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

Array Biopharma, now a wholly owned subsidiary of Pfizer

Overview

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.

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

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Conditions

Cardiomegaly

Interventions

MEK162DRUG

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 Years

Medical Language ↔ Plain English

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.

Locations (2)

Pfizer Investigative Site

Boston, Massachusetts, United States

Pfizer Investigative Site

London, United Kingdom

Outcomes

Primary Outcomes

Change from baseline in Left ventricular mass (LVM)

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 Outcomes

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.

Time frame: 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.

Time frame: 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.

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

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

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.

Time frame: Day 1 and Day 8

Data from ClinicalTrials.gov

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