CardiomegalyPhase 2NCT01556568
Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MEK162 in Noonan Syndrome Hypertrophic Cardiomyopathy
A Phase 2 study testing MEK162 in people with Cardiomegaly, run by Array Biopharma, now a wholly owned subsidiary of Pfizer at 2 sites in 2 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Cardiomegaly
- What is being tested?
- MEK162
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- 2 sitesin 2 countries
- Study dates
- Feb 2012to May 2017
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
2 sites in 2 countries.
2 sites in 2 countries
United States1 site
Pfizer Investigative Site
Boston, Massachusetts, 02115
About this study
Official title: An Open Label Study to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MEK162 in Noonan Syndrome Hypertrophic Cardiomyopathy
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.
Read the 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
- Conditions
- Cardiomegaly
- Being tested
- MEK162
- Keywords
- Noonan Syndrome, hypertrophic cardiomyopathy.
- Medical subject headings
- Cardiomegaly, Noonan Syndrome, Cardiomyopathy, Hypertrophic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MEK162Drug
| Study group | Role | What they receive |
|---|---|---|
| MEK162 | Experimental | Patients will be treated with MEK162 only and will be uptitrated or down titrated based on safety and tolerability observed. Receives: Drug: MEK162 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change from baseline in Left ventricular mass (LVM)
Change in LVM after 3 months and 6 months of treatment using magnetic resonance imaging.
Measured: Baseline to 3 months and 6 months
Secondary outcomes (15)
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.
Measured: Baseline to 3 months and 6 months
Number of patients with adverse events, serious adverse events and death
Abnormalities in Vital signs, ECG evaluations, clinical laboratory evaluations, will be collected.
Measured: 6 months
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.
Measured: Days 1, 8, 15, 28, 56, 84, 140 and 182
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.
Measured: Day 1 and Day 8
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.
Measured: Day 1 and Day 8
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.
Measured: Day 1 and Day 8
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.
Measured: Day 1 and Day 8
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)
Measured: Day 1 and Day 8
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.
Measured: Day 8
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.
Measured: Day 1 and Day 8
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.
Measured: baseline to 3 and 6 months of treatment
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.
Measured: Day 1 and Day 8
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.
Measured: baseline to 3 and 6 months of treatment
Ejection fraction
This parameter is derived from cine breath-hold magnetic resonance images acquired over the cardiac cycle.
Measured: baseline, 3 and 6 months of treatment
Cardiac index
This parameters is derived from cine breath-hold magnetic resonance images acquired over the cardiac cycle.
Measured: baseline, 3 and 6 months of treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Mar 2012 (estimated)
- Study startFeb 2012
- Primary completionMay 2017 (estimated)
Why it stopped: Study was withdrawn due to scientific and business considerations.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for CardiomegalyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Array Biopharma, now a wholly owned subsidiary of Pfizer
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Pfizer CT.gov Call Center, Study director, Pfizer
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01556568
- Sponsor's protocol ID
- CMEK162Y2201
- Other IDs
- 2011-003392-10
- Status last verified
- Oct 2020
- First submitted
- 15 Mar 2012
- Last updated
- 6 Oct 2020
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 6 Oct 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Open Label Study to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MEK162 in Noonan Syndrome Hypertrophic Cardiomyopathy
- ClinicalTrials.gov ID
- NCT01556568
- Acronym / sponsor ID
- CMEK162Y2201
- Conditions
- Cardiomegaly
- Keywords
- Noonan Syndrome, hypertrophic cardiomyopathy.
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Study was withdrawn due to scientific and business considerations.
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Array Biopharma, now a wholly owned subsidiary of PfizerIndustry (pharma, biotech, devices)
- Study start
- Feb 2012
- Primary completion
- May 2017 (estimated)
- First posted
- 16 Mar 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| MEK162 | Experimental | Drug: MEK162Patients will be treated with MEK162 only and will be uptitrated or down titrated based on safety and tolerability observed. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- 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.
Key exclusion criteria (6 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MEK162 | Drug | MEK162 |
Primary outcome
Change from baseline in Left ventricular mass (LVM)
Time frame: Baseline to 3 months and 6 months
Change in LVM after 3 months and 6 months of treatment using magnetic resonance imaging.
15 secondary outcomes
Change from baseline in Cardiac energetics state at 3 months and 6 months
Time frame: Baseline to 3 months and 6 months
Number of patients with adverse events, serious adverse events and death
Time frame: 6 months
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
Pharmacokinetics of MEK162 and metabolite (AR00426032): maximum drug exposure of MEK162 and its metabolite (AR00426032) in plasma
Time frame: Day 1 and Day 8
Pharmacokinetics of MEK162 and metabolite (AR00426032): time to reach peak concentration (Tmax) in plasma
Time frame: Day 1 and Day 8
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
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
Pharmacokinetics of MEK162 and metabolite (AR00426032): accumulation ratio (Racc)
Time frame: Day 1 and Day 8
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
Pharmacokinetics of MEK162: The ratio of Metabolite (AR00426032) to MEK162 in plasma on Days 1 and 8
Time frame: Day 1 and Day 8
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
Pharmacokinetics of MEK162 and metabolite (AR00426032):observed maximum plasma concentration (Cmax) following drug adminstration
Time frame: Day 1 and Day 8
Change from baseline in stroke volume and stroke output during 3 and 6 months
Time frame: baseline to 3 and 6 months of treatment
Ejection fraction
Time frame: baseline, 3 and 6 months of treatment
Cardiac index
Time frame: baseline, 3 and 6 months of treatment
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Oct 2020.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Pfizer CT.gov Call Center study director
Pfizer
2 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing MEK162 in people with Cardiomegaly, run by Array Biopharma, now a wholly owned subsidiary of Pfizer at 2 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 6 Oct 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States, United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change from baseline in Left ventricular mass (LVM) (time frame: Baseline to 3 months and 6 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Oct 2020.