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

Sponsor

Array Biopharma, now a wholly owned subsidiary of Pfizer (Industry)

Overall Status

Withdrawn

CT.gov ID

NCT01556568

Collaborator

(none)

Enrollment

Locations

Arm

Patients Per Site

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Cardiomegaly	Drug: MEK162	Phase 2

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:

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

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Feb 1, 2012

Anticipated Primary Completion Date :

May 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: MEK162 Patients will be treated with MEK162 only and will be uptitrated or down titrated based on safety and tolerability observed.	Drug: MEK162

Arm

Intervention/Treatment

Experimental: MEK162

Patients will be treated with MEK162 only and will be uptitrated or down titrated based on safety and tolerability observed.

Drug: MEK162

Outcome Measures

Primary Outcome Measures

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

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): 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.
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.
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.