A Study of SX-682 in Combination With Proton Craniospinal Irradiation (pCSI) in People With Leptomeningeal Disease

Inclusion Criteria: * Age ≥ 18 * Written informed consent * ECOG 0-2 * Patients must have radiographic and/or pathologically confirmed leptomeningeal metastasis established through at least one of the following: * Positive CSF cytology for malignancy and/or positive CSF circulating tumor cells * CSF cytology with suspicious cells is considered positive; CSF cytology with atypical cells is considered equivocal and not positive * Unequivocal radiographic diagnosis of leptomeningeal metastasis on contrast- enhanced MRI * Patients may receive steroids to control symptoms related to CNS involvement, but the dose must be \<= 8 mg per 24 hours of dexamethasone (or the equivalent). Patient's symptoms should experience stability of neurological symptoms for at least 7 days, or on a tapering dose of steroids Patients must have a confirmed pathological diagnosis of a metastatic or recurrent melanoma or non-small cell lung cancer * Patients will have progressed on standard of care therapies * Patients who have been treated with an approved oral targeted therapy (i.e. BRAF/MEKi, EGFR TKI, etc) will be allowed to remain on concurrent approved targeted therapy up until the start of the trial, with no washout * Washout for all other systemic treatment (i.e., chemotherapy, immunotherapy, VEGF): 14 days * Required Organ Function o Adequate hematologic function is defined as follows: * Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3 * Platelets ≥ 100,000 cells/mm3 (Note: use of transfusion or other intervention to achieve is acceptable) * Hemoglobin ≥ 8 g/dl (Note: use of transfusion or other intervention to achieve is acceptable) o Adequate renal function is defined as follows: * Creatinine clearance (CrCL) of ≥30 mL/min by institutional standard (i.e. the Cockcroft-Gault formula or 24-hour urine collection) o Adequate hepatic function is defined as follows: * Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (patients with known Gilbert's disease who have bilirubin level ≤ 3 x ULN may be enrolled) * AST and ALT ≤3 x institutional ULN (patients with known liver mets ≤5 x institutional ULN) o Adequate cardiac function is defined as follows: No history of unstable angina requiring hospitalization in the last 3 months; * No history of myocardial infarction within the last 3 months; * New York Heart Association Functional Classification II or better (NYHA Functional Classification III/IV are not eligible) (Note: Patients 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.) * Must be able to swallow pills * Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. * Subjects with major medical, neurologic, or psychiatric condition who are judged as unable to fully comply with study therapy or assessments should not be enrolled. * For patients with known HIV, HBV, and/or HCV infection \[HIV, HBV, and HCV testing do not need to be performed as part of the study; the below language provides guidelines for inclusivity of patients with known HIV, HBV, and/or HCV infection\]: * HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. * For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. * Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load. * The effects of proton CSI and CXCR1/2 inhibition on the developing human fetus are unknown. For this reason and because radiation as well as other therapeutic agents used in this trial are known to be teratogenic, participants of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) during study therapy and for 3 months following the completion of study therapy. Should a participant become pregnant or suspect pregnancy while participating in this study, they should inform their treating physician immediately. * Before enrollment, a women must be either: * Not of childbearing potential: premenarchal; postmenopausal (\>45 years of age with amenorrhea for at least 12 months); permanently sterilized (e.g., bilateral tubal occlusion \[which includes tubal ligation procedures as consistent with local regulations\], hysterectomy, bilateral salpingectomy, bilateral oophorectomy); or otherwise be incapable of pregnancy * Of childbearing potential and practicing effective method(s) of birth control consistent with local regulations regarding the use of birth control methods for subjects participating in clinical studies, as described below: * Practicing true abstinence (when this is in line with the preferred and usual lifestyle of the subject), which is defined as refraining from heterosexual intercourse during the entire period of the study, including up to 6 months after the last dose of study drug is given. Periodic abstinence (calendar, symptothermal, post-ovulation methods) is not considered an acceptable contraceptive method * Have a sole partner who is vasectomized Practicing 2 methods of contraception, including one highly effective method (i.e., established use of oral, injected or implanted hormonal methods of contraception; placement of intrauterine device \[IUD\] or intrauterine system \[IUS\], AND, a second method (e.g., condom with spermicidal foam/gel/film/cream/suppository or collusive cap \[diaphragm or cervical/vault caps\] with spermicidal foam/gel/film/ cream/suppository) * Subjects must agree to continue contraception throughout the study and continuing through 6 months after the last dose of study drug * NOTE: If the childbearing potential changes after start of the study (e.g., woman who is not heterosexually active becomes active, premenarchal woman experiences menarche) the woman must begin a highly effective method of birth control, as described above. * A woman of childbearing potential must have a negative serum (b-human chorionic gonadotropin \[b-hCG\]) at Screening * A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for 6 months after receiving the last dose of study drug * A man who is sexually active with a woman of childbearing potential must agree to use a condom with spermicidal foam/gel/film/cream/suppository and his partner must also be practicing a highly effective method of contraception (i.e., established use of oral, injected or implanted hormonal methods of contraception; placement of an intrauterine device \[IUD\] or intrauterine system \[IUS\]). If the subject is vasectomized, he must still use a condom (with or without spermicide), but his female partner is not required to use contraception. The subject must also not donate sperm during the study and for 6 months after receiving the last dose of study drug Exclusion Criteria: * Patient who is unable to undergo MRI brain and spine with gadolinium contrast * Previous radiotherapy to the intended treatment site that precludes developing a treatment plan that respects normal tissue tolerances * Multiple, serious neurologic deficits, including encephalopathy