Key Inclusion Criteria for Part 1:

1. Patient must be ≥ 18 years of age at the time of signing the informed consent form (ICF). 2. Patient must have histologically confirmed recurrent or progressive WHO Grade 2 glioma or Grade 3 glioma with IDH1 R132H or R132C mutation confirmed by immunohistochemistry or molecular genetic testing.4. The IDH mutation, and other applicable gene/molecular alterations (see Table 10-2) aredetermined by a validated assay as performed in Clinical Laboratory ImprovementAmendments (CLIA)-certified/College of American Pathologists (CAP)-accredited or locallyequivalent clinical laboratories. Prior clinical pathology report fulfilling thediagnosis criteria prior to screening with tumor samples collected is acceptable forpatient enrollment in both Part 1 and Part 2.5. Patient has received no more than 2 prior therapies for diseaserecurrence/progression.6. Patient has disease recurrence or progression or cannot tolerate the most recenttherapy.7. Patient must have a measurable lesion(s) as per the RANO-HGG criteria for primarilyenhancing lesions or RANO-LGG criteria for primarily non-enhancing lesions. The lesion(s) must be visible on 2 or more axial slices and have perpendicular diameters of atleast 10 × 10 mm. The definition of primarily enhancing lesions or primarilynon-enhancing lesions is referred to Section 8.3.1.

Key Inclusion Criteria for Part 2:

1. Must be ≥18 years old at the time of signing the ICF. 2. Diagnosis of histologically confirmed IDH1-mutant Grade 3 with high risk features or Grade 4 astrocytoma, per WHO 2021 classification and Investigator Assessment. 3. Have an IDH1 mutation (R132H/C/G/S/L) based on IHC (R132H only), polymerase chain reaction (PCR), or next-generation sequencing (NGS). CDKN2A/B status and at least 1 of the following must be confirmed: absence of 1p19q co-deletion by fluorescence in situ hybridization, array comparative genomic hybridization, or NGS; presence of an ATRX loss of function mutation by NGS; or loss of normal ATRX expression by IHC. A validated assay performed in a CLIA-certified/CAP-accredited (or local equivalent) clinical laboratory must be used for all of the aforementioned results. Documentation of biomarker status, including redacted molecular pathology and NGS reports, must be provided during Screening. 4. Must not have experienced disease recurrence or disease progression. 5. Participants must have completed radiation therapy with a minimum of 90% of planned treatment completed (with or without concurrent temozolomide) and between 6 and 12 cycles of adjuvant temozolomide and have no evidence of disease progression. Randomization must occur at least 28 days and not more than 75 days after the final dose of temozolomide. 6. Must agree to submit sufficient tumor tissue for retrospective biomarker and histological analyses. This requirement may be waived in rare circumstances with approval by the Sponsor. 7. Has adequate hematologic and organ functions

Key Exclusion Criteria for Part 1:

• Prior anti-cancer therapy, within the applicable periods shown below, before the start of the protocol treatment:
• Systemic drug therapies: within 3 weeks (lomustine within 6 weeks)
• Surgery: within 3 weeks
• Radiation therapy: within 12 weeks
• Investigational agents: within 5 half-lives for other investigational agents
• Patient did receive the prior therapy targeted to IDH1 mutation..
• Known hypersensitivity to safusidenib or to any drug with similar chemical structure or to any other excipient present in the pharmaceutical form of safusidenib.

Key Exclusion Criteria for Part 2:

1. Participants may not have received any anticancer treatments other than surgery, radiation, concurrent/adjuvant temozolomide, and tumor-treating fields. Tumor-treating fields must be discontinued prior to randomization. 2. Participants with prior or anticipated treatment with anti-angiogenic agents such as Avastin (bevacizumab), agents known to target IDH1 or IDH2, or investigational agents for glioma are excluded. 3. Have brainstem or spinal cord involvement either as primary location, site of multifocal involvement, or by significant tumor extension. 4. Significant functional or neurocognitive deficits, including uncontrolled seizures, that would preclude participation in protocol-defined study activities, as assessed by Investigator. 5. Evidence of diffuse leptomeningeal disease by MRI. 6. History of significant cardiac disease within 12 months prior to randomization. 7. If taking corticosteroids, must be on a stable or decreasing dose for the 14 days prior to randomization. 8. Participants with other malignancies must have received curative treatment and been disease-free for at least 3 years. Curatively resected non-melanoma skin cancer or curatively treated carcinoma in situ is allowed. 9. Have a condition that would interfere with, or increase the risk of, study participation.

Inclusion Criteria:

• Patients must be enrolled on APEC14B1 and have consented to testing through the Molecular Characterization Initiative (MCI), prior to enrollment on ANBL2131
• ≤ 30 years at the time of initial diagnosis with high-risk disease
• * Must have a diagnosis of neuroblastoma (NBL) or ganglioneuroblastoma (nodular) verified by tumor pathology analysis or demonstration of clumps of tumor cells in bone marrow with elevated urinary catecholamines
• Newly diagnosed, high risk neuroblastoma (HRNBL) defined as one of the following:
• Any age with International Neuroblastoma Risk Group (INRG) Stage L2, MS, or M and MYCN amplification
• Age ≥ 547 days and INRG stage M regardless of biologic features (clinical MYCN testing not required prior to enrollment)
• Any age initially diagnosed with INRG Stage L1 MYCN amplified NBL who have progressed to stage M without systemic chemotherapy
• Age ≥ 547 days of age initially diagnosed with INRG Stage L1, L2, or MS who have progressed to stage M without systemic chemotherapy (clinical MYCN testing not required prior to enrollment)
• Patients must have a body surface area (BSA) ≥ 0.25 m^2
• No prior anti-cancer therapy except as outlined below:
• Patients initially recognized to have high-risk disease treated with topotecan/cyclophosphamide initiated on an emergent basis and within allowed timing, and with consent
• Patients observed or treated with a single cycle of chemotherapy per a low or intermediate risk neuroblastoma regimen (e.g., as per ANBL0531, ANBL1232 or similar) for what initially appeared to be non-high-risk disease but subsequently found to meet the criteria
• Patients who received localized emergency radiation to sites of life threatening or function-threatening disease prior to or immediately after establishment of the definitive diagnosis
• Human immunodeficiency virus (HIV) -infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• A serum creatinine based on age/sex as follows:
• 1 month to < 6 months: Male 0.4 mg/dL and female 0.4mg/dL
• 6 months to < 1 year: Male 0.5 mg/dL and female 0.5 mg/dL
• 1 to < 2 years: Male 0.6 mg/dL and female 0.6 mg/dL
• 2 to < 6 years: Male 0.8 mg/dL and female 0.8 mg/dL
• 6 to < 10 years: Male 1 mg/dL and female 1 mg/dL
• 10 to < 13 years: Male 1.2 mg/dL and female 1.2 mg/dL
• 13 to < 16 years: Male 1.5 mg/dL and female 1.4 mg/dL
• ≥ 16 years: Male 1.7 mg/dL and female 1.4 mg/dL
• The threshold creatinine values were derived from the Schwartz formula for estimating glomerular filtration rate (GFR) utilizing child length and stature data published by the Centers for Disease Control (CDC)
• or a 24-hour urine creatinine clearance ≥ 70 mL/min/1.73 m^2 or
• or a GFR ≥ 70 mL/min/1.73 m^2. GFR must be performed using direct measurement with a nuclear blood sampling method or direct small molecule clearance method (iothalamate or other molecule per institutional standard)
• Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates are not acceptable for determining eligibility
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age
• Serum glutamic pyruvic transaminase (SGPT) (Alanine aminotransferase [ALT]) ≤ 10 x ULN*
• Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L
• * Shortening fraction of ≥ 27% by echocardiogram, or
• Ejection fraction of ≥ 50% by echocardiogram or radionuclide angiogram
• Ability to tolerate Peripheral Blood Stem Cell (PBSC) collection:No known contraindication to PBSC collection. Examples of contraindications might be aweight or size less than the collecting institution finds feasible, or a physicalcondition that would limit the ability of the child to undergo apheresis catheterplacement (if necessary) and/or the apheresis procedure

Exclusion Criteria:

• Patients who are 365-546 days of age with INRG Stage M and MYCN non-amplified NBL, irrespective of additional biologic features
• Patients ≥ 547 days of age with INRG Stage L2, MYCN non-amplified NBL, regardless of additional biologic features
• Patients with known bone marrow failure syndromes
• Patients on chronic immunosuppressive medications (e.g., tacrolimus, cyclosporine, corticosteroids) for reasons other than prevention/treatment of allergic reactions and adrenal replacement therapy are not eligible. Topical and inhaled corticosteroids are acceptable
• Patients with a primary immunodeficiency syndrome who require ongoing immune globulin replacement therapy
• Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required prior to enrollment for female patients of childbearing potential
• Lactating females who plan to breastfeed their infants
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation
• All patients and/or their parents or legal guardians must sign a written informed consent
• All institutional, food and drug administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Inclusion Criteria:

• Patients must be ≥ 3 years and < 30 years at the time of study enrollment
• Patients must be newly-diagnosed primary localized germinoma of the suprasellar and/or pineal region by pathology and/or serum and/or CSF hCGbeta 5-50 mIU/mL AND institutional normal AFP (or ≤ 10 ng/mL if no institutional normal exists), including tumors with contiguous ventricular or unifocal parenchymal extension. No histologic confirmation required
• Patients with EITHER (A) bifocal (pineal + suprasellar) involvement OR (B) pineal lesion with diabetes insipidus (DI) AND hCGbeta ≤ 100 mIU/mL in serum and/or CSF AND institutional normal AFP (or ≤ 10 ng/mL if no institutional normal exists) in both serum and CSF. No histologic confirmation required
• Patients with hCGbeta 51-100 mIU/mL in serum and/or CSF and institutional normal AFP (or ≤ 10 ng/mL if no institutional normal exists) in both serum and CSF. Histologic confirmation of germinoma IS required
• Patients with germinoma of the basal ganglia and or/thalamic primary sites are eligible
• Patients with metastatic germinoma including non-contiguous disease or distant disease in the brain, ventricles, or spine are eligible
• Patients with germinoma admixed with mature teratoma are eligible
• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients ≤ 16 years of age
• Patients must have eligibility confirmed by Rapid Central Imaging Review performed on APEC14B1-CNS
• Imaging studies must be obtained within 31 days prior to study enrollment and start of protocol therapy. (Note: for patients that have had surgery and post-operative imaging performed, it is the post-operative MRI that must be obtained within 31 days prior to enrollment.)
• Patients must have a cranial magnetic resonance imaging (MRI) with and without gadolinium at diagnosis/prior to enrollment. If surgical resection is performed, patients must have pre-operative and post-operative brain MRI with and without gadolinium. The post-operative brain MRI should be obtained within 72 hours of surgery. If patient has a biopsy only, post-operative brain MRI is recommended but not required
• Patients must have a spine MRI with gadolinium obtained at diagnosis/prior to enrollment
• Patients must be enrolled, and protocol therapy must begin, no later than 31 days after definitive surgery or clinical diagnosis, whichever is later
• Patients must have eligibility confirmed by Rapid Central Tumor Marker Review performed on APEC14B1-CNS
• Lumbar CSF must be obtained prior to study enrollment unless medically contraindicated. If a patient undergoes surgery and lumbar CSF cytology cannot be obtained at the time of surgery, then it should be performed at least 10 days following surgery and prior to study enrollment. False positive cytology can occur within 10 days of surgery. Of note, lumbar CSF should not be performed prior to obtaining spine MRI, as this can make interpretation of the spine MRI less clear
• Patients must have CSF tumor markers obtained prior to study enrollment unless medically contraindicated. Ventricular CSF obtained at the time of CSF diversion procedure (if performed) is acceptable for tumor markers but lumbar CSF is preferred. In case CSF diversion and biopsy/surgery are combined, CSF tumor markers should be collected first. Ideally serum and CSF tumor markers should be collected at the same time and processed without delay
• For patients with solid tumors: Peripheral absolute neutrophil count (ANC) >= 1000/uL (Must be performed within 7 days prior to enrollment unless otherwise indicated)
• For patients with solid tumors: Platelet count >= 100,000/uL (transfusion independent) (Must be performed within 7 days prior to enrollment unless otherwise indicated)
• For patients with solid tumors: Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) (Must be performed within 7 days prior to enrollment unless otherwise indicated)
• For pediatric patients (age 3-17 years): A serum creatinine based on age/gender as follows (Must be performed within 7 days prior to enrollment unless otherwise indicated):
• Age: 3 to < 6 years; maximum serum creatinine (mg/dL): 0.8 (male); 0.8 (female)
• Age: 6 to < 10 years; maximum serum creatinine (mg/dL): 1 (male); 1 (female)
• Age: 10 to < 13 years; maximum serum creatinine (mg/dL): 1.2 (male); 1.2 (female)
• Age: 13 to < 16 years; maximum serum creatinine (mg/dL): 1.5 (male); 1.4 (female)
• Age: ≥ 17 years; maximum serum creatinine (mg/dL): 1.7 (male); 1.4 (female) OR a 24-hour urine creatinine clearance ≥ 70 mL/min/1.73 m^2 OR a glomerular filtration rate (GFR) ≥ 50 mL/min/1.73 m^2. GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard).
• Note: Estimated GFR (eGFR) from serum or plasma creatinine, cystatin C or other estimates are not acceptable for determining eligibility.
• For adult patients (age 18 years or older) (Must be performed within 7 days prior to enrollment unless otherwise indicated):
• Creatinine clearance ≥ 70 mL/min, as estimated by the Cockcroft and Gault formula or a 24-hour urine collection. The creatinine value used in the calculation must have been obtained within 28 days prior to registration. Estimated creatinine clearance is based on actual body weight
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age (Must be performed within 7 days prior to enrollment unless otherwise indicated)
• Serum glutamic-pyruvic transaminase (SGPT) (alanine transaminase [ALT]) ≤ 135 U/L (Must be performed within 7 days prior to enrollment unless otherwise indicated)
• Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L
• No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% if there is clinical indication for determination
• Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled
• CNS toxicity =< grade 2
• Patients must not be in status epilepticus, coma or assisted ventilation prior to study enrollment
• HIV-infected patients on effective anti-retroviral therapy with undetectable viral load are eligible for this study

Exclusion Criteria:

• Patients with any of the following malignant pathological elements are not eligible:
• Endodermal sinus (yolk sac)
• Embryonal carcinoma, choriocarcinoma
• Malignant/immature teratoma and mixed germ cell tumor (GCT) (i.e., may include some germinoma)
• Patients with only mature teratoma upon tumor sampling at diagnosis and negative tumor markers are not eligible
• Patients who have received any prior tumor-directed therapy for their diagnosis of germinoma other than surgical intervention and corticosteroids are not eligible
• Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential.
• Note: Serum and urine pregnancy tests may be falsely positive due to HCGbeta-secreting germ cell tumors. Ensure the patient is not pregnant by institutional standards
• Lactating females who plan to breastfeed their infants
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation
• All patients and/or their parents or legal guardians must sign a written informed consent
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Inclusion Criteria:

• STEP 1 REGISTRATION: No known IDH mutation. (If tested before step 1 registration, patients known to have IDH mutation in the tumor on local or other testing are ineligible and should not be registered)
• STEP 1 REGISTRATION: Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block and hematoxylin and eosin (H&E) stained slide to be sent for central pathology review for confirmation of histology and MGMT promoter methylation status. Note that tissue for central pathology review and central MGMT assessment must be received by the New York University (NYU) Center for Biospecimen Research and Development (CBRD) on or before postoperative calendar day 30. If tissue cannot be received by postoperative calendar day 30, then patients may NOT enroll on this trial as central pathology review will not be complete in time for the patient to start treatment no later than 8 weeks following surgery. Results of central pathology review and central MGMT analysis will generally be completed within 10 business days of receipt of tissue. Results will be entered by the central lab directly into Rave. Note: In the event of an additional tumor resection(s), tissue must be received within 30 days of the most recent resection and the latest resection must have been performed within 30 days after the initial resection. Surgical resection is required; stereotactic biopsy alone is not allowed because it will not provide sufficient tissue for MGMT analysis
• STEP 1 REGISTRATION: Willing to use highly effective method of contraception for participants of childbearing potential (participants who may become pregnant or who may impregnate a partner) during therapy and for 6 months after completing treatment; this inclusion is necessary because the treatment in this study may be significantly teratogenic
• STEP 1 REGISTRATION: The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information
• STEP 2 REGISTRATION: Histopathologically proven diagnosis of glioblastoma (or gliosarcoma as a subtype of glioblastoma) confirmed by central pathology review
• STEP 2 REGISTRATION: MGMT promoter with methylation confirmed by central pathology review. Note: Patients with tissue that is insufficient or inadequate for analysis, fails MGMT testing, or has indeterminate or unmethylated MGMT promoter are excluded
• Note: Any MGMT result other than methylated would require step 2 registration to be reported as a "central review failure"
• STEP 2 REGISTRATION: Contrast-enhanced brain MRI performed either after surgery or prior to step 2 registration
• STEP 2 REGISTRATION: IDH mutation testing by at least one method (such as immunohistochemistry for IDH1 R132H) must be performed as part of standard of care and no mutation must be found (i.e IDH wildtype). (If a mutation is identified then the patient will be ineligible and must be registered as ineligible at step 2.)
• STEP 2 REGISTRATION: History/physical examination within 28 days prior to step 2 registration
• STEP 2 REGISTRATION: Karnofsky performance status (KPS) >= 70 within 28 days prior to step 2 registration
• STEP 2 REGISTRATION: Neurologic function assessment within 28 days prior to step 2 registration
• STEP 2 REGISTRATION: Age 18-70 years
• STEP 2 REGISTRATION: Hemoglobin >= 10 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 10.0 g/dl is acceptable) (Within 14 days prior to step 2 registration)
• STEP 2 REGISTRATION: Leukocytes >= 2,000/mm^3 (Within 14 days prior to step 2 registration)
• STEP 2 REGISTRATION: Absolute neutrophil count >= 1,500/mm^3 (Within 14 days prior to step 2 registration)
• STEP 2 REGISTRATION: Platelets >= 100,000/mm^3 (Within 14 days prior to step 2 registration)
• STEP 2 REGISTRATION: Total bilirubin =< 1.5 x institutional/lab upper limit of normal (ULN) (Within 14 days prior to step 2 registration)
• STEP 2 REGISTRATION: Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) =< 2.5 x ULN (Within 14 days prior to step 2 registration)
• STEP 2 REGISTRATION: Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN (Within 14 days prior to step 2 registration)
• STEP 2 REGISTRATION: Serum creatinine =< 1.5 x ULN OR creatinine clearance (CrCl) >= 50 mL/min (if using the Cockcroft-Gault formula) (Within 14 days prior to step 2 registration)
• STEP 2 REGISTRATION: For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Note: Known positive test for hepatitis B virus surface antigen (HBV sAg) indicating acute or chronic infection would make the patient ineligible unless the viral load becomes undetectable on suppressive therapy. Patients who are immune to hepatitis B (anti-hepatitis B surface antibody positive) are eligible (e.g. patients immunized against hepatitis B)
• STEP 2 REGISTRATION: For 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
• Note: Known positive test for hepatitis C virus ribonucleic acid (HCV ribonucleic acid [RNA]) indicating acute or chronic infection would make the patient ineligible unless the viral load becomes undetectable on suppressive therapy
• STEP 2 REGISTRATION: Known human immunodeficiency virus (HIV) infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months prior to step 2 registration are eligible for this trial. Testing is not required for entry into protocol
• STEP 2 REGISTRATION: Negative serum or urine pregnancy test (in persons of childbearing potential) within 14 days prior to step 2 registration
• Childbearing potential is defined as any person who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal

Exclusion Criteria:

• STEP 2 REGISTRATION: Prior therapy for tumor except for resection or prior laser interstitial thermal therapy (LITT). For example, prior chemotherapy, immunotherapy, or targeted therapy for GBM or lower grade glioma is disallowed (including but not limited to temozolomide, lomustine, bevacizumab, any viral therapy, ipilimumab or other CTLA-4 antibody, PD-1 antibody, CD-137 agonist, CD40 antibody, PDL-1 or 2 antibody, vaccine therapy, polio or similar viral injection as treatment for the tumor, and/or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) as is Gliadel wafer, radiotherapy, radiosurgery, vaccine or other immunotherapy, brachytherapy, or convection enhanced delivery
• Note: 5-aminolevulinic acid (ALA)-mediated fluorescent guided resection (FGR) photodynamic therapy (PDT) or fluorescein administered prior to/during surgery to aid resection is not exclusionary and is not considered a chemotherapy or intracerebral agent. Prior laser interstitial thermal therapy (LITT) is allowed
• STEP 2 REGISTRATION: Current or planned treatment with any other investigational agents for the study cancer
• STEP 2 REGISTRATION: Definitive clinical or radiologic evidence of metastatic disease outside the brain
• STEP 2 REGISTRATION: Prior invasive malignancy (except non-melanomatous skin cancer, cervical cancer in situ and melanoma in situ) unless disease free for a minimum of 2 years
• STEP 2 REGISTRATION: Prior radiotherapy to the head or neck that would result in overlap of radiation therapy fields
• STEP 2 REGISTRATION: Pregnancy and individuals unwilling to discontinue nursing due to the potential teratogenic effects and potential risk for adverse events in nursing infants
• STEP 2 REGISTRATION: History of allergic reactions attributed to compounds of similar chemical or biologic composition to temozolomide or lomustine
• STEP 2 REGISTRATION: History of pulmonary fibrosis
• STEP 2 REGISTRATION: Uncontrolled intercurrent illness including, but not limited to:
• Ongoing or active infection requiring intravenous (IV) antibiotics, IV antiviral, or IV antifungal treatment
• Symptomatic congestive heart failure, defined as New York Heart Association Functional Classification III/IV (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)
• Unstable angina pectoris within 6 months prior to Step 2 registration
• Uncontrolled cardiac arrhythmia
• Psychiatric illness/social situations that would limit compliance with study requirements
• STEP 2 REGISTRATION: No evidence of diffuse leptomeningeal disease that requires whole brain irradiation

Inclusion Criteria:

• Pathologically (histologically or cytologically) proven diagnosis of one of the following solid tumor malignancies within 5 years prior to registration:
• Non-small cell lung cancer
• Melanoma
• Breast cancer
• Renal cell carcinoma
• Gastrointestinal cancer
• If the original histologic proof of malignancy is greater than 5 years, then more recent pathologic confirmation (e.g., from a systemic site or brain metastasis) or unequivocal imaging confirmation of extracranial metastatic disease (e.g. CT of the chest/abdomen/pelvis, positron emission tomography [PET]/CT, etc.) is required
• Patients must have at least 1 and up to 8 total intact brain metastases detected on a contrast-enhanced MRI performed ≤ 21 days prior to registration
• At least 1 of the up to 8 lesions must be a study eligible lesion, defined as lesion with a maximum diameter as measured on any orthogonal plane (axial, sagittal, coronal) of ≥ 1.0 cm and ≤ 3.0 cm
• All brain metastases must be located outside of the brainstem and ≥ 5 mm from the optic nerves or optic chiasm and ≤ 3.0 cm in maximum dimension
• Note: brainstem metastases per the MRI within 21 days of registration are an exclusion criterion; however, if the MRI used for treatment planning performed within 7 days of SRS/FSRS reveals a brainstem metastasis, the patient remains eligible if the patient is considered an appropriate radiosurgery candidate per the local investigator
• Patients must have a diagnosis-specific graded prognostic assessment ≥ 1.5
• No more than 2 lesions planned for resection if clinically indicated
• No known leptomeningeal disease (LMD)
• Note: For the purposes of exclusion, LMD is a clinical diagnosis, defined as positive cerebrospinal fluid (CSF) cytology and/or unequivocal radiologic or clinical evidence of leptomeningeal involvement. Patients with leptomeningeal symptoms in the setting of leptomeningeal enhancement by imaging (MRI) would be considered to have LMD even in the absence of positive CSF cytology. In contrast, an asymptomatic or minimally symptomatic patient with mild or nonspecific leptomeningeal enhancement (MRI) would not be considered to have LMD. In that patient, CSF sampling is not required to formally exclude LMD, but can be performed at the investigator's discretion based on level of clinical suspicion
• Age ≥ 18 years
• Karnofsky performance status (KPS) ≥ 60
• Negative urine or serum pregnancy test (in persons of childbearing potential) within 14 days prior to registration. Childbearing potential is defined as any person who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal
• No prior radiotherapy to the brain (partial or whole brain irradiation, SRS, FSRS, or prophylactic cranial irradiation [PCI])
• 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)
• No active infection currently requiring intravenous (IV) antibiotic management
• No hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
• No chronic obstructive pulmonary disease exacerbation or other acute respiratory illness precluding study therapy

Inclusion Criteria:

1. Provision of signed and dated informed consent form 2. Stated willingness to comply with all study procedures and availability for the duration of the study 3. Age 18 years or older 4. Presumed diagnosis of glioblastoma IDH-wt (as per the 2021 WHO Classification of CNS Tumors) deemed to be potentially resectable and deemed to be a good candidate for post-operative standard of care temozolomide and radiation therapy. 1. Surgical objective is for gross total resection (GTR)ear-total resection (NTR) de-fined as ≥ 95% of contrast enhancing (CE) tumor removed plus ≤ 1 cm3 residual CE tumor. Patients with subtotal resection will still be eligible if at least 70% of the CE tumor is resected. 2. Eligibility will be confirmed after surgery when diagnosis of glioblastoma IDH-wt confirmed prior to randomization. Randomization can occur with only IDH1 immunohistochemistry and when additional molecular testing is available, if glioblastoma IDH-wt is not confirmed, the participant will be deemed a screen failure and replaced. 3. Patients with prior biopsy or subtotal resection are eligible if no other anti-cancer treatment received for glioblastoma and additional resection indicated. 5. Ability to receive filgrastim (e.g., Neupogen), leukapheresis and 3 bi-weekly injections of DOC1021 near deep cervical lymph nodes + weekly pIFN x 6 weeks. 6. Females of reproductive potential must have a negative serum pregnancy test and agree to use effective contraception (as determined appropriate for the patient by the investigator) during study treatment. 7. Adequate kidney, liver, bone marrow function, and immune function, as follows: 1. Hemoglobin ≥ 8.0 gm/dL 2. Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3 3. Platelet count ≥ 75,000/mm3 4. Calculated creatinine clearance (CrCl) > 30 mL/min using Cockcroft and Gault for-mula: i. For males = (140 - age[years]) x (body weight [kg]) / (72 x serum creatinine [mg/dL]) ii. For females = 0.85 x value from male formula e. Total bilirubin ≤ 1.5 times upper limit of normal (ULN) except in patients with Gilbert's disease for which total bilirubin must be ≤ 2 times ULN f. Aspartate transaminase AST (SGOT) and alanine aminotransferase ALT (SGPT) ≤ 3 times the ULN 8. Karnofsky Performance Score ≥ 70

Exclusion Criteria:

1. Infratentorial, recurrent, leptomeningeal or extracranial disease. 2. Patients who are pregnant or breastfeeding. 3. Known active HIV or hepatitis infection. Patients with HIV that is well-controlled and have undetectable viral titers remain eligible. Patients with history of HCV adequately treated such that RNA viral load is negative also remain eligible. 4. Any severe or uncontrolled medical condition or other condition that could affect participation in this study as determined by the investigator, including but not limited to: uncontrolled or severe cardiac disease, systemic autoimmune disorders requiring immunosuppression in the past 2 years*, autoimmune hyper/hypothyroidism, untreated viral hepatitis, autoimmune hepatitis. *autoimmune disorders include but are not limited to rheumatoid arthritis, psoriasis and inflammatory bowel disease and immunosuppressive medications include DMARDs like methotrexate, TNF inhibitors, IL-6 receptor blockers, CD80/86 inhibitors, anti-CD20 and JAK inhibitors 5. Treatment with another investigational drug or other experimental intervention within the last 30 days.