PLX038 in Primary Central Nervous System Tumors Containing MYC or MYCN Amplifications

Background: * The MYC genes encode a family of transcription factors (MYC-C, MYC-N, and MYC-L) that regulate the expression of a wide range of genes involved in cell division in development and adulthood. * Supraphysiologic levels of MYC are oncogenic and drive aggressive behavior across a range of human malignancies. Amplifications of MYC and MYCN are seen in multiple types of primary central nervous system (CNS) tumors, including high-grade gliomas, medulloblastomas, and ependymomas. * These CNS tumors are rare and there are limited prospective data to inform treatment choices and few efficacious options. At present, they are typically treated with maximal safe surgical resection followed by external beam radiation therapy, with the variable inclusion of cytotoxic chemotherapy regimens as first-line treatment and/or at recurrence. These "standard" options have shown limited to no antitumor activity, leading to an extremely poor prognosis. * MYC-driven increase in transcription induces the formation of topoisome complexes (MYC-C/N, Topoisomerase 1 (TOP1), Topoisomerase 2 (TOP2), DNA) that are essential to managing the torsional strain that would otherwise oppose transcription and replication. * PLX038 is a PEGylated macromolecule that contains 4 molecules of SN-38, the active metabolite of irinotecan, that is currently being investigated in non-CNS solid tumor trials. SN38 binds to and inhibits topoisomerase 1 and the unique formulation of PLX038 lead to a longer half-life, which is thought to increase tumor accumulation and potentially decrease toxicity. Objectives: * Phase I: To confirm the recommended Phase II dose (RP2D) of PLX038 in participants with progressive or recurrent primary CNS tumors. * Phase II: To assess the efficacy of PLX038 at RP2D in primary CNS tumors based on MYC or MYCN amplifications as measured by: * Progression-free survival (PFS) for Cohort Phase IIA (adjuvant treatment), and * Disease control rate (DCR), defined as confirmed complete response (CR) / partial response (PR) or durable stable disease (SD) (NOTE: Durable SD is SD lasting for at least 6 months) for Cohorts Phase IIB and Phase IIC (treatment for recurrence with a MYC or MYCN amplification). * Progression free Survival at 6 months (PFS6) for Cohort phase IID (recurrent glioblastoma without a MYC or MYCN amplification) Eligibility: * Subjects with histologically confirmed primary CNS tumors corresponding to any progressive or recurrent tumor type (Phase I) or one of the following tumor types (Phase II): * Cohort Phase IIA: Newly diagnosed MYCN amplified ependymoma post resection and radiotherapy. * Cohort Phase IIB: Recurrent or progressive MYCN amplified ependymoma or medulloblastoma with MYC or MYCN amplifications. * Cohort Phase IIC: All other recurrent or progressive primary CNS tumors containing MYC or MYCN amplifications. * Cohort Phase IID: Recurrent glioblastoma that does not contain MYC or MYCN amplifications. * Age \>= 18 years. * Karnofsky Performance Status \>= 70%. * Ability to self-report symptoms and physical function as determined by assessment of the clinical team. * Tumor tissue availability for central review and correlative studies. Design: This is an open-label phase I/II clinical trial. * During Phase I RP2D and maximum tolerated dose (MTD) of PLX038 will be estimated. * In the Phase II component, participants will be treated with the TOP1 inhibitor PLX038 at the RP2D intravenously every 3 weeks (+/- 3 days, = 1 cycle). The Phase II study will be comprised of 4 independent disease cohorts that can enroll simultaneously and will be evaluated independently for efficacy. * Treatment will continue until progression or unacceptable toxicity, or a maximum of 10 cycles, whichever occurs first. * Safety and toxicity assessments will occur prior to each treatment cycle (every 3 weeks). * Efficacy (by magnetic resonance (MR) imaging and/or other imaging techniques if extra CNS tumor is present) and patient-reported outcomes measures (PROs): participant reported toxicity using predetermined patient-reported outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE) symptoms, Patient Global Impression of Severity (PGI-S), Patient Global Impression-Change (PGI-C), Overall Side Effect Bother, self-reported symptom severity and interference with daily activities using MD Anderson Symptom Inventory for brain tumor (MDASI-BT), and/or MD Anderson Symptom Inventory for spine tumors (MDASI-SP) questionnaires; self-reported physical functioning using Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Functioning form 10b. PRO-CTCAE, PGI-S, PGI-C, Overall Side Effect Bother, and PROMIS Physical Function 10b will be obtained at baseline and weekly for the first two cycles of treatment then these and all other PRO assessments will be obtained at the time of disease imaging evaluation every 2 cycles (6 weeks). The only exceptions are the PGI-C and Overall Side Effect Bother which will not be obtained at baseline and Day 1 of Cycle 1. PRO measures will be completed prior to participants being informed of imaging results. * PLX038 drug distribution will be investigated in peripheral blood and tumor tissue post-treatment administration. Molecular biomarkers of treatment response or resistance will be investigated in an exploratory manner pre and post-treatment (after cycle 2 and after tumor progression) in tumor tissue, hair follicles, and peripheral blood.