Additional Study Information: This is a Phase 1 multicenter study of pevonedistat in combination with Temozolomide and Irinotecan in pediatric patients with refractory solid tumors, including CNS tumors and lymphoma. The study treatment is considered experimental because pevonedistat is not approved by the United States (US) Food and Drug Administration (FDA) for treating pediatric patients with refractory solid tumors, including CNS tumors and lymphoma. The purpose of this study is to estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of pevonedistat administered in combination with Temozolomide and Irinotecan. Another objective is to define the toxicities and potential antitumor activity of pevonedistat, a novel chemotherapy agent (first-in-class NEDD8 activating enzyme inhibitor), in combination with Temozolomide and Irinotecan in pediatric patients with refractory solid tumors, including CNS tumors and lymphoma. During Cycle 1, pevonedistat, starting at Dose Level 1 = 15mg/m2, will be administered as an intravenous infusion over 60 minutes on Days 1, 8, 10 and 12 of cycle 1 (28-day cycle). Temozolomide will be administered orally at 100 mg/m2/dose (maximum dose 200 mg) on days 8 through 12. Irinotecan will be administered as an intravenous infusion over 90 minutes on days 8 through 12 one hour after Temozolomide. During Cycle 2 and subsequent cycles, pevonedistat will be administered as an intravenous infusion over 60 minutes on Days 1, 3, and 5 of each cycle in combination with Temozolomide and Irinotecan on days 1 through 5. Cefixime or an available equivalent antibiotic will be used as diarrheal prophylaxis during all cycles. Patients must receive Pneumocystis (PCP) prophylaxis starting on Cycle 1 Day 8, twice daily for 3 consecutive days a week (i.e., BID Friday, Saturday, and Sunday) every week, or per institutional practice, until the end of protocol therapy. Blood samples will be collected to determine how much pevonedistat is in the blood during the