Pharmacokinetic Study of BKM120 in Subjects With Hepatic Impairment

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01727128
First received: November 12, 2012
Last updated: April 26, 2014
Last verified: April 2014
  Purpose

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


Condition Intervention Phase
Hepatic Impairment
Drug: BKM120
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: 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

Further study details as provided by Novartis:

Primary Outcome Measures:
  • Plasma concentration of pharmacokinctis (PK) parameter Tmax [ Time Frame: predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose ] [ Designated as safety issue: No ]
    Measurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter TMax (time to maximum concentration)

  • Plasma concentration of PK parameter Cmax [ Time Frame: predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose ] [ Designated as safety issue: No ]
    Measurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter CMax (maximum concentration)

  • Plasma concentration of PK parameter AUC-t [ Time Frame: predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose ] [ Designated as safety issue: No ]
    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

  • Plasma concentration of PK parameter AUC-last [ Time Frame: predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose ] [ Designated as safety issue: No ]
    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

  • Plasma concentration of PK parameter AUC-inf [ Time Frame: predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose ] [ Designated as safety issue: No ]
    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)

  • Plasma concentration of PK parameter CL/F [ Time Frame: predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose ] [ Designated as safety issue: No ]
    infMeasurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter CL/F (clearance)

  • Plasma concentration of PK parameter Vz/F [ Time Frame: predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose ] [ Designated as safety issue: No ]
    FMeasurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter Vz/F (Volume distribution)

  • Plasma concentration of PK parameter terminal T 1/2 [ Time Frame: predose,0.5,1,1.5,2,3,4,6,8,12,24,48,72,96,144,192,240,288,336 hours post dose ] [ Designated as safety issue: No ]
    Measurment of effect of liver impairment on PK of BKM120 by assessment of the PK parameter terminal T 1/2 (terminal half-life)


Secondary Outcome Measures:
  • Adverse events severity [ Time Frame: From baseline day-1 to 30 days post dose ] [ Designated as safety issue: Yes ]
    Severtiy of adverse events severity based on the CTCAE criteria to assess safety and tolerability of a single dose of BKM120

  • Change from baseline in laboratory parameters [ Time Frame: From baseline day-1 to 30 days post dose ] [ Designated as safety issue: Yes ]
    Change from baseline in hematological and biochemical laboratory parameters

  • Change from baseline in ECG parameters [ Time Frame: From baseline day-1 to 30 days post dose ] [ Designated as safety issue: Yes ]
    Change from baseline in ECG parameters

  • Change from baseline between PK parameters and total bilirubin, prothrombin time or INR and serum albumin [ Time Frame: From baseline day-1 to 15 days post dose ] [ Designated as safety issue: Yes ]
    Relationship between PK parameters and baseline hepatic function parameters

  • measurement of plasma binding [ Time Frame: From baseline day-1 to 15 days post dose ] [ Designated as safety issue: Yes ]
    Determination of the free fraction of BKM120 in plasmaexpressed weher relevant in terms of unbound drug concentration

  • Adverse events frequency [ Time Frame: From baseline day-1 to 30 days post dose ] [ Designated as safety issue: Yes ]
    Frequency of adverse events severity based on the CTCAE criteria to assess safety and tolerability of a single dose of BKM120


Enrollment: 31
Study Start Date: October 2011
Study Completion Date: August 2013
Primary Completion Date: August 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01727128

Locations
Bulgaria
Novartis Investigative Site
Sofia, Bulgaria, 1618
Germany
Novartis Investigative Site
Berlin, Germany, 14050
Russian Federation
Novartis Investigative Site
Moscow, Russian Federation, 117198
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01727128     History of Changes
Other Study ID Numbers: CBKM120C2104, 2011-002311-28
Study First Received: November 12, 2012
Last Updated: April 26, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Novartis:
Hepatic impairment
Clinical pharmacology study
Volunteer study

Additional relevant MeSH terms:
Liver Diseases
Digestive System Diseases

ClinicalTrials.gov processed this record on September 18, 2014