This study will include children and young adults > 6 months to <22 years of age with recurrent or progressive high grade glioma (HGG).

This is a randomized, double-blinded, three-arm, placebo-controlled, pilot phase 1 trial to evaluate the immunological local and systemic changes following neoadjuvant checkpoint inhibition, as well as the preliminary efficacy of neoadjuvant checkpoint inhibition followed by surgery and adjuvant combination checkpoint inhibition in children and young adults with progressive or recurrent HGG.

• Group A: Participants will receive one-time dose of nivolumab and placebo prior to surgery.
• Group B: Participants will receive one-time dose of nivolumab and ipilimumab prior to surgery.
• Group C: Participants will receive one-time dose of placebo and ipilimumab prior to surgery.

All participants then proceed with maximum safe surgical resection. Once a participant recovers from surgery, they will receive the same adjuvant therapy regardless of the neoadjuvant group. Nivolumab and ipilimumab will be given every three weeks for a total of three post-operative doses followed by nivolumab every 2 weeks as per the recommended phase 2 dose (RP2D) for pediatric patients. 

More effective treatments are needed for pediatric high grade gliomas. Despite aggressive multimodality therapy, the long-term survival is poor, and known cures do not exist for recurrence. Immunotherapy has been shown to be a promising treatment for a number of types of cancer, including melanoma and non-small cell lung cancer. Results have varied across tumor models as immune suppression has proven a significant barrier to successful outcomes, particularly within bulky and recurrent solid tumors.

The timing of how, and when, immunotherapy is initiated may be critical for the optimal activation and expansion of tumor–specific T lymphocytes. Neoadjuvant immunotherapy serves as a primer for systemic immune responses, activating tumor-specific T-cells that seek out distant tumor cell deposits. We hypothesize neoadjuvant checkpoint inhibition prior to surgery with CTLA-4 and/or PD-1 antibody blockade in children and young adults with recurrent or progressive HGG will induce a local immune response. This local immune response will become amplified by the surgical removal of the immune suppressive cells within the tumor microenvironment, resulting in enhanced efficacy.

• To measure the relative changes in cell cycle-related genetic signature of the tumor microenvironment post administration of neoadjuvant nivolumab and placebo, ipilimumab and placebo, and nivolumab and ipilimumab in children and young adults with recurrent or progressive HGG when compared to a cohort of archived non-treated recurrent pediatric HGG samples.
• To characterize the safety and tolerability of neoadjuvant nivolumab and placebo, neoadjuvant ipilimumab and placebo, and neoadjuvant ipilimumab and nivolumab followed by adjuvant ipilimumab and nivolumab in children and young adults with recurrent or progressive HGG.

INCLUSION CRITERIA

• Male/female participants with recurrent or progressive HGG (WHO grade III or grade IV) who are candidates for surgical tumor debulking will be enrolled in this trial
• All screening 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.
• 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.
• Have evidence of recurrence or progression of disease by MRI scan
• 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.
• A primary goal of surgery must be cytoreduction, and not solely on diagnostic biopsy.
• Age: Participants must be > 6 months and < 22 years of age at time of enrollment
• 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.
• 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 are known to occur. The duration of this interval must be discussed with the study chair.
• Anti-cancer agents not known to be myelosuppressive (e.g. not associated with reduced platelet or ANC counts): At least 7 days after the last dose of agent.
• Interleukins, Interferons and Cytokines (other than Hematopoetic Growth Factors): ≥ 21 days after the completion of interleukins, interferon or cytokines (other than Hematopoetic 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.
• Participants must not have received prior exposure to PD-1, PD-L1 or CTLA4 inhibitors.
• Stem Cell Infusion (with or without TBI):
  • Autologous stem cell infusion including boost infusion: ≥ 42 days
• Participants must be willing to forego cytotoxic anti-tumor therapies except study-defined therapy while being treated on study
• Organ Function Requirements
  • Adequate bone marrow function
  • Adequate renal function
  • Adequate liver function
• Pregnancy: The effects of nivolumab and ipilimumab on the developing human fetus are unknown.  For this reason women of child-bearing potential and men 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 4 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.
• MRI within 28 days prior to registration

EXCLUSION CRITERIA

• Current or planned participation in a study of an investigational agent or using an investigational device.
• Has a diagnosis of immunodeficiency.
• Has tumor primarily localized to the brainstem or spinal cord.
• Has presence of diffuse leptomeningeal disease or extracranial disease.
• Has received systemic immunosuppressive treatments (such as methotrexate, chloroquine, azathioprine, etc.), aside from anti-neoplastic chemotherapy or systemic corticosteroids within six months of registration.
• Participants with a concurrent condition requiring systemic treatment with either corticosteroids (> 0.25 mg/kg daily prednisone equivalent) or other immunosuppressive medications within 14 days of start of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses > 0.25 mg/kg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
• Unable to taper steroids due to ongoing mass effect; a maximum       dexamethasone dose of 0.1 mg/kg/day is allowed, but preferably have been discontinued (inhaled or topical use of steroids is allowed).
• Has a known history of active TB (Bacillus Tuberculosis).
• Has a known additional malignancy that is progressing or requires active treatment within 3 years of registration. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Has known history of, or any evidence of active non-infectious pneumonitis.
• Has an active infection requiring systemic therapy.
• Has a known hypersensitivity to any of the study therapy products.
• Has a known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed at sites where mandated locally.
• Any prior positive test result for hepatitis B virus or hepatitis C virus indicating presence of virus, e.g., Hepatitis B surface antigen (HBsAg, Australia antigen) positive, or Hepatitis C antibody (anti-HCV) positive (except if HCV-RNA negative).
• Participants who have had prior allogenic hematopoietic stem cell transplant (HSCT)
• Any serious or uncontrolled medical disorder that, in the opinion of the investigator may increase the risk associated with study participation or study drug administration, impair the ability of the participant to receive protocol therapy or interfere with interpretation of study results.

Funding is provided by BMS, Kids Shouldn’t Have Cancer Foundation, and Fabulous Faith’s Foundation.