Troriluzole or Placebo Plus Ipi Plus Nivo in Mel Brain Mets

Inclusion Criteria:

Participants must have histologically or cytologically confirmed melanoma. All melanoma subtypes are included, except for ocular melanoma.
Participants must have measurable disease in the brain (intraparenchymal brain metastases), defined as at least one lesion that can be accurately measured by magnetic resonance imaging (MRI) in at least one dimension as ≥5 mm and ≤ 3 cm in longest diameter. See Section 11 (Measurement of Effect) for the evaluation of measurable disease. Measurable disease in the extracranial compartment (body) is not required. Measurable lesions may not have received previous treatment with radiation therapy. Prior stereotactic radiation therapy (SRT; e.g. GammaKnife, CyberKnife) is allowed for lesions other than the lesions selected as measurable target lesions. Prior craniotomy with resection of brain metastases is allowed.
Participants must have received prior systemic treatment with anti-PD-1 therapy (e.g. pembrolizumab, or nivolumab) in any setting (neoadjuvant, adjuvant or metastatic). Prior anti-CTLA-4 monotherapy is allowed (e.g. ipilimumab). Prior targeted therapy (e.g. BRAF inhibitors, MEK inhibitors) is allowed.
Age ≥18 years. Because no dosing or adverse event data are currently available on the use of troriluzole in participants <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
ECOG performance status 0 or 1 (see Appendix A).

Participants must have adequate organ and marrow function as defined below:

absolute neutrophil count ≥1,000/mcL
total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN), or in the case of Gilbert's disease ≤ 3x ULN
AST(SGOT)/ALT(SGPT) ≤3 × institutional ULN
Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants should be class 2B or better.
The effects of troriluzole on the developing human fetus are unknown. For this reason and because ipilimumab is a pregnancy category C, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence from heterosexual intercourse) prior to study entry, for the duration of study participation, and 4 months after completion of all study drugs. 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 all study drugs.
Ability to swallow pills.
Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

Ocular subtype of melanoma.
Cytologically confirmed leptomeningeal metastases, or convincing imaging evidence of leptomeningeal spread.
Prior whole brain radiation therapy (WBRT).
Prior combination therapy with concurrent ipilimumab (3 mg/kg IV) + nivolumab (1 mg/kg IV) in the 24 months prior to the date of registration.
Participants who have had systemic therapy (immunotherapy, chemotherapy, or targeted therapy), radiotherapy, or major surgery within 3 weeks prior to the date of registration.
Participants who require immediate local treatment (surgical resection or radiosurgery) of brain metastases due to neurological symptoms, or brain metastases located in sensitive areas of the brain requiring immediate local treatment.
Participants who have required systemic steroids to manage neurologic symptoms (seizures, cerebral edema, severe headache, nausea/vomiting, etc.) within 1 week prior to the date of registration.
Participants who are receiving any other investigational agents for cancer or neurologic disease.
Extreme claustrophobia that would interfere with performing brain MRIs or severe allergy to gadolinium contrast.
History of severe or life-threatening allergic reactions attributed to compounds of similar chemical or biologic composition to troriluzole, riluzuole, ipilimumab, or nivolumab.
Second primary malignancy that is a competing cause of death in the opinion of the treating investigator (prognosis < 6 months).
Patients with a history of solid organ transplant, or allogeneic bone marrow transplant.
Active autoimmune disease or any other condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other systemic immunosuppressive medications within 3 weeks of registration.
History of grade 4 immune related adverse event from prior cancer treatment, (with the exception of asymptomatic elevation of serum amylase or lipase).
History of immune-related adverse event from prior cancer immunotherapy treatment that has not improved to grade 0-1 (with the exception of patients with ongoing thyroid, adrenal or gonadal insufficiency requiring continued medical treatment, vitiligo, or asymptomatic elevation of serum amylase or lipase).
Participants receiving any medications or substances that are inhibitors or inducers of the liver enzyme Cytochrome P-450 CYP1A2, including fluvoxamine, cimetidine, amiodarone, efavirenz, fluoroquinolones (including ciprofloxacin and levofloxacin), fluvoxamine, furafylline, interferon, methoxsalen, mibefradil, or ticlopidine. These medications must be discontinued at least 7 days prior to registration.
Participants with uncontrolled intercurrent illness.
Participants with psychiatric illness/social situations that would limit compliance with study requirements.
Pregnant and nursing (breastfeeding) women are excluded from this study because the effects of troriluzole on the developing human fetus are unknown, and because ipilimumab is pregnancy category