Targeted Approach to Langerhans Cell Histiocytosis (LCH) Using MEK Inhibitor, Trametinib

Inclusion Criteria:

• Diagnosis/disease status:

• Patients with newly diagnosed Langerhans cell histiocytosis (LCH) OR

• Patients with relapsed or refractory disease OR

• Patients with newly diagnosed or relapsed/refractory disease who are receivingthe liquid formula of trametinib OR

• Patients who have been receiving trametinib as a treatment for LCH sinceJanuary 1, 2020 may be included in the observational chart review to tracklong-term follow-up. Eligibility for chart review cohort will include receivingtrametinib as treatment.

• Diagnosis confirmed with biopsy prior to start of treatment

• Patient must have adequate cardiac function evident through Echocardiogram (ECHO)and Electrocardiogram (EKG) within 30 days of starting treatment.

• Shortening fraction of ≥ 27% by echocardiogram or

• Ejection fraction of ≥ 50% by gated radionuclide study

• QTC < 480 msec

• Performance status: Patients must have a performance status corresponding to ECOGscores of 0, 1, or 2. Use Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥50% for patients ≤16 years of age.

• Adequate organ and marrow function as defined below:

• Absolute Neutrophil count ≥ 1,500/μL

• Platelets ≥ 100x103/μL

• Total bilirubin ≤ 1.5X ULN for age

• AST/ALT ≤ 2.5 X ULN for age

• Serum creatinine based on age/gender

• Hemoglobin ≥ 8 g/dL

• Patients with bone marrow disease must have hemoglobin ≥ 8 g/dL withtransfusion support allowed

• Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, forthe duration of study participation, and for 4 months after the last dose. Should awoman become pregnant or suspect she is pregnant while participating in this study,she should inform her treating physician immediately.

• Ability to understand study procedures and to comply with them for the entire lengthof the study.

Exclusion Criteria:

• Patients diagnosed with Low-Risk True Skin Only or a Single Bone lesion that doesnot require treatment and will only be observed will not be eligible, with theexception of CNS-risk lesions/special site disease or functionally critical lesions:

• CNS-risk/special site includes: Sphenoid, Mastoid, Orbital, zygomatic, ethmoid,maxillary, or temporal bones, the cranial fossa, pituitary gland orneurodegenerative disease, odontoid peg, vertebral lesion with intraspinal softtissue extension

• Functionally critical: A single lesion not described above which may cause "functionally critical anatomic abnormality" wherein attempts at local therapywould cause unacceptable morbidity. This can be at the discretion of thePrincipal Investigator.

• Patients whose genetic testing reveals a class 3 MAP2K1 mutation:

• I103_K104del

• E102_I103del

• L98_K104delinsQ

• L98_I103del

• I99_K104del

• Patients who present with jaundice at diagnosis.

• Patients who are pregnant or breastfeeding are not eligible. Women of childbearingpotential must receive a negative pregnancy test within 14 days of startingtreatment or the patient will not be eligible.

• Patients who are allergic to trametinib

• Current drug or alcohol use or dependence that, in the opinion of the siteinvestigator, would interfere with adherence to study requirements.

• Inability or unwillingness of patient or parent/legally authorized representative togive written informed consent.