Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MEK162 in Noonan Syndrome Hypertrophic Cardiomyopathy
- Registration Number
- NCT01556568
- Lead Sponsor
- Array Biopharma, now a wholly owned subsidiary of Pfizer
- 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
Recruitment & Eligibility
- Status
- WITHDRAWN
- Sex
- All
- Target Recruitment
- Not specified
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description MEK162 MEK162 Patients will be treated with MEK162 only and will be uptitrated or down titrated based on safety and tolerability observed.
- Primary Outcome Measures
Name Time Method Change from baseline in Left ventricular mass (LVM) Baseline to 3 months and 6 months Change in LVM after 3 months and 6 months of treatment using magnetic resonance imaging.
- Secondary Outcome Measures
Name Time Method Change from baseline in Cardiac energetics state at 3 months and 6 months Baseline to 3 months and 6 months Energetic state represented by phosphocreatine (PCr)/adenosine triphosphate (ATP) ratio using magnetic resonance spectroscopy.
Number of patients with adverse events, serious adverse events and death 6 months Abnormalities in Vital signs, ECG evaluations, clinical laboratory evaluations, will be collected.
Pharmacokinetics of MEK162 and metabolite (AR00426032): The trough plasma concentration (Ctrough) just prior to drug administration Days 1, 8, 15, 28, 56, 84, 140 and 182 pre-dose concentration of MEK162 and its metabolite (AR00426032) in plasma. All blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein.
Pharmacokinetics of MEK162 and metabolite (AR00426032): maximum drug exposure of MEK162 and its metabolite (AR00426032) in plasma Day 1 and Day 8 All blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein.
Pharmacokinetics of MEK162 and metabolite (AR00426032): time to reach peak concentration (Tmax) in plasma Day 1 and Day 8 All blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein.
Pharmacokinetics of MEK162 and metabolite (AR00426032): Area under the plasma concentration-time profile from time zero to 12 hours post dose (AUC0-12h) Day 1 and Day 8 All blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein.
Pharmacokinetics of MEK162 and metabolite (AR00426032): Area under the plasma concentration-time profile from time zero to the last quantifiable sample (AUClast) Day 1 and Day 8 All blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein.
Pharmacokinetics of MEK162 and metabolite (AR00426032):observed maximum plasma concentration (Cmax) following drug adminstration Day 1 and Day 8 All blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein.
Pharmacokinetics of MEK162 and metabolite (AR00426032): accumulation ratio (Racc) Day 1 and Day 8 Comparison of the drug exposures as AUCs and Cmax of MEK162 and its metabolite (AR00426032) in plasma after 8 days treatment in relation to the data from the first day (Day 8/Day 1)
Pharmacokinetics of MEK162: The degree of fluctuation of MEK162 and its metabolite (AR00426032) in plasma at steady state (on Day 8) Day 8 All blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein. The dgree of fluctuation is calculated as (Cmax,ss - Cmin,ss)/Cav,ss at steady state.
Pharmacokinetics of MEK162: The ratio of Metabolite (AR00426032) to MEK162 in plasma on Days 1 and 8 Day 1 and Day 8 All blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein.
Change from baseline in end systolic and end diastolic right and left vetricular volumes in 3 and 6 months baseline to 3 and 6 months of treatment These parameters are derived from cine breath-hold magnetic resonance images acquired over the cardiac cycle.
Change from baseline in stroke volume and stroke output during 3 and 6 months baseline to 3 and 6 months of treatment These parameters are derived from cine breath-hold magnetic resonance images acquired over the cardiac cycle.
Ejection fraction baseline, 3 and 6 months of treatment This parameter is derived from cine breath-hold magnetic resonance images acquired over the cardiac cycle.
Cardiac index baseline, 3 and 6 months of treatment This parameters is derived from cine breath-hold magnetic resonance images acquired over the cardiac cycle.
Trial Locations
- Locations (1)
Pfizer Investigative Site
🇬🇧London, United Kingdom