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

• INCLUSION CRITERIA:

• Participants must have documented pathologic diagnosis of confirmed primary centralnervous system (CNS) tumor with one of the below diagnoses:

• Cohort Phase I: Any recurrent or progressive primary CNS tumor, regardless ofmolecular features.

• Cohort Phase IIA: Newly diagnosed MYCN amplified ependymoma after surgery andradiation.

• 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 MYCor MYCN amplifications.

• Cohort Phase IID: Any recurrent glioblastoma without MYC or MYCNamplifications.

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

NOTE 2: The presence of MYCN or MYC amplification will be determined 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-fixedparaffin-embedded (FFPE) unstained slides) available for NCI LP review of MYC orMYCN amplification status and for correlative studies:

• Cohorts Phase I, Phase IIB, Phase IIC, and Phase IID: tumor tissue obtained atany point before trial treatment initiation, but preferably from most recentsurgical 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 radiationat least 4 weeks and no more than 10 weeks from the last dose of radiation prior tostudy treatment initiation.

• Participants in Cohorts Phase I, Phase IIB, Phase IIC, and Phase IID must havecompleted prior cytotoxic chemotherapy or radiation at least 4 weeks prior to studytreatment 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; atleast 4 weeks if the last regimen included a checkpoint inhibitor or any other typeof immunotherapy or cellular therapy; at least 5 half-lives if the last regimenincluded any investigational agent(s). Participants previously treated with PHOTONradiation to at least 2 segments of the spine must have completed radiation at least 12 months before study treatment initiation.

• Age >= 18 years.

• Karnofsky >= 70%. NOTE: Participants with severe paraparesis/paraplegia who needminimal assistance for self-care due to their motor deficit but are otherwisefunctionally 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 toachieve this level)

• total bilirubin within normal institutional limits

• aspartate aminotransferase (AST) / alanine aminotransferase (ALT) <2.5 Xinstitutional upper limit of normal (ULN)

• creatinine within normal institutional limits OR

• estimated glomerular filtrate rate (eGFR) using chronic kidney diseaseepidemiology collaboration) (CKD-EPI) equation:>= 60 mL/min/1.73 m^2 forparticipants with creatinine levels above institutional normal

• Women of child-bearing potential (WOCBP) and those who can father children mustagree to use effective contraception (barrier, hormonal contraception, intrauterinedevice (IUD), surgical sterilization, barrier at the study entry, for the durationof study treatment and up to 6 months (WOCBP) and 3 months (those who can fatherchildren) after the last dose of study treatment.

• Breastfeeding participants must be willing to discontinue breastfeeding from studytreatment initiation through 6 months after the last dose of the study drug.

• Ability to self-report symptoms and physical function as determined by assessment ofthe clinical team performed at screening.

• Participants must be able to understand and willing to sign a written informedconsent document.

EXCLUSION CRITERIA:

• History of allergic reactions to compounds of similar chemical composition toPLX038.

• Major surgery within 2 weeks prior to study treatment initiation. NOTE: The surgeryis considered major if a mesenchymal barrier is opened (pleural cavity, peritoneum,meninges).

• Participants who require treatment with strong inhibitors or inducers of CYP3A orwith UGT1A1 inhibitors during the planned period of investigational treatment withPLX038. Lists including medications and substances known or with the potential tointeract with CYP3A or UGT1A1 are provided inhttps://drug-interactions.medicine.iu.edu/maintable.

• History of treatment with pegylated topoisomerase inhibitors.

• Has documented >= grade 2 PHOTON craniospinal irradiation (CSI) induced GIdysfunction.

• Participants with history of homozygous for the UGT1A1*28 variant allele withseverely 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 orurine 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 havethe potential to interfere with the safety or efficacy assessment of theinvestigational 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 examthat would limit compliance with study requirements.