STAT3 Inhibitor WP1066 in Treating Patients With Recurrent Malignant Glioma or Progressive Metastatic Melanoma in the Brain

Inclusion Criteria:

* Patients must have histologically confirmed progressive brain metastases from melanoma or recurrent/progressive malignant glioma (glioblastoma, anaplastic glioma), for which standard curative or palliative measures, with the exception of surgery, do not exist or are no longer effective
* Patients must have measurable disease in the brain, defined as at least one lesion that can be accurately measured in at least one dimension as \>= 10 mm by brain magnetic resonance imaging (MRI); MRI of the brain (with and without gadolinium enhancement) is to be performed using standard 5-mm slices with 2.5-mm spacing for comparison to subsequent MRI scans
* In the case of malignant glioma patients, they must have previously undergone standard-of-care treatment including surgery, radiation, and first line adjuvant chemotherapy prior to the experimental treatment (WP1066); in the case of melanoma patients with brain metastasis, they may have previously undergone a resection (with radiographic evidence of progression), have undergone gamma knife radiosurgery (with radiographic evidence of progression), or have been treated with other systemic therapies that failed
* Karnofsky performance scale score \>= 60%
* Leukocytes \>= 3,000/mcL
* Absolute neutrophil count \>= 1,000/mcL
* Platelets \>= 75,000/mcL
* Total bilirubin =\< 1.6
* Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x institutional upper limit of normal
* Creatinine within normal institutional limits OR creatinine clearance \>= 60 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal
* Prothrombin time (PT)/partial thromboplastin time (PTT) \< 1.5 x normal institutional standard
* Ability to understand and the willingness to sign a written informed consent document
* Melanoma patients must be intolerant of, or have disease that has proven refractory to approved therapies such as BRAF or MEK inhibitors for BRAF-positive metastatic melanoma and/or checkpoint blockade with either anti-PD1 or anti-CTLA-4 for metastatic melanoma
* Willing and able to tolerate brain MRI's with contrast
* Patients with stable seizures (e.g., no seizures for \>= 14 days and not requiring escalation or addition of anti-epileptic drugs for 14 days from starting treatment) will be eligible
* Patients who are eligible for the surgical expansion cohort are identified by the clinical team who have made the independent decision that the patient would benefit from non-emergent palliative surgical resection (i.e. they are not a candidate for gamma knife or other type of standard therapy)

Exclusion Criteria:

* Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier; biological agents, immune modulators, and targeted therapeutic approaches require a 2-week washout window
* Patients who are receiving any other investigational agents require a 4 week washout period; patients who have received cellular or gene therapy at any time are not eligible
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to WP1066
* The enzymatic metabolism profile of WP1066 is unknown; patients who are receiving drugs that significantly interact with the cytochrome P450 (CYP450) enzyme(s) are ineligible; however, if they are switched to other medications with a 2-week washout window, they will be eligible; patients are also excluded if they have been exposed within 7 days of planned first study treatment day to medications that are predominantly cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6), cytochrome P450, family 2, subfamily C, polypeptide 9 (2C9) or cytochrome P450, family 2, subfamily C, polypeptide 19 (2C19) substrates, strong inhibitors or inducers, and sensitive substrates of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) with narrow therapeutic range; patients requiring escalation of the corticosteroid dose will be excluded, but patients receiving a stable or decreasing dose for at least one week will be eligible
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
* No single lesion can be larger than 3 cm in maximal diameter; there may not be midline shift exceeding 5 mm or hydrocephalus
* Pregnant women are excluded from this study because WP1066 could potentially be teratogenic or have abortifacient effects; breastfeeding should be discontinued if the mother is treated with WP0166; female subjects of childbearing potential should be willing to use 2 methods of birth control prior to study entry, during the study, and for 2 months after the last dose of the study drug or be surgically sterile; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 1 year; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of WP1066 administration
* Human immunodeficiency virus (HIV)-positive patients receiving combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with WP1066
* Patients who have received bevacizumab, Gliadel, or are on active therapy with Optune are not eligible
* The potential for further hemorrhaging with the use of WP1066 is unknown; furthermore, because brain melanoma metastases commonly hemorrhage, toxicity may be inappropriately attributed to WP1066 in this setting; it will be at the principal investigator's (PIs) discretion to enroll a patient who has a small, asymptomatic brain hemorrhage, but patients who have had symptomatic hemorrhages will be excluded
* Patients with uncontrolled seizures or seizure requiring escalation or addition of anti-epileptic drugs will be excluded
* Because one of the secondary objectives is PFS based on radiographic volumetric analysis of the tumor, the presence of diffuse leptomeningeal disease will be an exclusion criterion for this study; this is secondary to the inadequacy of measuring the extent of the tumor burden within this setting and the very poor prognosis of these patients
* The cardiac toxicities of WP1066 are unknown; thus, patients who have a corrected QT (QTc) interval \> 450 ms at base line will be excluded; concomitant use of agents that prolong the QT interval will be avoided
* Malignant glioma patients within 12 weeks of completion of radiation concurrent temozolomide will be excluded
* Melanoma patients with large or symptomatic brain metastasis, and in whom neurosurgical removal is indicated will not be eligible for this trial