Inclusion Criteria:

• PHASE I: Patients between ≥ 1 year and ≤ 21 years of age at the time of study enrollment
• PHASE II: Patients between ≥ 1 year and ≤ 39 years of age at the time of study enrollment
• PHASE I: Patients with recurrent/refractory solid tumors excluding primary central nervous system tumors
• PHASE II: Patients with (FLC), which must include genomic confirmation of the DNAJB1:PRKACA fusion performed at a Clinical Laboratory Improvement Act (CLIA)-certified laboratory
• PHASE I: Patients must have either measurable or evaluable disease
• PHASE II: Patients must have measurable disease
• PHASE I: Patient's current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life
• PHASE II: Patients must have FLC which is recurrent/refractory to at least one line of prior systemic therapy
• Patients with FLC that is unresectable at initial diagnosis but is not recurrent/refractory to at least one prior line of systemic therapy nor metastatic are NOT eligible for either phase 1 or phase 2
• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients ≤ 16 years of age. See https://www.cogmembers.org/site/pages/default.aspx?page=Prot_reference_materials under Standard Sections for Protocols
• Patients must have fully recovered (grade < 2) 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 numerical eligibility criteria are met, eg, blood count criteria, the patient is considered to have recovered adequately
  • Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive: See Developmental Therapeutics (DVL) homepage on the Children's Oncology Group (COG) members site for commercial and investigational agent classifications. For agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned research coordinator prior to enrollment
    • Solid tumor patients: ≥ 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea). Please refer to the table of myelosuppressive/anticancer agents on the COG website: https://www.cogmembers.org/uploadedFiles/Site/Disc/DVL/Documents/TableOfMyelosuppressiveAnti-CancerAgents.pdf
  • Anti-cancer agents not known to be myelosuppressive (eg, not associated with reduced platelet or absolute neutrophil count [ANC] counts): ≥ 7 days after the last dose of agent. See the DVL homepage on the COG Members site for commercial and investigational agent classifications. For agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned research coordinator prior to enrollment
  • 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
  • Corticosteroids: If used to modify immune adverse events related to prior therapy, ≥ 14 days must have elapsed since last dose of corticosteroid
  • Hematopoietic growth factors: ≥ 14 days after the last dose of a long-acting growth factor (eg, 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
  • Interleukins, interferons and cytokines (other than hematopoietic growth factors): ≥ 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors)
  • Stem cell Infusions (with or without total body irradiation [TBI]):
    • Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor lymphocyte infusion (DLI) or boost infusion: ≥ 84 days after infusion and no evidence of graft versus host disease (GVHD)
    • Autologous stem cell infusion including boost infusion: ≥ 30 days
  • Cellular therapy: ≥ 30 days after the completion of any type of cellular therapy (eg, modified T cells, natural killer [NK] cells, dendritic cells, etc.)
  • Radiotherapy (XRT)/external beam irradiation including protons: ≥ 14 days after local XRT; ≥ 150 days after TBI, craniospinal XRT or if radiation to ≥ 50% of the pelvis; ≥ 42 days if other substantial bone marrow (BM) radiation
  • Radiopharmaceutical therapy (eg, radiolabeled antibody, lobenguane I-131 [131I-MIBG]): ≥ 42 days after systemically administered radiopharmaceutical therapy
  • Patients must not have received prior BCL-XL specific therapy (e.g. navitoclax, DT2216). Prior therapy with irinotecan or other topoisomerase 1 inhibitors and/or other BH3 mimetics which are not BCL-XL selective (e.g. venetoclax) are acceptable
  • Surgical Procedure:
    • Central line placement, open or core needle biopsy of sites other than liver: ≥ 2 days prior to enrollment
    • Open or laparoscopic biopsies or core needle biopsies of liver > 7 days prior to enrollment
    • All other surgeries ≥ 14 days prior to enrollment
• For patients with solid tumors without known bone marrow involvement: Peripheral absolute neutrophil count (ANC) ≥ 1000/µL
• For patients with solid tumors without known bone marrow involvement: Platelet count ≥ 100,000/µL (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
• Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions). These patients will not be evaluable for hematologic toxicity. At least 5 of every cohort of 6 patients must be evaluable for hematologic toxicity for the dose-escalation part of the study. If dose-limiting hematologic toxicity is observed, all subsequent patients enrolled must be evaluable for hematologic toxicity
• Pediatric patients (< 18 years):
  • A creatinine based on age/gender as follows:
    • 1 to < 2 years: Maximum serum creatinine (mg/dL) 0.6 (male), 0.6 (female)
    • 2 to < 6 years: Maximum serum creatinine (mg/dL) 0.8 (male), 0.8 (female)
    • 6 to < 10 years: Maximum serum creatinine (mg/dL) 1 (male), 1 (female)
    • 10 to < 13 years: Maximum serum creatinine (mg/dL) 1.2 (male), 1.2 (female)
    • 13 to < 16 years: Maximum serum creatinine (mg/dL) 1.5 (male), 1.4 (female)
    • ≥ 16 years: Maximum serum creatinine (mg/dL) 1.7 (male), 1.4 (female)
      • OR a 24 hour urine creatinine clearance ≥ 70 mL/min/1.73 m^2
      • OR a glomerular filtration rate (GFR) ≥ 70 mL/min/1.73 m^2. GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard). Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates are not acceptable for determining eligibility
• Patients with solid tumors: Bilirubin (sum of conjugated + unconjugated or total) ≤ 1.5 x upper limit of normal (ULN) for age
• Patients with solid tumors: Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) ≤ 135 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L
• Patients with solid tumors: Albumin ≥ 2 g/dL
• Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled as evidenced by no increase in seizure frequency in the prior 7 days. If needed, evaluate use of enzyme-inducing anticonvulsants
• Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE] version [v]5) resulting from prior therapy must be ≤ grade 2, with the exception of decreased tendon reflex (DTR). Patient with any grade of tendon reflex decrease are eligible

Exclusion Criteria:

• Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies, OR because there is yet no available information regarding human fetal or teratogenic toxicities. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use two effective methods of birth control, including a medically accepted barrier or contraceptive method (eg, male or female condom) for the duration of the study. Abstinence is an acceptable method of birth control. Patients who could become pregnant should use highly effective contraception during therapy and for 6 months after the last irinotecan dose or 120 days after the last dose of DT2216, whichever is longer. Patients with partners who could become pregnant should use condoms during therapy and for 3 months after the last dose irinotecan or 120 days after the last dose of DT2216, whichever is longer
• Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible. If used to modify immune adverse events related to prior therapy, ≥ 14 days must have elapsed since last dose of corticosteroid
• Patients who are currently receiving another investigational drug are not eligible
• Patients who are currently receiving other anti-cancer agents are not eligible
• Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial
• Patients who have received drugs that are strong inducers or inhibitors of CYP3A4 within 7 days prior to study enrollment are not eligible
• Patients with lymphoma are excluded
• Patients who have an uncontrolled infection are not eligible
• Patients with grade ≥ 2 diarrhea at baseline are not eligible
• Patients who have received a prior solid organ transplantation are not eligible
• 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
• Dedicated central nervous system (CNS) imaging is not required but patients with current active CNS metastasis whether symptomatic or discovered incidentally without clinical symptoms, are not eligible