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

Primary Purpose

Cardiomegaly

Status

Withdrawn

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

MEK162

About this trial

This is an interventional treatment trial for Cardiomegaly focused on measuring Noonan Syndrome, hypertrophic cardiomyopathy.

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept 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.

Sites / Locations

Pfizer Investigative Site
Pfizer Investigative Site

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

MEK162

Arm Description

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

Outcomes

Primary Outcome Measures

Change from baseline in Left ventricular mass (LVM)

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

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

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

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

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

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)

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)

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)

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)

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

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

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

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

These parameters are derived from cine breath-hold magnetic resonance images acquired over the cardiac cycle.

Ejection fraction

This parameter is derived from cine breath-hold magnetic resonance images acquired over the cardiac cycle.

Cardiac index

This parameters is derived from cine breath-hold magnetic resonance images acquired over the cardiac cycle.

Full Information

NCT ID

NCT01556568

First Posted

March 15, 2012

Last Updated

October 2, 2020

Sponsor

Array Biopharma, now a wholly owned subsidiary of Pfizer

1. Study Identification

Unique Protocol Identification Number

NCT01556568

Brief Title

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

2. Study Status

Record Verification Date

October 2020

Overall Recruitment Status

Withdrawn

Why Stopped

Study was withdrawn due to scientific and business considerations.

Study Start Date

February 2012 (undefined)

Primary Completion Date

May 2017 (Anticipated)

Study Completion Date

undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Array Biopharma, now a wholly owned subsidiary of Pfizer

4. Oversight

Data Monitoring Committee

5. 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.

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Cardiomegaly

Keywords

Noonan Syndrome, hypertrophic cardiomyopathy.

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

MEK162

Arm Type

Experimental

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

MEK162

Primary Outcome Measure Information:

Title

Change from baseline in Left ventricular mass (LVM)

Description

Change in LVM after 3 months and 6 months of treatment using magnetic resonance imaging.

Time Frame

Baseline to 3 months and 6 months

Secondary Outcome Measure Information:

Title

Change from baseline in Cardiac energetics state at 3 months and 6 months

Description

Energetic state represented by phosphocreatine (PCr)/adenosine triphosphate (ATP) ratio using magnetic resonance spectroscopy.

Time Frame

Baseline to 3 months and 6 months

Title

Number of patients with adverse events, serious adverse events and death

Description

Abnormalities in Vital signs, ECG evaluations, clinical laboratory evaluations, will be collected.

Time Frame

6 months

Title

Pharmacokinetics of MEK162 and metabolite (AR00426032): The trough plasma concentration (Ctrough) just prior to drug administration

Description

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.

Time Frame

Days 1, 8, 15, 28, 56, 84, 140 and 182

Title

Pharmacokinetics of MEK162 and metabolite (AR00426032): maximum drug exposure of MEK162 and its metabolite (AR00426032) in plasma

Description

All blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein.

Time Frame

Day 1 and Day 8

Title

Pharmacokinetics of MEK162 and metabolite (AR00426032): time to reach peak concentration (Tmax) in plasma

Description

All blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein.

Time Frame

Day 1 and Day 8

Title

Pharmacokinetics of MEK162 and metabolite (AR00426032): Area under the plasma concentration-time profile from time zero to 12 hours post dose (AUC0-12h)

Description

All blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein.

Time Frame

Day 1 and Day 8

Title

Pharmacokinetics of MEK162 and metabolite (AR00426032): Area under the plasma concentration-time profile from time zero to the last quantifiable sample (AUClast)

Description

All blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein.

Time Frame

Day 1 and Day 8

Title

Pharmacokinetics of MEK162 and metabolite (AR00426032): accumulation ratio (Racc)

Description

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)

Time Frame

Day 1 and Day 8

Title

Pharmacokinetics of MEK162: The degree of fluctuation of MEK162 and its metabolite (AR00426032) in plasma at steady state (on Day 8)

Description

Time Frame

Day 8

Title

Pharmacokinetics of MEK162: The ratio of Metabolite (AR00426032) to MEK162 in plasma on Days 1 and 8

Description

All blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein.

Time Frame

Day 1 and Day 8

Title

Change from baseline in end systolic and end diastolic right and left vetricular volumes in 3 and 6 months

Description

These parameters are derived from cine breath-hold magnetic resonance images acquired over the cardiac cycle.

Time Frame

baseline to 3 and 6 months of treatment

Title

Pharmacokinetics of MEK162 and metabolite (AR00426032):observed maximum plasma concentration (Cmax) following drug adminstration

Description

All blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein.

Time Frame

Day 1 and Day 8

Title

Change from baseline in stroke volume and stroke output during 3 and 6 months

Description

These parameters are derived from cine breath-hold magnetic resonance images acquired over the cardiac cycle.

Time Frame

baseline to 3 and 6 months of treatment

Title

Ejection fraction

Description

This parameter is derived from cine breath-hold magnetic resonance images acquired over the cardiac cycle.

Time Frame

baseline, 3 and 6 months of treatment

Title

Cardiac index

Description

This parameters is derived from cine breath-hold magnetic resonance images acquired over the cardiac cycle.

Time Frame

baseline, 3 and 6 months of treatment

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Pfizer CT.gov Call Center

Organizational Affiliation

Pfizer

Official's Role

Study Director

Facility Information:

Facility Name

Pfizer Investigative Site

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02115

Country

United States

Facility Name

Pfizer Investigative Site

City

London

ZIP/Postal Code

W1G 8PH

Country

United Kingdom

12. IPD Sharing Statement

Learn more about this trial

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

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