Mirdametinib Monotherapy in Adults With Neurofibromatosis 1 (NF1) and Cutaneous Neurofibromas (cNF).

Inclusion Criteria:

1. Meet the diagnostic criteria for NF12

2. ≥ 18 years of age

3. Have a minimum of 24 measurable cNF (2 target areas of ≥6 measurable cNF) a. Measurable is defined as: i. non-pedunculated (no stalk) ii. surrounded byuninvolved skin and not adjacent to another cNF lesion iii. measuring ≥ 0.5 cm inthe longest diameter and ≥ 0.5 cm in height iv. the 24 cNF must be located in twoTarget Areas. One target area must be located on the back and must have at least 6measurable cNF. The second target area can be in any of the following body regionswith at least 6 cNF: head and neck; upper extremities; anterior chest wall, anteriorabdominal wall; pelvic region/gluteal region; lower extremities.

4. Participants must have cNF that meet eligibility criteria located within the twostudy designated target areas or outside of the target areas amenable to biopsy. Ifbiopsy is taken within the target area there must be a minimum of 6 cNF remainingfor long term surveillance after biopsy. Participants must be willing to undergopre-, and on-treatment tumor biopsies providing fresh tumor tissue; there should beno contraindication for serial biopsy

5. Karnofsky performance level of ≥ 80%.

6. Adequate organ and bone marrow function as defined by the following Screeninglaboratory values:

7. Absolute neutrophil count ≥ 1500 cells/µL;

8. Platelets ≥ 100 x 103/µL;

9. Hemoglobin ≥ 9.5 g/dL;

10. Serum albumin ≥ 2.8 g/dL;

11. Calculated creatinine clearance at Screening ≥ 60 mL/min (by Cockcroft-Gaultformula) OR a normal serum creatinine.

12. Participant is willing and able to comply with all aspects of the protocol

13. Ability to understand and the willingness to sign written informed consentdocument(s).

14. Women of childbearing potential (WOCBP) must not be pregnant or breastfeeding duringany portion of the study and must use an adequate method to avoid pregnancy duringthe study period and for 6 months after treatment conclusion and agrees not todonate eggs (ova, oocytes) for the purpose of reproduction during the study and fora period of 6 months after last dose of study treatment. The Investigator shouldevaluate the effectiveness of the contraceptive method in relationship to the firstdose 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 musthave ≥ 12 months of non-therapy-induced amenorrhea or be surgically ormedically sterile.

• WOCBP must have a negative serum pregnancy test result at Screening and anegative urine pregnancy test result at the Baseline visit prior to the firstdose of study treatment.

• The Investigator is responsible for review of medical history, menstrualhistory, and recent sexual activity to decrease the risk for inclusion ofa woman with an early undetected pregnancy.

10. Male participants are eligible to participate if they agree to the following duringthe treatment period and for at least 90 days after the last dose of studytreatment:

• Refrain from donating sperm

PLUS either:

• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (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 andtheir 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 oruterus in females)

• Unsterilized male study participants must use a male condom and their female partnermust use one of the methods below:

• Unsterilized female study participants must use one of the following highlyeffective 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 therelease of eggs from the ovary (oral, intravaginal, or transdermal)

• Progestogen-only hormonal contraception that stops the release of eggs from theovary (oral, injectable, implantable)

• Intrauterine device (IUD)

• Intrauterine hormone-releasing system (IUS)

• Bilateral tubal occlusion or bilateral tubal ligation

Exclusion Criteria:

1. Participant has a altered screening values:

2. alanine transaminase (ALT) value of > 2.0 x upper limit of normal (ULN);

3. total bilirubin value of > 1.5 x ULN (isolated bilirubin > 1.5 x ULN isacceptable if bilirubin is fractionated and direct bilirubin < 35%);

4. Participant has a history of malignancy associated hypercalcemia;

5. Participant has an active parathyroid disorder, hyperphosphatemia at Screening (serum phosphorus > 1 x ULN), or serum calcium (mg/dL) x serum phosphorus (mg/dL)product > 70 at Screening;

6. Any clinically significant active or known history of liver disease, or knownhepatic or biliary abnormalities (with the exception of Gilbert's syndrome orasymptomatic gallstones);

7. Hepatitis serology will be tested at Screening. Participants who are hepatitis Bsurface antigen (HBsAg) positive or hepatitis C virus (HCV) antibody positive atScreening 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;

8. Lymphoma, leukemia, or any malignancy (including malignant glioma or MPNST) withinthe past 5 years except for basal cell or squamous epithelial carcinomas of the skinthat have been resected with no evidence of metastatic disease for 3 years;

9. Breast cancer within the past 3 years;

10. Active optic glioma or other low-grade glioma requiring treatment with chemotherapyor radiation therapy. a. Participants not requiring treatment are eligible. Ophthalmological findingssecondary to long-standing optic pathway glioma (such as visual loss, optic nervepallor or strabismus) or long-standing orbito-temporal PN (such as visual loss,strabismus) will NOT be considered a significant abnormality for the purposes of thestudy;

11. Abnormal QT interval corrected by Fridericia's formula (> 450 msec for maleparticipants, > 470 msec for female participants, or > 480 msec for participantswith known bundle branch block), calculated from triplicate ECG readings takenapproximately 2 to 3 minutes apart and averaged at Screening;

12. Participant has experienced any of the following within 6 months (24 weeks) ofsigning informed consent/assent: clinically significant cardiac disease, myocardialinfarction, severe/unstable angina, coronary/peripheral artery bypass graft,cerebrovascular accident, transient ischemic attack, or symptomatic pulmonaryembolism;

13. A recorded LVEF < 55% at screening or within 3 years of signing informedconsent/assent, OR has a history of congestive heart failure;

14. Participants with 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 > 200mg/dL);

• Hypertension (BP ≥ 140/90 mm Hg)

13. History of glaucoma;

14. Known history of a positive human immunodeficiency virus (HIV) antibody test;

15. Known malabsorption syndrome or preexisting gastrointestinal conditions that mayimpair absorption of mirdametinib (e.g., gastric bypass, lap band, or other gastricprocedures). Delivery of mirdametinib via nasogastric tube or gastrostomy tube isnot allowed.

16. Previously treated with MEK inhibitor including mirdametinib (PD-0325901) and had tostop treatment due to adverse event.

17. 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 ofstudy treatment.

18. Received radiation therapy within the 6 months prior to prior to first dose of studytreatment. Participants who have received radiation to the orbit at any time areexcluded.

19. Pregnant or breastfeeding women may not take study drug.

20. Current enrollment or past participation in any other clinical study (excludingobservational studies) within 28 days of first dose of study treatment.

21. Known sensitivity to the study treatment, or components thereof, or drug or otherallergy that, could compromise safety of the subject

22. Participant is receiving systemic (oral, inhaled, of IV/SC) or ocular glucocorticoidtherapy (with the exception of participants with endocrine deficiencies who areallowed to receive physiologic or stress doses of steroids, if necessary) within 14days prior to first dose of study treatment;

23. Participants are excluded if they have severe and/or uncontrolled medical disease orsocial situation, which could compromise participation in the study (e.g.uncontrolled diabetes, uncontrolled hypertension, severe infection, severemalnutrition, chronic liver or renal disease, active upper GI tract ulceration,congestive heart failure, drug or alcohol dependence, etc.).

24. Participants is receiving systemic treatment of a pan-cytochrom 450 (CYP) inducerssuch as rifampin or ritonavir within 14-days prior to first dose of study treatmentDrug Development and Drug Interactions