Testing the Combination of Two Immunotherapy Drugs (Nivolumab and Ipilimumab) in Children, Adolescent, and Young Adult Patients With Relapsed/Refractory Cancers That Have an Increased Number of Genetic Changes, The 3CI Study

PRIMARY OBJECTIVE: I. To confirm the safety and tolerability of nivolumab-based combination therapy in children, adolescent and young adult (CAYA) patients with relapsed/refractory hypermutant cancers (including solid tumors, central nervous system \[CNS\] tumors, neuroblastoma, and lymphoma). Ia. To determine the tolerability, define and describe the toxicities, and determine the recommended phase 2 dose (RP2D) of nivolumab and ipilimumab combination therapy in CAYA patients with relapsed/refractory hypermutant cancers. SECONDARY OBJECTIVE: I. To assess objective overall response rate (ORR) to the nivolumab-based combination therapy in CAYA patients with relapsed/refractory hypermutant cancers within the confines of a Phase 1b study. EXPLORATORY OBJECTIVES: I. To assess clinical benefit rate (CBR) (objective response and stable disease for at least two \[2\] protocol reassessments), progression-free survival (PFS), and overall survival (OS) following nivolumab-based combination therapy in CAYA patients with relapsed/refractory hypermutant cancers. II. To explore correlations between tumor genotype (including tumor mutation burden \[TMB\], specific gene mutations, etc.) and response to nivolumab-based combination therapy in CAYA patients with relapsed/refractory hypermutant cancers. III. To discover biomarkers predicting response of hypermutant CAYA cancers undergoing PD-1 blockade including tumor neoantigen formation, specific T-cell receptor rearrangements (TCRR) of tumor infiltrating lymphocytes (TILs), and detailed characterization and activation of the immune infiltrations including the TILs. IV. To explore the use of minimally invasive methods to monitor and predict response to immune checkpoint inhibition in hypermutant cancers including assessment of circulating tumor deoxyribonucleic acid (DNA) and circulating T-cells immunophenotypic profiling (differentiation markers, cytokines, etc.). OUTLINE: PART I: Patients undergo collection of tissue samples for TMB level. Patients with elevated TMB may be eligible for Part II. PART II: Patients are assigned to 1 of 2 dose levels. DOSE LEVEL 1: Patients receive nivolumab intravenously (IV) over 30-90 minutes and ipilimumab IV over 30 minutes on day 1. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab IV over 30-90 minutes on days 1 and 15. Treatment repeats every 28 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity. DOSE LEVEL -1: Patients receive nivolumab IV over 30-90 minutes on days 1 and 15. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then every 12 weeks for 1 year.