Clinical Trial of a MEK Inhibitor for RASopathy-Associated Severe Infantile Hypertrophic Cardiomyopathy: Baby MERIT

This project seeks to perform a Phase 3 clinical trial to test whether an FDA-approved cancer drug called trametinib is effective in treating young infants with genetic conditions called RASopathies and a severe, life-threatening heart problem called hypertrophic cardiomyopathy. The purpose of this research is to demonstrate that trametinib is effective in preventing these sick babies from dying, receiving a heart transplant or undergoing heart surgery to remove extra heart muscle over a one-year period. In addition, the investigators will determine how often this heart problem comes back when the trametinib treatment is stopped.

Inclusion Criteria: * Molecular genetic diagnosis of a RASopathy signaling through the RAS/MAPK pathway as identified by molecular assays performed in a Clinical Laboratory Improvements of 1988 (CLIA) or similarly certified laboratories. Qualifying genotypes will included variants in any gene causing Noonan, Costello or cardiofaciocutaneous syndrome curated as pathogenic or likely pathogenic and consistent with the genetic mechanism (i.e., one allele in genes acting in an autosomal dominant manner and two alleles in trans for the autosomal recessive form of LZTR1-related Noonan syndrome). * Diagnosis of HCM, as defined by LV and interventricular septal wall thickness with a z-score \> 2 by echocardiography * Age ≥ 28 days and ≤ 6 months * Ross classification of HF of III or IV * Hospitalization * In the opinion of the site investigator, ability to comply with study protocol requirements * Signed informed consent for the trial by a parent or legal guardian Exclusion Criteria: * PTPN11 pathogenic/likely pathogenic variants causing NSML * Prior treatment with a MEK inhibitor * Requiring treatment with strong inhibitors of CYP2C19 and CYP3A4, strong inducers of CYP3A4, and substrates of CYP2C9 with a narrow therapeutic index * Platelet count \< 50,000/µL * Neoplastic disorder requiring treatment (e.g., juvenile myelomonocytic leukemia)