subjects must be able to communicate well with the investigator, to understand the requirements of the study and agree to use strict contraception for 16 weeks after the last BKM120 dose

  ---Additional inclusion criteria Group 1 - control healthy subjects

• Subjects should be matched to the hepatic impaired subjects of group 2 in gender, age (± 10 years), weight (± 20%), and BMI (±5%)

  ---Additional inclusion criteria Group 2 - hepatic impaired subjects

• Subjects with physical signs consistent with stable hepatic impairment
• Child-Pugh Clinical Assessment Score consistent with degree of hepatic impairment (mild , moderate or severe)
• Subjects must be free of significant medical disorders unrelated to the subject's hepatic disorder as judged by the investigator.
• Absolute neutrophil count (ANC) ≥ 1.5 x 109 /L
• Platelet count ≥ 50 x 109 /L
• serum creatinine ≤ 1.5 x ULN

Exclusion Criteria:

• Significant illness, including infections, or hospitalization within the 2 weeks prior to dosing, except for the hepatic impaired subjects who due to their liver disease may be affected by significant medical problems which require frequent hospitalizations. Invasive systemic fungal infections need to be fully resolved prior to study entry
• Use of tobacco products within 2 weeks prior to dosing or during the study.
• Consumption of alcohol within 2 days prior to dosing or during the study
• Subjects with known ongoing alcohol and or/drug abuse within 1 month prior to dosing, or evidence of such abuse as indicated by the laboratory assays conducted during screening and/or at baseline
• Subjects not willing to avoid certain study prohibited food, drink, over the counter medicines and supplements
• Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, or which may jeopardize the subject in case of participation in the study.
• Medical history of cardiac disease and/or clinically significant ECG abnormalities.
• History of clinically significant hematologic, renal, endocrinologic, pulmonary cardiovascular, hepatic, or allergic disease medically documented
• Medical history of relevant psychiatric disorders
• Subjects with Diabetes Mellitus or subjects with glucose levels out of normal range as judge by the investigator

• History of immunodeficiency diseases, including Human Immunodeficiency Virus (HIV), as confirmed by (HIV-1, HIV-2) test

  • Additional exclusion criteria Group 1 (matched healthy control subjects) History or presence of liver disease or liver injury as indicated by an abnormal liver function profile A positive Hepatitis C test or a positive Hepatitis B surface antigen (HBsAg)
  • Additional exclusion criteria Group 2- hepatic impaired subjects
• Subjects with clinically significant abnormal findings, not consistent with clinical disease, upon physical examination, ECG or laboratory evaluation
• Any evidence of progressive liver disease (within the last 4 weeks prior to the screening visit) as indicated by liver transaminases, alkaline phosphatase and GGT or a ≥ 50% worsening of serum bilirubin or prothrombin time
• Total bilirubin > 6mg/dl
• Subject has ascites requiring intervention

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Mild Hepatic Impaired Group; Subjects can only be enroled into this group if they fit the Child -Pugh score criteria of severity category - mildly hepatically impaired	Drug: BKM120
Experimental: Moderate Hepatic Impaired group; Subjects can only be enroled into this group if they fit the Child -Pugh score criteria of severity category - moderately hepatically impaired	Drug: BKM120
Experimental: Severe Hepatic Impaired Group; Subjects can only be enroled into this group if they fit the Child -Pugh score criteria of severity category - Severely hepatically impaired	Drug: BKM120
Experimental: Control Group; Matching healthy control subjects who do not have hepatic impairment and are matched to the hepatic impaired subjects by sex, age, gender and BMI	Drug: BKM120

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma concentration of pharmacokinctis (PK) parameter Tmax	Measurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter TMax (time to maximum concentration)	predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose
Plasma concentration of PK parameter Cmax	Measurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter CMax (maximum concentration)	predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose
Plasma concentration of PK parameter AUC-t	Measurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter AUC-t (Area under the curve at specified timepoint) The specific key measure(s) or observation(s) that will be used to determine the effect of the intervention(s). Example: Change in left ventricular end systolic volume (LVESD) as measured by echocardiography Time to tumor progression Overall tumor response	predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose
Plasma concentration of PK parameter AUC-last	Measurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter AUC-last (Area under the curve at last timepoint) The specific key measure(s) or observation(s) that will be used to determine the effect of the intervention(s). Example: Change in left ventricular end systolic volume (LVESD) as measured by echocardiography Time to tumor progression Overall tumor response	predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose
Plasma concentration of PK parameter AUC-inf	Measurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter AUC-inf (Area under the curve to time infinity)	predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose
Plasma concentration of PK parameter CL/F	infMeasurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter CL/F (clearance)	predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose
Plasma concentration of PK parameter Vz/F	FMeasurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter Vz/F (Volume distribution)	predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose
Plasma concentration of PK parameter terminal T 1/2	Measurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter terminal T 1/2 (terminal half-life)	predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events severity	Severtiy of adverse events severity based on the CTCAE criteria to assess safety and tolerability of a single dose of BKM120	From baseline day-1 to 30 days post dose
Change from baseline in laboratory parameters	Change from baseline in hematological and biochemical laboratory parameters	From baseline day-1 to 30 days post dose
Change from baseline in ECG parameters	Change from baseline in ECG parameters	From baseline day-1 to 30 days post dose
Change from baseline between PK parameters and total bilirubin, prothrombin time or INR and serum albumin	Relationship between PK parameters and baseline hepatic function parameters	From baseline day-1 to 15 days post dose
measurement of plasma binding	Determination of the free fraction of BKM120 in plasmaexpressed weher relevant in terms of unbound drug concentration	From baseline day-1 to 15 days post dose
Adverse events frequency	Frequency of adverse events severity based on the CTCAE criteria to assess safety and tolerability of a single dose of BKM120	From baseline day-1 to 30 days post dose

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• Results for CBKM120C2104 can be found on the Novartis Clinical Trial Results Website

Study record dates

Study Major Dates

• Study Start: October 1, 2011
• Primary Completion (Actual): August 1, 2013
• Study Completion (Actual): August 1, 2013

Study Registration Dates

• First Submitted: November 12, 2012
• First Submitted That Met QC Criteria: November 12, 2012
• First Posted (Estimate): November 15, 2012

Study Record Updates

• Last Update Posted (Actual): December 9, 2020
• Last Update Submitted That Met QC Criteria: December 6, 2020
• Last Verified: April 1, 2014

More Information

Terms related to this study

• Keywords: Clinical pharmacology study; Hepatic impairment; Volunteer study
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases
• Other Study ID Numbers: CBKM120C2104; 2011-002311-28 (EudraCT Number)