Mirdametinib for the Treatment of Neurofibromatosis 1 and Cutaneous Neurofibromas

Inclusion Criteria

• Meet the diagnostic criteria for NF1
• ≥ 18 years of age
• Have a minimum of 12 measurable cNFs across two target areas each with ≥ 6 measurable cNFs to be assessed longitudinally. One target area must be located on the back and must have at least 6 measurable cNFs. The second target area can be in any of the following body regions with at least 6 measurable cNFs: head and neck; upper extremities; anterior chest wall, anterior abdominal wall; pelvic region/gluteal region; lower extremities. * Measurable is defined as: ** Non-pedunculated (no stalk) ** Surrounded by uninvolved skin and not adjacent to another cNF lesion ** Measuring ≥ 0.5 cm in the longest diameter and ≥ 0.5 cm in height ** cNF Atlas
• Participants must have an additional 12 cNFs that meet eligibility criteria amenable to shave removal. If a cNF targeted for shave removal is taken within the target area, the original minimum of 6 cNFs assigned for observation on treatment must remain for long term surveillance after removal of cNFs. Participants must be willing to undergo pre-, and on-treatment tumor biopsies providing fresh tumor tissue; there should be no contraindication for serial biopsies
• Total required eligible cNFs are 24: 12 on the back (6 for observation and 6 for sampling) and 12 in one other target region (6 for observation and 6 for sampling)
• Karnofsky performance level of ≥ 80%
• Absolute neutrophil count ≥ 1000 cells/uL
• Platelets ≥ 100 x 10^3/uL
• Hemoglobin ≥ 9.5 g/dL
• Serum albumin ≥ 2.8 g/dL
• Calculated creatinine clearance at screening ≥ 60 mL/min (by Cockcroft-Gault formula) OR a normal serum creatinine
• Alanine aminotransferase (ALT) < 2 x upper limit of institutional norm
• Total bilirubin value of ≤ 1.5 x upper limit of normal (ULN) (isolated bilirubin ≥ 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%)
• Participant is willing and able to comply with all aspects of the protocol
• Ability to understand and willingness to sign written informed consent document(s)
• Women of childbearing potential (WOCBP) must not be pregnant or breastfeeding during any portion of the study and must use an adequate method to prevent pregnancy during the study period and for 6 months after treatment conclusion and agree not to donate eggs (ova, oocytes) for the purpose of reproduction during the study and for a period of 6 months after last dose of study treatment. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study treatment (see the approved methods of birth control listed below). * In order for a woman to be determined not of childbearing potential, she must have ≥ 12 months of non-therapy-induced amenorrhea or be surgically or medically sterile. * WOCBP must have a negative serum pregnancy test result at screening and a negative urine pregnancy test result at the baseline visit prior to the first dose of study treatment. * The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy
• Male participants are eligible to participate if they agree to the following during the treatment period and for at least 90 days after the last dose of study treatment: * Refrain from donating sperm PLUS either: * Be abstinent from heterosexual intercourse (abstinent on a long term and persistent basis) and agree to remain abstinent until 90 days after the last study drug treatment; OR * Must agree to use a male condom when having sexual intercourse with a WOCBP and their female partner must utilize one the approved methods of birth control below: ** Approved Methods of birth control for this study are: *** Total abstinence *** Male or female sterilization (vasectomy in males or surgical removal of ovaries or uterus in females) *** Unsterilized male study participants must use a male condom and their female partner must use one of the methods below: *** Unsterilized female study participants must use one of the following highly effective methods listed below: ** Acceptable birth control methods which are considered highly effective if they result in a failure rate of less than 1% per year when used consistently and correctly: *** Combined (estrogen and progestogen containing) hormonal contraceptive that stops the release of eggs from the ovary (oral, intravaginal, or transdermal) *** Progestogen-only hormonal contraception that stops the release of eggs from the ovary (oral, injectable, implantable) *** Intrauterine device (IUD) *** Intrauterine hormone-releasing system (IUS) *** Bilateral tubal occlusion or bilateral tubal ligation

Exclusion Criteria

• Alanine transaminase (ALT) value of > 2.0 x upper limit of normal (ULN)
• Total bilirubin value of > 1.5 x ULN (isolated bilirubin > 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%)
• Participant has a history of malignancy associated hypercalcemia
• Any clinically significant active or known history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
• Hepatitis serology will be tested at Screening. Participants who are hepatitis B surface antigen (HBsAg) positive or hepatitis C virus (HCV) antibody positive at screening must not be enrolled until further definite testing with hepatitis B virus (HBV) deoxyribonucleic acid (DNA) titers is < 500 IU/mL or HCV ribonucleic acid (RNA) polymerase chain reaction test is negative
• Lymphoma, leukemia, or any solid tumor (including malignant glioma or malignant peripheral nerve sheath tumor [MPNST]) within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years
• Breast cancer within the past 3 years
• Active optic glioma or other low-grade glioma requiring treatment with chemotherapy or radiation therapy. * Participants not requiring treatment are eligible. Ophthalmological findings secondary to long-standing optic pathway glioma (such as visual loss, optic nerve pallor or strabismus) or long-standing orbito-temporal PN (such as visual loss, strabismus) are eligible
• Abnormal QT interval corrected by Fridericia’s formula (> 450 msec for male participants, > 470 msec for female participants, or > 480 msec for participants with known bundle branch block), calculated from triplicate electrocardiogram (ECG) readings taken approximately 2 to 3 minutes apart and averaged at screening
• Participant has experienced any of the following within 6 months (24 weeks) of signing informed consent/assent: clinically significant cardiac disease, myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, cerebrovascular accident, transient ischemic attack, or symptomatic pulmonary embolism
• A recorded left ventricular ejection fraction (LVEF) < 55% at screening or within 3 years of signing informed consent/assent, OR has a history of congestive heart failure
• Participants with 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); * Hypertension (BP ≥ 140/90 mm Hg)
• History of glaucoma
• Known history of a positive human immunodeficiency virus (HIV) antibody test
• Known malabsorption syndrome or preexisting gastrointestinal conditions that may impair absorption of mirdametinib (e.g., gastric bypass, lap band, or other gastric procedures). Delivery of mirdametinib via nasogastric tube or gastrostomy tube is not allowed
• Previously treated with MEK inhibitor including mirdametinib (PD-0325901) and had to stop treatment due to adverse event
• Currently receiving therapy with a MEK inhibitor including mirdametinib (PD-0325901) or treated with a MEK inhibitor in the 12 months prior to prior to first dose of study treatment
• Received radiation therapy within the 6 months prior to prior to first dose of study treatment. Participants who have received radiation to the orbit at any time are excluded
• Pregnant or breastfeeding women may not take study drug
• Current enrollment or past participation in any other clinical study (excluding observational studies) within 28 days of first dose of study treatment
• Known sensitivity to the study treatment, or components thereof, or drug or other allergy that, could compromise safety of the subject
• Participant is receiving systemic (oral or intravenous [IV]/subcutaneous [SC]) or ocular glucocorticoid therapy (with the exception of participants with endocrine deficiencies who are allowed to receive physiologic or stress doses of steroids, if necessary) within 14 days prior to first dose of study treatment
• Participants are excluded if they have severe and/or uncontrolled medical disease or social situation, which could compromise participation in the study (e.g., uncontrolled diabetes, uncontrolled hypertension, severe infection, severe malnutrition, chronic liver or renal disease, active upper gastrointestinal [GI] tract ulceration, congestive heart failure, drug or alcohol dependence, etc.)
• Participants is receiving systemic treatment of a pan-cytochrome 450 (CYP) inducers such as rifampin or ritonavir within 14-days prior to first dose of study treatment drug development and drug interactions