Mirdametinib in Histiocytic Disorders

The purpose of this study is to see if treatment with mirdametinib in patients with Langerhans cell histiocytosis (LCH) or other histiocytic disorders will be better than current treatments and with fewer side effects.

Langerhans cell histiocytosis (LCH) is a rare blood disorder. Though affecting all ages, LCH occurs more often in children, with an increased incidence in children less than 1 year of age. The disease presents in various ways, with most children suffering bony lesions, and skin rashes. In some patients, LCH affects vital organs such as liver, spleen, bone marrow, and the central nervous system. This group of patients are at significant risk of serious illness and death and are thus said to have risk-organ-positive (RO+) LCH. Current treatments for LCH consist of chemotherapy combined with other medications. However, many patients, especially those with RO+ disease, do not respond to therapy. Of the patients that do respond, many suffer progression of disease after an initial response to therapy, or recurrence of disease after completion of therapy.

The purpose of this study is to see if treatment with mirdametinib in patients with LCH or other histiocytic disorders will be better than current treatments and with fewer side effects.

Eligibility Criteria:
Inclusion Criteria:

1. All subjects must have a biopsy-proven diagnosis of histiocytic neoplasm. confirmed by a CCHMC pathologist. - Exceptions include those with isolated pituitary/CNS disease where biopsy is not feasible, and those patients who have a positive blood test for a mutation associated with histiocytic neoplasm (eg.

   BRAF-V600E) and clinical features of histiocytosis (such as but not limited to lytic bony lesion, rash, ear drainage, diabetes insipidus). If diagnostic confirmation is performed by outside facility pathologist subjects may continue to enroll as long as biopsy material from either diagnosis or relapse is available for a second confirmation by a CCHMC pathologist and received at CCHMC by cycle 1 day 1. The subjects must have LCH, JXG, RDD, or other histiocytosis with a known activating mutation in MAP-kinase pathway genes such as RAS, RAF or MAP2K1. Each patient must have 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 from isolated CNS-LCH)
   * Special site (solitary bone lesion in a precarious location such as the odontoid 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 will NOT 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 periods as described below:

   * Myelosuppressive Chemotherapy: must not have received any cytotoxic chemotherapy which impacts the growth and development of cells in the bone marrow including, but not limited to, cytarabine, cladribine, clofarabine, mercaptopurine, methotrexate or vinblastine within 14 days of enrollment onto this 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 after administration, this period must be extended beyond the time during which adverse events are known to occur. These subjects must be discussed with the Protocol Chair on a case-by-case basis.
   * Investigational Drugs: Subjects must not have received an investigational drug within 30 days of study enrollment.
   * Steroids: Subjects with endocrine deficiencies are allowed to receive physiologic or stress doses of steroids if necessary. Chronic systemic (oral/IV) steroid use outside of this indication are not permitted.
   * Glucocorticoids: Due to the increased risk of an ocular event, the use of systemic oral, inhaled, or ocular glucocorticoid therapy is prohibited within the 14 days prior to first dose of mirdametinib and throughout the treatment period.
   * XRT: Subjects who have received radiation to the orbit at any time are excluded.
   * Surgery: Must demonstrate adequate post-operative recovery, approaching pre-operative state of health with appropriate wound healing and minimal residual side effects.
7. Organ Function Requirements

   * Adequate Renal Function defined as: maximum serum creatinine 2x ULN for age OR a 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 ≥ 100 x 109/L, except where bleeding leading to low hemoglobin level is an indication for 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 stress doses 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 ocular event, the use of systemic, inhaled, or ocular glucocorticoid therapy is prohibited within the 14 days prior to first dose of mirdametinib with the exception of sporadic treatment such as during anesthesia, treatment of allergic reaction, asthma exacerbation, or other acute medical condition. Any patients requiring prolonged courses of steroids are not eligible. While on mirdametinib, intermittent steroid therapy may be administered upon discussion with the PI.
5. Subjects with glaucoma, or any other significant abnormality on ophthalmic examination 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 ophthalmologic examination that is considered a risk factor for central serous retinopathy, retinal vein occlusion (RVO), or neovascular macular degeneration. Participants will be excluded from study participation if they have any of the following risk factors for RVO at Screening:

   * Intraocular pressure \> 21 mmHg: If IOP is unable to be obtained due to subject unwilling, or unable to tolerate the procedure (eg due to young age), therefore yielding inaccurate results, the ophthalmologist's exam findings and overall assessment will be utilized. If in the ophthalmologist's assessment there are no signs of raised IOP, the subject will be considered eligible for this specific parameter;
   * 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 exceeding parameters 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 for age +12 mmHg;
7. Participant has recorded a LVEF \&lt; 55% at Screening or within 3 years of signing informed consent/assent, OR has a history of congestive heart failure;
8. History (within 6 months before the start of the study treatments) of clinically significant cardiac disease (New York Heart Association Class III or IV), myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, clinically significant transient ischemic attack, symptomatic pulmonary embolism, unexplained syncope, or long QT syndrome
9. History or current evidence of an active parathyroid disorder, or of malignancy-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 compromise participation in the study (e.g., uncontrolled diabetes, uncontrolled hypertension, uncontrolled hypercholesterolemia, uncontrolled hypertriglyceridemia, uncontrolled or severe infection, severe malnutrition, chronic liver or renal disease unrelated to 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 have agreed to use a highly effective contraceptive method during the period they are receiving the study drug and for 6 months thereafter. Abstinence, barrier (use of condom by male partner of female patient), implantable and oral forms of contraception are acceptable methods of birth control. Women of childbearing potential will be given a pregnancy test within 7 days prior to administration of mirdametinib and must have a negative serum pregnancy test.
14. Subjects unwilling to or unable to comply with the protocol, or who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study
15. Previously treated with a MEK inhibitor including mirdametinib (PD-0325901) and had to 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 is greater) prior to first dose of study treatment
17. Patients who have a MAP2KI mutation that is known to not be responsive to MEK inhibitors, such as mutations affecting amino acid residues 98-104 of the MEK protein
18. Patients that enroll in the study who do not have a biopsy-proven diagnosis of histiocytic 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 activating mutation in MAP-kinase pathway genes such as RAS, RAF or MAP2K1. Biopsy material must be received at CCHMC before starting therapy. If CCHMC pathologist finds patient to not have one of these diagnoses when completing their second opinion on provided biopsy material then patient will be taken off study, and replacement patients added. The potential benefit of mirdametinib outweighs the risk of starting therapy in a patient prior to confirming pathology. As mentioned in 4.1.1, tissue biopsy is not required for patients with isolated CNS disease where a biopsy is not feasible, and in those patients with clinical features of histocytosis and a mutation detected in peripheral blood.
19. Patients that enroll in the study who do not have mutation analysis prior to study entry may still enroll in study if tissue available for mutational analysis. If they are found to have a mutation known to be resistant to MEK inhibitors such as mutations involving amino acid residues 98-104 of the MEK protein, known to be unresponsive to MEK inhibitors, they will be taken off study, and replacement patients added. These mutations have been reported in the literature and believed to be exceedingly rare. The potential benefit of mirdametinib outweighs the risk of starting therapy in a patient prior to knowledge of mutation data. In the unlikely event a patient is found to have this specific, unresponsive mutation, therapy would be discontinued.