Clinical trial NCT01556568: Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MEK162 in Noonan Syndrome Hypertrophic Cardiomyopathy
Official title: An Open Label Study to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MEK162 in Noonan Syndrome Hypertrophic Cardiomyopathy
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: Cardiomegaly
Keywords: Noonan Syndrome, hypertrophic cardiomyopathy.
Lead sponsor: Array BioPharma
Sponsor class: INDUSTRY
First posted: 2012-03-16
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of the study is to determine whether the ability of MEK162 to antagonize MEK activation in NS HCM patients, who usually have upstream mutations in the Ras-Raf-Mek-Erk pathway that lead to MEK activation, would be beneficial over a 6 month treatment period in hypertrophy regression.

Detailed description: This study is designed as a proof of concept of MEK162 in NS HCM patients. The purpose of the present study is to determine whether the ability of MEK162 to antagonize MEK activation in NS HCM patients, who usually have upstream mutations in the Ras-Raf-Mek-Erk pathway that lead to MEK activation, would be beneficial over a 6 month treatment period by causing hypertrophy regression. Such regression might result in cardiovascular clinical benefits with longer term treatment.

The information gained from this study will be three fold:

1. the safety/tolerability of treatment with MEK162 over 6 month in the NS HCM patient population
2. the pharmacokinetics and pharmacodynamics of MEK162 in the target patient population
3. proof of the therapeutic concept that MEK inhibition will reduce cardiac hypertrophy in the target NS HCM patient population

Eligibility criteria: Inclusion:

* Male and female Noonan syndrome patients with confirmed cardiac hypertrophy, age 18 to 65 years of age included, and in general good health as determined by past medical history, physical examination, vital signs, electrocardiogram, and laboratory tests at screening.
* Cardiac hypertrophy is defined by left ventricular wall thickness greater than or equal to 12 mm by echocardiography or MRI, or the change in wall thickness is accompanied by an associated increase in left ventricular mass which is defined by echo or MRI as greater than 134 g/m2 and 110 g/m2 in men and women, respectively.
* Subjects must weigh at least 45 kg to participate in the study, and must have a body mass index (BMI) within the range of 18 - 34 kg/m2.

Exclusion criteria:

* Primary Long QT syndrome or a history of significant ECG abnormalities judged by the investigators to be inappropriate for participation in the current study.
* History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
* Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant.
* Sexually active males must use a condom during intercourse while taking the drug during treatment, for 5 half lives after stopping treatment and should not father a child in this period.
* Use of any prescription drugs other than beta-blockers, diuretics, CCB, amiodarone, disopyramide, herbal supplements, within four (4) weeks prior to initial dosing, and/or over-the-counter (OTC) medication, dietary supplements (vitamins included) within two (2) weeks prior to initial dosing. If needed, (i.e. an incidental and limited need) paracetamol or acetaminophen is acceptable, but must be documented in the Concomitant medications/Significant non-drug therapies page of the eCRF.

Other protocol-defined inclusion/exclusion criteria may apply.

Primary outcomes:
measure: Change from baseline in Left ventricular mass (LVM)
timeFrame: Baseline to 3 months and 6 months
Secondary outcomes:
measure: Change from baseline in Cardiac energetics state at 3 months and 6 months
timeFrame: Baseline to 3 months and 6 months
measure: Number of patients with adverse events, serious adverse events and death
timeFrame: 6 months
measure: Pharmacokinetics of MEK162 and metabolite (AR00426032): The trough plasma concentration (Ctrough) just prior to drug administration
timeFrame: Days 1, 8, 15, 28, 56, 84, 140 and 182
measure: Pharmacokinetics of MEK162 and metabolite (AR00426032): maximum drug exposure of MEK162 and its metabolite (AR00426032) in plasma
timeFrame: Day 1 and Day 8
measure: Pharmacokinetics of MEK162 and metabolite (AR00426032): time to reach peak concentration (Tmax) in plasma
timeFrame: Day 1 and Day 8
measure: Pharmacokinetics of MEK162 and metabolite (AR00426032): Area under the plasma concentration-time profile from time zero to 12 hours post dose (AUC0-12h)
timeFrame: Day 1 and Day 8
measure: Pharmacokinetics of MEK162 and metabolite (AR00426032): Area under the plasma concentration-time profile from time zero to the last quantifiable sample (AUClast)
timeFrame: Day 1 and Day 8
measure: Pharmacokinetics of MEK162 and metabolite (AR00426032): accumulation ratio (Racc)
timeFrame: Day 1 and Day 8
measure: Pharmacokinetics of MEK162: The degree of fluctuation of MEK162 and its metabolite (AR00426032) in plasma at steady state (on Day 8)
timeFrame: Day 8
measure: Pharmacokinetics of MEK162: The ratio of Metabolite (AR00426032) to MEK162 in plasma on Days 1 and 8
timeFrame: Day 1 and Day 8
measure: Change from baseline in end systolic and end diastolic right and left vetricular volumes in 3 and 6 months
timeFrame: baseline to 3 and 6 months of treatment
measure: Pharmacokinetics of MEK162 and metabolite (AR00426032):observed maximum plasma concentration (Cmax) following drug adminstration
timeFrame: Day 1 and Day 8
measure: Change from baseline in stroke volume and stroke output during 3 and 6 months
timeFrame: baseline to 3 and 6 months of treatment
measure: Ejection fraction
timeFrame: baseline, 3 and 6 months of treatment
measure: Cardiac index
timeFrame: baseline, 3 and 6 months of treatment
Other outcomes:
Locations:
city: Boston
country: United States
facility: Pfizer Investigative Site
state: Massachusetts
city: London
country: United Kingdom
facility: Pfizer Investigative Site
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References: