Clinical trial NCT02050815: MEK162 in Healthy Subjects With Normal Hepatic Function and Subjects With Impaired Hepatic Function
Official title: A Phase I, Multicenter, Open-label, Single-dose Study to Assess the Pharmacokinetics of MEK162 in Subjects With Mild, Moderate and Severe Hepatic Impairment
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Hepatic Impairment
Keywords: MEK162
Hepatic impairment
Healthy subjects
Lead sponsor: Array BioPharma
Sponsor class: INDUSTRY
First posted: 2014-01-31
Enrollment: 27
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study is a phase I, multi-center, open-label, single oral dose, parallel group study to assess the PK and safety of MEK162 in subjects with impaired hepatic function and healthy subjects with normal hepatic function. Subjects will be assigned by hepatic function defined by elevation of serum total bilirubin and serum AST as determined at the screening and baseline visits. The study population will be healthy male and postmenopausal or sterile female subjects who meet all of the inclusion and none of the exclusion criteria. A minimum of 24 evaluable subjects (6 subjects per group) will be enrolled. The groups are: Group 1-healthy volunteers, Group 2-Mild hepatic impairment, Group 3-Moderate hepatic impairment and Group 4-Severe hepatic impairment. Once approved for enrollment, participants will be confined to the facility for 5 days, given a single dose of MEK162 and monitored for safety assessments, labs and PK will be assessed.


Eligibility criteria: Inclusion Criteria:

* Written informed consent prior to any screening procedures
* Male or female (postmenopausal or sterilized)
* Subject body weight at least 45 kg and a body mass index (BMI) in the range of 18 to 35.0 kg/m2
* Subjects with normal hepatic function must have total bilirubin ≤ upper limit of normal (≤ ULN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT) and alkaline phosphatase (AP) ≤ ULN, serum creatinine ≤ ULN, serum amylase and lipase ≤ ULN

Additional inclusion criteria for subjects with abnormal liver function determined by elevation of serum total bilirubin are:

* Absolute neutrophil count (ANC) \> 1000 cell/mm3
* Hb \> 9 mg/dl,
* Platelet count \> 30,000/mm3
* Serum creatinine ≤ 1.8 mg/dl
* Otherwise considered healthy and free of significant medical disorders unrelated to the subject's hepatic disorder

Exclusion Criteria:

* Women of child-bearing potential
* Pregnant or nursing (lactating) women
* Subjects with impaired cardiovascular function or clinically significant cardiovascular diseases
* Uncontrolled arterial hypertension despite medical treatment
* History or current evidence of retinal vein occlusion (RVO) or current risk factors of RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes),
* History of Gilbert's syndrome
* Immuno-compromised subjects (including known history/seropositivity of HIV)
* Any surgical or medical condition (other than hepatic impairment) or receiving any pharmacological treatment which might significantly alter the absorption or metabolism of drugs or which may jeopardize the subject in case of participation in the study
* Antecedent of malignancy with the following exceptions: adequately treated basal cell or squamous cell carcinoma of the skin
* Subjects who have neuromuscular disorders that are associated with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
* Subjects who have undergone major surgery ≤ 3 weeks prior to starting study drug or who have not recovered from side effects of such procedure
* History of clinically significant drug allergy
* Prior therapy with a MEK-inhibitor
* Use of an investigational drug within 30 days of screening
* Current smoker or has used tobacco products or products containing nicotine within 7 days prior to dosing of study drug
* Consumption of alcohol within 3 days prior to dosing or during the study

Additional exclusion criteria for subjects with normal hepatic function:

- Clinical evidence of liver disease or liver injury as indicated by abnormal liver function tests such as ALT, AST, GGT, alkaline phosphatase, or serum bilirubin. ALT and AST beyond the normal range before inclusion Presence of impaired renal function as indicated by abnormal creatinine (creatinine clearance \< 80 mL/min) values and/or serum creatinine ≥1.8 mg/dL- A positive Hepatitis B or Hepatitis C test result

Additional exclusion criteria for subjects with elevation of serum bilirubin \> UNL:

* Symptoms or history of encephalopathy (Grade II or worse) within 4 weeks of study entry
* Clinical evidence of severe ascites requiring intervention
* International normalized ratio (INR) \>2.5
* Any evidence of progressive liver disease within the last 3 weeks prior to the screening visit) as indicated by worsening of clinical manifestations (i.e.: ascites, encephalopathy) and/or laboratories abnormalities (liver transaminases, alkaline phosphatase and GGT or a ≥ 50% worsening of serum bilirubin or prothrombin time)
* History of surgical portosystemic shunt with complications (i.e. hepatic encephalopathy, heart failure)
* Active bleeding during the last 28 days prior to dosing including variceal bleeding

Primary outcomes:
measure: PK parameters assessed by Tmax
timeFrame: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120
measure: PK parameters assessed by Cmax
timeFrame: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120
measure: PK parameters assessed by AUCinf
timeFrame: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120
measure: PK parameters assessed by AUC0last
timeFrame: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120
Secondary outcomes:
measure: Relationship between PK parameters versus hepatic function laboratory parameters
timeFrame: Screening, Baseline, Day 2, Day 6 (Day of discharge)
measure: Number of subjects with adverse events as a measure of safety and tolerability
timeFrame: Screening, Baseline, Day 2, Day 6 (Day of discharge)
Other outcomes:
Locations:
city: Lakewood
country: United States
facility: DaVita Clinical Research-Denver
state: Colorado
city: Miami
country: United States
facility: Clinical Pharmacology of Miami (CPMI)
state: Florida
city: Orlando
country: United States
facility: Orlando Clinical Research Center
state: Florida
city: Minneapolis
country: United States
facility: DaVita Clinical Research
state: Minnesota
city: Kansas City
country: United States
facility: Kansas City Research Institute, LLC
state: Missouri
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References: