Mirdametinib in Patients With Advanced NF1-mutant Melanoma

Inclusion Criteria:

• Patients with unresectable or metastatic melanoma with an NF1 mutation; Variance ofNF1 of unknown/ uncertain significance will not be eligible; The genetic analysisfor somatic mutations must be performed in a lab that has obtained CLIAcertification.

• Patients must have a report of NF1 sequencing analysis performed at CLIA-certifiedlaboratory (by either tissue-based sequencing or liquid biopsy)

• Must have been previously treated with

• anti PD-1/PD-L1 antibody; AND anti CTLA-4 antibody and/or anti LAG3 antibody;

• UNLESS these standard checkpoint inhibitors are not clinically indicated orsuitable (for example, comorbid conditions, such as autoimmune disease, orsignificant toxicity with prior checkpoint inhibitor treatment)

• Tumors must be progressing at the time of the enrollment

• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance statusof ≤ 2

• Patients must be ≥ 18 years of age

• Patients must have measurable metastatic disease according to RECIST 1.1

• Patients must have adequate organ function, defined as follows:

• Absolute neutrophil count ≥ 1,500/μL

• Platelets ≥ 100,000/μL

• Hemoglobin ≥ 9 g/dL

• Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or calculated creatinineclearance ≥ 30 mL/min using the Cockcroft-Gault equation. Estimated glomerularfiltration rate (eGFR) ≥60 mL/min/1.73 m2 calculated by the Chronic Kidney DiseaseEpidemiology Collaboration (CKD-EPI) equation (Grade ≤1). • Total bilirubin ≤ 1.5 xULN OR direct bilirubin ≤ 1 x ULN (except patients with Gilbert's Syndrome, who musthave a total bilirubin less than 3.0 mg/dL)

• Aspartate aminotransferase and alanine aminotransferase ≤ 3.0 x ULN (Grade ≤1)unless liver metastases are present, in which case they must be ≤ 5 x ULN (Grade ≤2).

• Adequate coagulation function, as determined by:

• International Normalized Ratio (INR) ≤ 1.5 × ULN (Grade ≤ 1). If the participantreceives anticoagulant therapy, the INR > 1.5 × ULN is permitted, but the dose mustbe stable for at least 2 weeks before the start of the study treatments.

• PTT ≤ 1.5 × ULN.

• Adequate cardiac function, as determined by:

• Systolic blood pressure < 160 mmHg and diastolic blood pressure < 100 mmHg (Grade ≤ 2).

• LVEF ≥ 50% by MUGA or ECHO.

• No clinically significant ECG waveform abnormalities assessments at screening (onetriplicate).

• Have normal serum calcium and phosphate levels (calcium level may be corrected foralbumin level).

• Female patients are eligible to enroll and participate in the study if:

• Patient is of non-childbearing potential (i.e., physiologically incapable ofbecoming pregnant), including any female who:

1. has had a hysterectomy.

2. has had a bilateral oophorectomy (ovariectomy).

3. has had bilateral tubal ligation.

4. is postmenopausal (total cessation of menses for ≥1 year), OR

• Women of child-bearing potential must agree to use highly effective contraceptivemethods (hormonal or barrier method of birth control or abstinence) during the trialperiod through at least six months after the last dose. Male patients or theirpartners must be surgically sterile or agree to use adequate contraception whilereceiving trial treatment and for three months thereafter. Contraceptive use by menor women should be consistent with Clinical Trials Coordination Group (CTCG)guidance.

• Patients must be able to understand the study procedures and agree to participate inthe study by providing written informed consent.

Exclusion Criteria:

• Patients who were previously treated with MEK, ERK or RAF inhibitor therapy

• Patients with symptomatic brain metastasis or active brain lesions ≥ 6 mm size orthose who require steroid treatment for brain lesions or leptomeningeal disease

• No systemic cancer therapy within 28 days of the study drug administration,

• Patients must not be simultaneously enrolled in any therapeutic clinical trial

• Patients must not have had investigational therapy administered ≤ 4 weeks, or withina time interval less than at least 5 half-lives of the investigational agent,whichever is longer, prior to the first scheduled day of dosing in this study.

• Patient 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 > 200mg/dL);

• History or current evidence of glaucoma or clinically significant abnormalities onthe ophthalmological exam, including but not limited to cataract limiting theability to examine the retina or any optical coherence tomography (OCT) finding thatcould be a significant risk factor for RVO, retinopathy or neovascular maculardegeneration. o Note: Mild and controlled/stable age-related macular degeneration ornon-proliferative diabetic retinopathy may be acceptable at the investigator'sdiscretion after consultation with the ophthalmologist.

• 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.

• Patient who is pregnant or breastfeeding.

• Patient with active bacterial, fungal, or viral infection, including but not limitedto the use of antibiotics, antifungals, or antiviral agents at the time ofScreening;

• Underlying medical conditions, laboratory abnormality, or alcohol or drug abuse ordependence that, in the Investigator's opinion, will be unfavorable for theadministration of study treatment or affect the explanation of drug toxicity oradverse events; or insufficient compliance during the study according toInvestigator's judgement; or

• Patient has experienced other severe acute or chronic medical or psychiatricconditions, including recent (within 1 year of signing informed consent/assent) oractive suicidal ideation or behavior, or a laboratory abnormality that may increasethe risk associated with study participation or study treatment administration ormay interfere with the interpretation of study results and, in the judgment of theInvestigator, would make the participant inappropriate for entry into this study.