Pilot Study of the MEK1/2 Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate) for Adults With Neurofibromatosis Type 1 (NF1) and Cutaneous Neurofibromas (CNF)

• Patients be \>= 18 years old at the time of enrollment and must have a documented germline neurofibromatosis 1 (NF1) mutation in a Clinical Laboratory Improvement Act (CLIA) certified laboratory or a diagnosis of NF1 based on clinical National Institutes of Health (NIH) consensus criteria; in addition to substantial cutaneous neurofibroma burden, at least one of the criteria below have to be present

‣ Six or more cafe-au-lait macules (\>= 0.5 cm in prepubertal subjects or \>= 1.5 cm in post pubertal subjects)

⁃ Freckling in axilla or groin

⁃ Optic glioma

⁃ Two or more Lisch nodules

⁃ A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning of long bone cortex)

⁃ A first-degree relative with NF1

⁃ Histologic confirmation of tumor is not necessary in the presence of consistent clinical findings

• Patients must have substantial cutaneous neurofibroma burden causing distress to the patient by disfigurement or itching; patients must have \>= 9 measurable cutaneous neurofibromas; for the purpose of this study measurability will be defined for each of the lesions selected as target lesions as a neurofibroma with a longest diameter \>= 4 mm in the longest diameter

• Eastern Cooperative Oncology Group (ECOG) performance status =\< 2

• Hemoglobin \>= 10 g/dL (not requiring red blood cell \[RBC\] transfusions)

• Absolute neutrophil count \>= 1,500/mcL

• Platelets \>= 100,000/mcL (not requiring platelet transfusions)

• Total bilirubin =\< 1.5 X upper limit of normal (ULN), with the exception of patients with Gilbert syndrome who are required to have =\< 3 X ULN

• Alanine transferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 3.0 X ULN

• Creatinine within normal institutional limits OR creatinine clearance \>= 60 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal

• Ability of subject or legally authorized representative (LAR) to understand and the willingness to sign a written informed consent document

• Willingness to avoid excessive sun exposure and use adequate sunscreen protection if sun exposure is anticipated

• Willingness to avoid the ingestion of grapefruit and Seville oranges (as well as other products containing these fruits, e.g. grapefruit juice or marmalade) during the study

• Since there is no standard effective chemotherapy for patients with NF1 and cutaneous neurofibromas, patients may be treated on this trial without having received prior medical therapy directed at their plexiform neurofibromas (PN)

• Since selumetinib is not expected to cause substantial myelosuppression, there will be no limit to number of prior myelosuppressive regimens previously received for NF1 related; or other tumor manifestations

• Patients who have received previous investigational agents or biologic therapy, such as tipifarnib, pirfenidone, Peg-intron, sorafenib, or other vascular endothelial growth factor (VEGFR) inhibitors are eligible for enrollment

• Growth factors that support platelet or white cell number or function must not have been administered within the past 7 days and are not permitted while on the study

• At least 6 weeks must have elapsed prior to enrollment since the patient received any prior radiation therapy, and the target cutaneous neurofibromas have to be in areas outside of a prior radiation field

• At least 4 weeks must have elapsed since receiving medical therapy directed at NF1 related tumor manifestations

• At least 4 weeks must have elapsed since any surgeries, with evidence of completed wound healing

• Patients who received prior medical therapy for a NF1 related tumor must have recovered from the acute toxic effects of all prior therapy to =\< grade 1 Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 before entering this study

• The effects of selumetinib on the developing human fetus at the recommended therapeutic dose are unknown; for this reason women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 4 weeks after dosing with selumetinib ceases; women of child-bearing potential must have a negative pregnancy test prior to entry; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, the patient should inform her treating physician immediately; please note that the selumetinib manufacturer recommends that adequate contraception for male patients should be used for 12 weeks post-last dose due to sperm life cycle

• Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial must only be done after obtaining written informed consent from all patients, which can be accomplished using the study specific informed consent or another consent, such as the National Cancer Institute (NCI), Pediatric Oncology Branch (POB) screening protocol; studies or procedures that were performed for clinical indications (not exclusively to determine eligibility) may be used for screening or baseline values even if the studies were done before informed consent was obtained, if the patient agrees