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

The researchers are doing this study to find out whether SX-682 in combination with proton craniospinal irradiation (pCSI) is a safe treatment approach for people with melanoma or non-small cell lung cancer (NSCLC) with leptomeningeal disease (LMD). The researchers will also look at whether the treatment combination is effective against participants' cancer.

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 \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