Mirdametinib in Histiocytic Disorders

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase II Trial of the MEK Inhibitor Mirdametinib in Histiocytic Disorders

Conditions
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Langerhans Cell Histiocytosis (LCH), Juvenile Xanthogranuloma (JXG), Rosai-Dorfman Disease (RDD), Histiocytic Disorders

Intervention / Treatment
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* Drug: Mirdametinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All subjects must have a biopsy-proven diagnosis of histiocytic neoplasm confirmed by a Cincinnati Children's Hospital Medical Center (CCHMC) pathologist. The only exception is those with isolated pituitary/CNS disease where biopsy is not feasible. Biopsy material must be available from either diagnosis or relapse. The subjects must have LCH, JXG, RDD, or other histiocytosis with a known activating mutation in mitogen-activated protein (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. 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) Measurable disease: as evidenced by PET scan, brain MRI (for active CNS disease) Age: Subjects must be ≥ 2 years of age at the time of study entry. Durable Power of Attorney: Adults who are unable to provide informed consent will NOT be enrolled on this study. 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 topical or systemic 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. 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: 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. Subjects who have received radiation within 14 days of study enrollment. Subjects who have received radiation to the orbit at any time previously. Subjects requiring 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 and throughout the treatment period. Subjects with glaucoma, or any other significant abnormality on ophthalmic examination classified as ≥ grade 2, and uncontrolled with intervention (evaluation/management by an ophthalmologist). 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; 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 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; Participant has recorded a LVEF < 55% at Screening or within 3 years of signing informed consent/assent, OR has a history of congestive heart failure; 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 History or current evidence of an active parathyroid disorder, or of malignancy-associated Grade ≥2 hypercalcemia despite optimal remedial therapy. Absence of measurable disease (clinical or radiologic) 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.) Women who are pregnant or breast feeding. 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. 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 Previously treated with a MEK inhibitor including mirdametinib (PD-0325901) and had to stop treatment due to disease progression. 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 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 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.

Ages Eligible for Study
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Minimum Age: 2 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mirdametinib<br>Mirdametinib will be dosed by mouth twice a day at a dose of 2 mg/m2 BID with a max of 4 mg BID (8 mg per day max). | Drug: Mirdametinib<br>* Mirdametinib is administered at a dose of 2 mg/m2, twice a day (BID) with a maximum dose of 4 mg BID on a continuous daily schedule. Consecutive doses should be separated by minimum 6 hours and maximum 14 hours.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate to mirdametinib | Best overall response rate to mirdametinib after 13 four-week cycles as defined by positron emission tomography (PET) or magnetic resonance imaging (MRI) (for isolated pituitary/central nervous system (CNS) disease) response criteria. | 1 year (completion of 13 four week cycles) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sustained response to mirdametinib | Proportion of patients with sustained response to mirdametinib at completion of 26 cycles as defined by PET or MRI (for isolated pituitary/CNS disease) response criteria. | 2 years (completion of 26 four week cycles) | 
| Response to mirdametinib in the risk organs of patients with risk organ positive (RO+) LCH | PET will be used to determine proportion of patients with risk organ positive (RO+) LCH who have objective response in the risk organs (liver, spleen, marrow). | 8 weeks (completion of 2 four week cycles) | 
| Feasibility of uninterrupted prolonged mirdametinib administration | Percentage of patients that require disruption or dose adjustments. | 2 years (completion of 26 four week cycles) | 
| Toxicity of uninterrupted prolonged mirdametinib administration | Percentage of patients developing toxicity of each type - skin, cardiac, hepatic etc. | 1 year (completion of 13 four week cycles) | 
| Maximum Plasma Concentration (Cmax) | Blood samples will be drawn for the pharmacokinetic profile before, and during mirdametinib therapy. Maximum plasma concentration will be calculated as data allow. | Day 1 of the first 5 four week cycles) | 
| Time to peak drug concentration (Tmax) | Blood samples will be drawn for the pharmacokinetic profile before, and during mirdametinib therapy. Time to peak drug concentration (Tmax) will be calculated as data allow. | Day 1 of the first 5 four week cycles) | 
| Area under the plasma concentration time curve (AUC) | Blood samples will be drawn for the pharmacokinetic profile before, and during mirdametinib therapy. Area under the plasma concentration time curve (AUC) will be calculated as data allow. | Day 1 of the first 5 four week cycles) | 
| Rate of molecular responses with mirdametinib in patients with circulating BRAF-V600E. | Molecular response is defined as decreasing or absence of circulating BRAF-V600E detected by droplet digital polymerase chain reaction (PCR). | Comparing baseline to 1 year (completion of 13 four week cycles) |