PNOC019: This study is assessing the side effects of immunotherapy before and after surgery in treating children and young adults with high grade glioma that has come back (recurrent) or is increasing in scope or severity (progressive)A Randomized, Double-Blinded, Pilot Trial of Neoadjuvant Checkpoint Inhibition Followed by Combination Adjuvant Checkpoint Inhibition in Children and Young Adults With Recurrent or Progressive High Grade Glioma (HGG)

Inclusion

1. Participants with recurrent or progressive high-grade gliomas (HGG) (World Health Organization (WHO) grade III or grade IV) who are candidates for surgical tumor debulking will be enrolled in this trial
2. All assessments are to occur within 14 days of registration except where otherwise noted. The participant and their legal parent/guardian must be thoroughly informed about all aspects of the study, including the study visit schedule and required evaluations and all regulatory requirements for informed consent. The written informed consent must be obtained from the participant and legal parent/guardian prior to enrollment
3. Have a history of previously treated histologically confirmed World Health Organization grade III or IV HGG. Previous first line therapy with radiation and/or chemotherapy
4. Have evidence of recurrence or progression of disease by MRI scan
5. Participants must be adequate medical candidates for surgical resection. The intent of surgical resection is to allow both cytoreduction and tumor debulking as part of standard of care, and also collect a minimum of 100 mg of tumor tissue for the study tissue endpoints
6. A primary goal of surgery must be cytoreduction, and not solely on diagnostic biopsy
7. Age: Participants must be > 6 months and < 22 years of age at time of enrollment
8. Karnofsky >= 50 for participants > 16 years of age and Lansky >= 50 for participants =< 16 years of age. Participants who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
9. Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to enrollment (on stable or tapering dosing of steroids). A baseline detailed neurological exam should clearly document the neurologic status of the patient at the time of enrollment on the study.

10. Prior Therapy: Participants must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. If after the required timeframe, the defined eligibility criteria are met, e.g. blood count criteria, the patient is considered to have recovered adequately

    • Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive. At least 21 days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days if prior nitrosourea)
    • An interval of at least 12 weeks from the completion of radiation therapy to registration unless there is unequivocal histologic confirmation of tumor progression

    • Hematopoietic growth factors: At least 14 days after the last dose of a long-acting growth factor (e.g. pegfilgrastim) or 7 days for short acting growth factor. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events (AEs) are known to occur. The duration of this interval must be discussed with the study chair.

      • Had their last dose of biologic (anti-neoplastic agent) ≥7 days prior to study registration, or beyond the time during which AEs are known to occur.
    • Anti-cancer agents not known to be myelosuppressive (e.g. not associated with reduced platelet or absolute neutrophil count [ANC] counts): At least 7 days after the last dose of agent
    • Interleukins, interferons and cytokines (other than hematopoietic growth factors): >= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors)
    • Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1
    • An interval of at least 12 weeks from prior exposure to PD-1 or PD-L1 inhibitors.
    • Participants must not have received prior exposure to CTLA4 inhibitors.

    • Stem cell infusion (with or without total-body irradiation (TBI)):

      • Autologous stem cell infusion including boost infusion: >= 42 days
11. Participants must be willing to forego cytotoxic anti-tumor therapies except study-defined therapy while being treated on study

12. Organ Function Requirements:

    • Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
    • Platelet count >= 100,000/mm^3

    • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 OR a serum creatinine based on age/gender as follows:

      • Age: Maximum Serum Creatinine (mg/dL)
      • 6 months to < 3 years: 0.6 (male and female)
      • 3 to < 6 years: 0.8 (male and female)
      • 6 to < 10 years: 1 (male and female)
      • 10 to < 13 years: 1.2 (male and female)
      • 13 to < 16 years: 1.5 (male), 1.4 (female)
      • >= 16 years: 1.7 (male), 1.4 (female)
    • Bilirubin (sum of conjugated and unconjugated) =< 1.5 x upper limit of normal (ULN) for age (except participants with Gilbert syndrome who must have a total bilirubin level of < 3.0
    • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3.0 x ULN
    • Serum albumin >= 2
13. Pregnancy: The effects of nivolumab and ipilimumab on the developing human fetus are unknown. For this reason women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and 5 months after completion of therapy. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
14. MRI within 28 days prior to registration.