Pilot Study of Nivolumab in Pediatric Patients With Hypermutant Cancers

This is an open-label, single arm, multi-center, pilot study of Nivolumab in pediatric patients with recurrent or refractory hypermutant malignancies aged 12 months to 18 years of age. This study is to assess clinical and radiological benefits of treatment with Nivolumab in children with hypermutated cancers, including those with bMMRD syndrome. It is our expectation that patients with bMMRD syndrome will account for the majority of patients enrolled on this study.

Inclusion Criteria: Part I 1. Consent/ Assent: Patient and/or Legally Acceptable Representative (LAR; such as a parent or guardian, as applicable) must be willing and able to provide written informed consent/assent for the trial as per local requirements. 2. Age: patients must be ≥ 12 months and \ 92% on room air. e. Adequate Pancreatic Function Defined as: Serum lipase ≤ ULN. Patients with glucose intolerance should be on a stable regiment and be monitored. 10\. For patients with brain tumors, debulking surgery prior to treatment with nivolumab should be considered when appropriate to reduce the risk of pseudoprogression-associated toxicities. Such debulking surgery is not mandatory for trial enrollment. Patients should be recovered from surgery and wait at least 7 days from surgery before first dose. Exclusion Criteria: Part II Only 1. Women who are pregnant or breastfeeding and men who are sexually active with women of childbearing potential (WOCBP)\* who are not willing to use effective contraception, or to practice abstinence if this is the usual lifestyle and preferred contraception for the patient. \*\* * Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as there is yet no available information regarding human fetal or teratogenic toxicities. * WOCBP must have a negative serum pregnancy test every 4 weeks. and During Part II screening, WOCBP must have a negative serum pregnancy test. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of nivolumab administration. WOCBP who are sexually active, must be willing to adhere to effective contraception during treatment and for 5 months after the last dose of nivolumab. * Men who are sexually active with WOCBP must be willing to adhere to effective contraception during treatment and for 7 months after the last dose of nivolumab. * Women who are surgically sterile, as well as azoospermic men do not require contraception. 2. Concomitant Medications 1. Corticosteroids: Patients requiring systemic steroid therapy or any other form of immunosuppressive therapy within seven (7) days prior to first dose of trial therapy or while on trial are not eligible. The use of physiologic doses of corticosteroids (up to 5mg/m2/day prednisone equivalent) is permitted following discussion with the Study Chair or Co-Chair. 2. Investigational Drugs: Patients who are currently receiving another investigational drug are not eligible. 3. Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents are not eligible. 3. Patients with a History of Autoimmune Disease • Patients with a history of autoimmune disorder that has required systemic treatment in the previous two (2) years are not eligible. Asymptomatic laboratory abnormalities (e.g. ANA, rheumatoid factor, altered thyroid function studies) will not render a patient ineligible in the absence of a diagnosis of an autoimmune disorder. Replacement therapy (e.g. thyroxine, insulin or physiologic corticosteroid replacement therapy) is not considered a form of systemic treatment. 4. Infection: Patients who have an uncontrolled infection are not eligible. 5. HIV and/or Hepatitis B/C patients: Patients with known HIV/AIDS or acute/chronic Hepatitis B or C are excluded. 6. Transplant patients: Patients who have received prior allogeneic Bone Marrow (BM) transplants or prior solid organ transplantation are not eligible. 7. Non-Compliance: Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible. 8. Previous anti-PD-1 and/or anti-PD-L1 therapy: Patients who have received prior anti-PD-1 and/or anti-PD-L1 directed therapy (mAb or small molecule) are not eligible. 9. Live vaccines: Patients who have received a live vaccine within 30 days of start of study treatment are not eligible.