Mirdametinib in Histiocytic Disorders

Inclusion Criteria:

1. All subjects must have a biopsy-proven diagnosis of histiocytic neoplasm. confirmedby a CCHMC pathologist. - Exceptions include those with isolated pituitary/CNSdisease where biopsy is not feasible, and those patients who have a positive bloodtest for a mutation associated with histiocytic neoplasm (eg. BRAF-V600E) and clinical features of histiocytosis (such as but not limited to lyticbony lesion, rash, ear drainage, diabetes insipidus). If diagnostic confirmation isperformed by outside facility pathologist subjects may continue to enroll as long asbiopsy material from either diagnosis or relapse is available for a secondconfirmation by a CCHMC pathologist and received at CCHMC by cycle 1 day 1. Thesubjects must have LCH, JXG, RDD, or other histiocytosis with a known activatingmutation in MAP-kinase pathway genes such as RAS, RAF or MAP2K1. Each patient musthave tissue available for mutational analysis if not done prior to study enrollment.

2. Subjects must have disease that requires systemic therapy such as:

• multi-system disease (with or without risk-organ involvement)

• multi-focal bone disease

• isolated CNS/pituitary disease

• CNS-risk lesion (single bone lesion in the skull outside of the calvarium,which puts a patient at risk of developing CNS disease, this is different fromisolated CNS-LCH)

• Special site (solitary bone lesion in a precarious location such as theodontoid process, neck-of-femur)

3. Measurable disease: as evidenced by PET scan, brain MRI (for active CNS disease)

4. Age: Subjects must be ≥ 2 years of age at the time of study entry.

5. Durable Power of Attorney: Adults who are unable to provide informed consent willNOT be enrolled on this study.

6. Subjects may have been previously treated for histiocytosis with chemotherapy,surgery, glucocorticoids, or MAP kinase pathway inhibitors but with washout periodsas described below:

• Myelosuppressive Chemotherapy: must not have received any cytotoxicchemotherapy which impacts the growth and development of cells in the bonemarrow including, but not limited to, cytarabine, cladribine, clofarabine,mercaptopurine, methotrexate or vinblastine within 14 days of enrollment ontothis study.

• Biologic (Anti-Neoplastic Agent): Must not have received biologic agent within 30 days (or 5 half-lives, whichever is longer) of enrollment into this study.For agents that have known adverse events occurring beyond 14 days afteradministration, this period must be extended beyond the time during whichadverse events are known to occur. These subjects must be discussed with theProtocol Chair on a case-by-case basis.

• Investigational Drugs: Subjects must not have received an investigational drugwithin 30 days of study enrollment.

• Steroids: Subjects with endocrine deficiencies are allowed to receivephysiologic or stress doses of steroids if necessary. Chronic topical orsystemic steroid use outside of this indication are not permitted.

• Glucocorticoids: Due to the increased risk of an ocular event, the use ofsystemic oral, inhaled, or ocular glucocorticoid therapy is prohibited withinthe 14 days prior to first dose of mirdametinib and throughout the treatmentperiod.

• XRT: Subjects who have received radiation to the orbit at any time areexcluded.

• Surgery: Must demonstrate adequate post-operative recovery, approachingpre-operative state of health with appropriate wound healing and minimalresidual side effects.

7. Organ Function Requirements

• Adequate Renal Function defined as: maximum serum creatinine 2x ULN for age ORa creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2

• Adequate Liver Function defined as: ALT ≤ 3x ULN AND normal INR

• Adequate hematologic and end-organ function: Hematology: Albumin ≥ 2.8 g/dL;Hemoglobin ≥ 9.0 g/dL; Absolute neutrophil count ≥ 1.5 x 109/L; Platelets ≥ 100x 109/L, except where bleeding leading to low hemoglobin level is an indicationfor treatment, in which case hemoglobin < 9.0 g/dL is acceptable

Exclusion Criteria:

1. Chronic treatment with systemic steroids or another immunosuppressive agent.Subjects with endocrine deficiencies are allowed to receive physiologic or stressdoses of steroids if necessary.

2. Subjects who have received radiation within 14 days of study enrollment.

3. Subjects who have received radiation to the orbit at any time previously.

4. Subjects requiring prolonged glucocorticoids. Due to the increased risk of an ocularevent, the use of systemic, inhaled, or ocular glucocorticoid therapy is prohibitedwithin the 14 days prior to first dose of mirdametinib with the exception ofsporadic treatment such as during anesthesia, treatment of allergic reaction, asthmaexacerbation, or other acute medical condition. Any patients requiring prolongedcourses of steroids are not eligible. While on mirdametinib, intermittent steroidtherapy may be administered upon discussion with the PI.

5. Subjects with glaucoma, or any other significant abnormality on ophthalmicexamination classified as ≥ grade 2, and uncontrolled with intervention (evaluation/management by an ophthalmologist).

6. Participant has a history of, or evidence of, retinal pathology on ophthalmologicexamination that is considered a risk factor for central serous retinopathy, retinalvein occlusion (RVO), or neovascular macular degeneration. Participants will beexcluded from study participation if they have any of the following risk factors forRVO at Screening:

• Intraocular pressure > 21 mmHg;

• Serum cholesterol > 300 mg/dL;

• Serum triglycerides > 300 mg/dL;

• Hyperglycemia (fasting blood glucose > 125 mg/dL or random blood glucose > 200 mg/dL);

• Age specific hypertension with 3 separate consecutive measurements exceedingparameters below

• Participants ≥ 13 years of age with a blood pressure ≥ 140/90 mm Hg

• Participants ≤ 12 years of age with a blood pressure ≥ 95th percentile forage +12 mmHg;

7. Participant has recorded a LVEF < 55% at Screening or within 3 years of signinginformed consent/assent, OR has a history of congestive heart failure;

8. History (within 6 months before the start of the study treatments) of clinicallysignificant cardiac disease (New York Heart Association Class III or IV), myocardialinfarction, severe/unstable angina, coronary/peripheral artery bypass graft,symptomatic congestive heart failure, cerebrovascular accident, clinicallysignificant transient ischemic attack, symptomatic pulmonary embolism, unexplainedsyncope, or long QT syndrome

9. History or current evidence of an active parathyroid disorder, or ofmalignancy-associated Grade ≥2 hypercalcemia despite optimal remedial therapy.

10. Absence of measurable disease (clinical or radiologic)

11. Other concurrent severe and/or uncontrolled medical disease, which could compromiseparticipation in the study (e.g., uncontrolled diabetes, uncontrolled hypertension,uncontrolled hypercholesterolemia, uncontrolled hypertriglyceridemia, uncontrolledor severe infection, severe malnutrition, chronic liver or renal disease unrelatedto histiocytosis, congestive heart failure, etc.)

12. Women who are pregnant or breast feeding.

13. Males or females of reproductive potential may not participate unless they haveagreed to use a highly effective contraceptive method during the period they arereceiving the study drug and for 6 months thereafter. Abstinence, barrier (use ofcondom by male partner of female patient), implantable and oral forms ofcontraception are acceptable methods of birth control. Women of childbearingpotential will be given a pregnancy test within 7 days prior to administration ofmirdametinib and must have a negative serum pregnancy test.

14. Subjects unwilling to or unable to comply with the protocol, or who in the opinionof the investigator may not be able to comply with the safety monitoringrequirements of the study

15. Previously treated with a MEK inhibitor including mirdametinib (PD-0325901) and hadto stop treatment due to disease progression.

16. Currently receiving therapy with a MEK inhibitor including mirdametinib (PD-0325901)or treated with a MEK inhibitor within 30 days or 5 half-lives (whichever isgreater) prior to first dose of study treatment

17. Patients who have a MAP2KI mutation that is known to not be responsive to MEKinhibitors, such as mutations affecting amino acid residues 98-104 of the MEKprotein

18. Patients that enroll in the study who do not have a biopsy-proven diagnosis ofhistiocytic neoplasm confirmed by a CCHMC pathologist may still enroll in the study.The subjects must have LCH, JXG, RDD, or other histiocytosis with a known activatingmutation in MAP-kinase pathway genes such as RAS, RAF or MAP2K1. Biopsy materialmust be received at CCHMC before starting therapy. If CCHMC pathologist findspatient to not have one of these diagnoses when completing their second opinion onprovided biopsy material then patient will be taken off study, and replacementpatients added. The potential benefit of mirdametinib outweighs the risk of startingtherapy in a patient prior to confirming pathology. As mentioned in 4.1.1, tissuebiopsy is not required for patients with isolated CNS disease where a biopsy is notfeasible, and in those patients with clinical features of histocytosis and amutation detected in peripheral blood.

19. Patients that enroll in the study who do not have mutation analysis prior to studyentry may still enroll in study if tissue available for mutational analysis. If theyare found to have a mutation known to be resistant to MEK inhibitors such asmutations involving amino acid residues 98-104 of the MEK protein, known to beunresponsive to MEK inhibitors, they will be taken off study, and replacementpatients added. These mutations have been reported in the literature and believed tobe exceedingly rare. The potential benefit of mirdametinib outweighs the risk ofstarting therapy in a patient prior to knowledge of mutation data. In the unlikelyevent a patient is found to have this specific, unresponsive mutation, therapy wouldbe discontinued.