Clinical Trial: Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MEK162 in Noonan Syndrome Hypertrophic Cardiomyopathy

Study Status: Withdrawn
Recruit Status: Withdrawn
Study Type: Interventional

Official Title: An Open Label Study to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MEK162 in Noonan Syndrome Hypertrophic Cardiomyopathy

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 Summary:

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

Sponsor: Array BioPharma

Current Primary Outcome: Change from baseline in Left ventricular mass (LVM) [ Time Frame: Baseline to 3 months and 6 months ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

• Change from baseline in Cardiac energetics state at 3 months and 6 months [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: baseline to 3 and 6 months of treatment ]
  These parameters are derived from cine breath-hold magnetic resonance images acquired over the cardiac cycle.
• Pharmacokinetics of MEK162 and metabolite (AR00426032):observed maximum plasma concentration (Cmax) following drug adminstration [ Time Frame: 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 stroke volume and stroke output during 3 and 6 months [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: baseline, 3 and 6 months of treatment ]
  This parameters is derived from cine breath-hold magnetic resonance images acquired over the cardiac cycle.

Original Secondary Outcome: Same as current

Information By: Array BioPharma

Dates:
Date Received: March 15, 2012
Date Started: February 2012
Date Completion:
Last Updated: December 28, 2015
Last Verified: December 2015