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

* INCLUSION CRITERIA:
* Participants must have documented pathologic diagnosis of confirmed primary central nervous system (CNS) tumor with one of the below diagnoses:

  * Cohort Phase I: Any recurrent or progressive primary CNS tumor, regardless of molecular features.
  * Cohort Phase IIA: Newly diagnosed MYCN amplified ependymoma after surgery and radiation.
  * Cohort Phase IIB:

    * Recurrent or progressive MYCN amplified ependymoma, OR
    * Recurrent or progressive medulloblastoma with MYC or MYCN amplifications
  * Cohort Phase IIC: Any other recurrent or progressive primary CNS tumor with MYC or MYCN amplifications.
  * Cohort Phase IID: Any recurrent glioblastoma without MYC or MYCN amplifications.

NOTE 1: Recurrence or progression may involve CNS, extra CNS, or both.

NOTE 2: The presence of MYCN or MYC amplification must be confirmed by documented history. Participants who do not have documented history will be tested by NSR device (via next-generation sequencing panel TruSight(TM) Oncology 500) and the threshold of MYCN or MYC amplification for eligibility purposes is a fold change (FC) of \>=2.5X (5 copies) with a minimum tumor content of 20%.

* Participants must have archival tumor tissue (either a block or 15 formalin-fixed paraffin-embedded (FFPE) unstained slides) available for NCI LP review of MYC or MYCN amplification status (if necessary) and for correlative studies:

  * Cohorts Phase I, Phase IIB, Phase IIC, and Phase IID: tumor tissue obtained at any point before trial treatment initiation, but preferably from most recent surgical resection before study treatment initiation.
  * Cohort Phase IIA: tumor tissue obtained at original diagnosis.
* Participants in Cohort Phase IIA must have completed surgery followed by radiation at least 4 weeks and no more than 10 weeks from the last dose of radiation prior to study treatment initiation.
* Participants in Cohorts Phase I, Phase IIB, Phase IIC, and Phase IID must have completed prior cytotoxic chemotherapy or radiation at least 4 weeks prior to study treatment initiation (at least 6 weeks if the last regimen included lomustine (CCNU) or carmustine (BCNU); at least 3 weeks if the last regimen included bevacizumab; at least 4 weeks if the last regimen included a checkpoint inhibitor or any other type of immunotherapy or cellular therapy; at least 5 half-lives if the last regimen included any investigational agent(s).
* Age \>= 18 years.
* Karnofsky \>= 70%. NOTE: Participants with severe paraparesis/paraplegia who need minimal assistance for self-care due to their motor deficit but are otherwise functionally independent will be eligible.
* Participants must have adequate organ and marrow function as defined below:

  * leukocytes \>=3,000/microliter
  * absolute neutrophil count \>1,500/microliter
  * platelets \>100,000/microliter
  * hemoglobin \>= 9 g/ dL (may be transfused within 2 weeks prior to treatment to achieve this level)
  * total bilirubin within normal institutional limits
  * aspartate aminotransferase (AST) / alanine aminotransferase (ALT) \<2.5 X institutional upper limit of normal (ULN)
  * creatinine within normal institutional limits OR
  * estimated glomerular filtrate rate (eGFR) using chronic kidney disease epidemiology collaboration) (CKD-EPI) equation:\>= 60 mL/min/1.73 m\^2 for participants with creatinine levels above institutional normal
* Women of child-bearing potential (WOCBP) and those who can father children must agree to use effective contraception (barrier, hormonal contraception, intrauterine device (IUD), surgical sterilization, barrier at the study entry, for the duration of study treatment and up to 6 months (WOCBP) and 3 months (those who can father children) after the last dose of study treatment.
* Breastfeeding participants must be willing to discontinue breastfeeding from study treatment initiation through 6 months after the last dose of the study drug.
* Ability to self-report symptoms and physical function as determined by assessment of the clinical team performed at screening.
* Participants must be able to understand and willing to sign a written informed consent document.

EXCLUSION CRITERIA:

* History of allergic reactions to compounds of similar chemical composition to PLX038.
* Major surgery within 2 weeks prior to study treatment initiation. NOTE: The surgery is considered major if a mesenchymal barrier is opened (pleural cavity, peritoneum, meninges).
* Participants who require treatment with strong inhibitors or inducers of CYP3A or with UGT1A1 inhibitors during the planned period of investigational treatment with PLX038. Lists including medications and substances known or with the potential to interact with CYP3A or UGT1A1 are provided in https://drug-interactions.medicine.iu.edu/maintable.
* History of treatment with pegylated topoisomerase inhibitors.
* Has unresolved or persistent grade 2 or higher GI toxicity from any type of RT at screening
* Participants with history of homozygous for the UGT1A1\*28 variant allele with severely reduced UGT1A1 activity.
* Participants positive for Human immunodeficiency virus (HIV), Hepatitis C virus (HCV), and Hepatitis B virus (HBV).
* Pregnancy (confirmed with beta human chorionic gonadotropin (beta-HCG) serum or urine pregnancy test performed in females of childbearing potential at screening).
* Participants unable to have MRIs.
* Prior or concurrent malignancy unless its natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen (https://deainfo.nci.nih.gov/advisory/ctac/1117/4-JournalClinicalOncology.pdf, https://ctep.cancer.gov/protocolDevelopment/docs/CTEP\_Broadened\_Eligibility\_Criteria\_Guidance.pdf)
* Uncontrolled intercurrent illness evaluated by history, weight, and physical exam that would limit compliance with study requirements.