Glioma Clinical Trials

⁃ 3.1.1 Age: Patients must be ≥12 months and ≤25 years of age at the time of signing informed consent/assent.

⁃ 1.2 Diagnosis: Patients must have a histologically confirmed diagnosis of glioblastoma.

⁃ 1.3 Proof of RRD: By tumor immunohistochemistry showing functional loss of mismatch repair gene expression (MLH1, MSH2, MSH6, PMS2), or based on prior germline testing confirming congenital mismatch repair deficiency (CMMRD) or Lynch syndrome. To be done locally. Results have to be available within four weeks of last surgery.

⁃ 1.4 Tumor Tissue Specimen: Provide a tumor tissue specimen for molecular profiling, including TMB analysis. Any tumor sequencing data if available at time of enrolment will be recorded for relevant pathogenic variants in the mismatch repair and polymerase-proofreading genes to suggest RRD. A specimen from the time of relapse/ progression while on the study is required as well, when applicable.

⁃ 1.5 Favorable immune markers: High PD1 and CD8 positivity as detailed in the lab manual. To be done locally. Results have to be available within 4 weeks of last surgery.

⁃ 1.6 Surgical and disease status: Patients should have had Gross total resection (GTR)/Near Total Resection (NTR) as confirmed by the post-surgery scan. Patients are allowed a second look surgery to achieve NTR/GTR provided no tumor directed systemic or radiation therapy has been administered before this second surgery. Patients should be able to start therapy within 4 weeks of last surgery.

⁃ 1.7 Allowable Prior Therapy: 3.1.7.1 Patients must have recovered from the acute toxic effects of all prior anti-cancer therapies (with the exception of alopecia and lymphopenia). Previous treatment with nivolumab and/or other anti- PD-1/PD-L1 inhibitors for other prior tumors (other than high-grade glioma) will be permitted.

⁃ 1.7.2

‣ Prior Therapy: No prior therapy except surgery will be permitted for high grade glioma. If the patient was previously diagnosed and treated for another tumor (other than high grade glioma), the patients must have completed that treatment and have no active disease in order to be enrolled in this trial The following time periods apply for prior therapy for other tumors:

⁃ Cytotoxic chemotherapy: At least 21 days prior to initiation of protocol therapy from the last dose of cytotoxic or myelosuppressive chemotherapy; at least 42 days if prior nitrosourea (such as lomustine, CCNU).

⁃ Hematopoietic growth factors: At least 7 days prior to initiation of protocol therapy from the last dose of short-acting growth factor; at least 14 days for long-acting.

⁃ Anti-cancer agents not known to be myelosuppressive: At least 7 days prior to initiation of protocol therapy from the last dose.

⁃ Interleukins, interferons, and cytokines (other than hematopoietic growth factors): At least 21 days prior to initiation of protocol therapy from the last dose.

⁃ Antibodies: At least 21 days prior to initiation of protocol therapy from the last dose and toxicity related to prior antibody therapy must be recovered to Grade ≤1.

⁃ Radiotherapy: At least 14 days prior to initiation of protocol therapy from local radiotherapy; at least 150 days from total body irradiation (TBI), craniospinal radiotherapy, or radiation to

⁃ ≥50% of the pelvis; at least 42 days from other substantial bone marrow radiation.

⁃ Radiopharmaceutical therapy (e.g., 131I-MIBG): At least 42 days prior to initiation of protocol therapy from systemically administered radiopharmaceutical therapy.

⁃ Autologous stem cell infusion including boost infusion: At least 42 days prior to initiation of protocol therapy.

⁃ Cellular therapy: At least 42 days prior to initiation of protocol therapy from any type of cellular therapy.

⁃ 1.8 Performance Status: Lansky play score ≥50 if ≤16 years of age; Karnofsky performance scale ≥50 if \>16 years of age. See Appendix A. Patients unable to walk due to paralysis but who are using a wheelchair will be considered ambulatory for the purpose of assessing the performance score.

⁃ 1.9 Organ Function: 3.1.9.1

‣ Adequate bone marrow function defined as:

⁃ peripheral absolute neutrophil count (ANC) ≥750/mm3 (0.75x109/L)

⁃ platelet count ≥75,000/mm3 (75x109/L), transfusion independent, defined as not receiving platelet transfusions at least 7 days prior to initiation of protocol therapy 3.1.9.2

‣ Adequate renal function defined as:

• creatinine clearance or radioisotope GFR ≥60 mL/min/1.73 m2; OR serum creatinine based on age/gender 3.1.9.3

‣ Adequate liver function defined as:

⁃ bilirubin (sum of conjugated and unconjugated) ≤1.5 x upper limit of normal (ULN) for age

⁃ ALT (SGPT) ≤135 U/L (i.e., 3 x ULN). For the purposes of this study, the ULN for ALT (SGPT) is 45 U/L 3.1.9.4

‣ Adequate pulmonary function defined as:

• no evidence of dyspnea at rest, no exercise intolerance due to pulmonary insufficiency, and pulse oximetry ≥92% while breathing room air 3.1.9.5

‣ Adequate cardiac function defined as:

⁃ no signs or symptoms of heart failure in a patient who has no history of congestive heart failure, no prior exposure to cardiotoxic drugs, and no radiotherapy to the heart; OR

⁃ shortening fraction of ≥27% or ejection fraction of ≥50% by echocardiogram 3.1.9.6

‣ Adequate pancreatic function defined as:

• serum lipase ≤ ULN at screening 3.1.9.7

‣ Viral Infection:

⁃ Human immunodeficiency virus (HIV): Infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months prior to initiation of protocol therapy are eligible.

⁃ Hepatitis B virus (HBV): Patients with evidence of chronic infection with undetectable viral load are eligible. Suppressive therapy, if indicated, is allowed.

⁃ Hepatitis C virus (HCV): Infected patients currently on treatment with undetectable viral load are eligible. Patients with a history of infection must have been treated and cured.

‣ Note: Routine screening for HBV, HCV or HIV status prior to enrollment is not required.

⁃ 1.9.8 Informed Consent: All patients and/or their parents or legally authorized representatives must have the ability to understand and the willingness to sign, provide a thumbprint (e.g.., for illiterate patients), or use an authorized method to duly document the informed consent in line with the local IRB/IEC requirements and the regulations in force). Assent, where appropriate, will be obtained according to local regulations.