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

Inclusion Criteria:

• PART 1: Patients must have histologically or cytologically confirmed malignancy atthe time of initial diagnosis, relapse, or recurrence. Patients must have recurrentor refractory cancer for which standard curative or palliative measures do not existor are no longer effective

• Patients with multiple concurrent and/or sequential neoplasms are eligible

• Patients with central nervous system (CNS) tumors are eligible, except thosewith diffuse intrinsic pontine glioma

• Patients with lymphoma are eligible; patients with leukemia are excluded

• Chemotherapy-naive patients are eligible in cases where first-line therapy doesnot include chemotherapy (e.g., surgery only for ependymoma management)

• PART 1: Patients must have evidence of one or more of the following criteria incurrent or previous tumor:

• Microsatellite instability (MSI-H)

• Mutation causing functional loss of mismatch repair gene expression (MLH1,MSH2, MSH6, PMS2, EPCAM, MSH3)

• Hypermutation in any tumor (including primary malignancy for patients withrelapse or previous cancer diagnoses)

• Functional mutation of POLE or POLD1 genes

• A syndrome linked to hypermutant cancer predisposition such as congenitalmismatch repair deficiency (CMMRD), Lynch syndrome, or xeroderma pigmentosum (XP) is also permitted

• Other factors or sequencing evidence not listed above but which may bepredictive of hypermutant cancer may be permitted after discussion with theprotocol principal investigator

• PART 1: A tumor tissue specimen must be provided for molecular profiling, includingTMB analysis. The specimen may be archival or prospective, from a medicallynecessary surgery, biopsy, or excision. Tissue will not be obtained solely for thistrial. A specimen from the time of most recent relapse/progression is preferred, butnot mandatory

• Tissue is preferred. However, if necessary, previously extracted DNA may beused with the approval of the protocol principal investigator if extracted in aclinically certified laboratory and prepared in an Foundation Medicine Inc. (FMI), TMB assay-compatible manner

• PART 1: All patients and/or their parents or legally authorized representatives musthave the ability to understand and the willingness to sign a written informedconsent. Assent, where appropriate, will be obtained according to local policy.Patients with impaired decision-making capacity will not be excluded

• PART 2: Patients must have histologically or cytologically confirmed malignancy atthe time of initial diagnosis, relapse, or recurrence. Patients must have recurrentor refractory cancer for which standard curative or palliative measures do not existor are no longer effective

• Patients with multiple concurrent and/or sequential neoplasms are eligible

• Patients with CNS tumors are eligible, except those with diffuse intrinsicpontine glioma or bulky tumors

• Patients with lymphoma are eligible (provided other criteria, such as bonemarrow function, are met); patients with leukemia are excluded

• Chemotherapy-naive patients are eligible in cases where first-line therapy doesnot include chemotherapy (e.g., surgery only for ependymoma management)

• PART 2: Patients must have measurable disease

• Patients with neuroblastoma without measurable soft tissue but with iobenguane (MIBG) avid disease are eligible

• Patients with bone marrow only disease are excluded

• PART 2: Patients must have confirmation of cancer with a TMB of >= 10 mutations (mut)/megabase (Mb) as determined by an next generation sequencing (NGS) targetedcancer gene panel performed by Foundation Medicine Inc. (FMI). Proof of TMBeligibility can be from Part 1 participation or a previously acquired FMI report

• PART 2: Patients must have recovered from the acute toxic effects of all prioranti-cancer therapies (with the exception of alopecia and lymphopenia)

• Previous treatment with nivolumab and/or other anti-PD-1/PD-L1 inhibitors ispermitted

• Previous treatment with ipilimumab and/or other anti-CTLA-4 inhibitors ispermitted

• Previous treatment with combined anti-PD-1/PD-L1 and anti-CTLA-4 inhibitors isnot be permitted

• PART 2: The following time periods apply for prior therapy. Patients must have:

• Cytotoxic chemotherapy: At least 21 days prior to treatment initiation from thelast dose of cytotoxic or myelosuppressive chemotherapy; at least 42 days ifprior nitrosourea (such as lomustine, CCNU)

• Hematopoietic growth factors: At least 7 days prior to treatment initiationfrom the last dose of short-acting growth factor; at least 14 days forlong-acting

• Anti-cancer agents not known to be myelosuppressive: At least 7 days prior totreatment initiation from the last dose

• Interleukins, interferons, and cytokines (other than hematopoietic growthfactors): At least 21 days prior to treatment initiation from the last dose

• Antibodies: At least 21 days prior to treatment initiation from the last doseand toxicity related to prior antibody therapy must be recovered to grade =< 1

• Radiotherapy: At least 14 days prior to treatment initiation from localradiotherapy; at least 150 days from total body irradiation (TBI), craniospinalradiotherapy, or radiation to >= 50% of the pelvis; at least 42 days from othersubstantial bone marrow radiation

• Radiopharmaceutical therapy (e.g., 131I-MIBG): At least 42 days prior totreatment initiation from systemically administered radiopharmaceutical therapy

• Autologous stem cell infusion including boost infusion: At least 42 days priortreatment initiation

• Cellular therapy: At least 42 days prior to treatment initiation from any typeof cellular therapy

• PART 2: Lansky play score >= 50 if =<16 years of age; Karnofsky performance scale >= 50 if =< 16 years of age. Patients unable to walk due to paralysis but who are usinga wheelchair will be considered ambulatory for the purpose of assessing performancestatus

• PART 2: Peripheral absolute neutrophil count (ANC) >= 750/mm^3 (0.75 x 10^9/L)

• PART 2: Platelet count >= 75,000/mm^3 (75 x 10^9/L), transfusion independent,defined as not receiving platelet transfusions at least 7 days prior to treatmentinitiation

• PART 2: Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 60mL/min/1.73 m^2; OR serum creatinine based on age/gender as follows:

• Age: 1 to < 2 years; Maximum serum creatinine: 0.6 mg/dL; 53 umol/L (male); 0.6mg/dL; 53 umol/L (female)

• Age: 2 to < 6 years; Maximum serum creatinine: 0.8 mg/dL; 71 umol/L (male); 0.8mg/dL; 71 umol/L (female)

• Age: 6 to < 10 years; Maximum serum creatinine: 1 mg/dL; 88 umol/L (male); 1mg/dL; 88 umol/L (female)

• Age: 10 to < 13 years; Maximum serum creatinine: 1.2 mg/dL; 106 umol/L (male); 1.2 mg/dL; 106 umol/L (female)

• Age: 13 to < 16 years; Maximum serum creatinine: 1.5 mg/dL; 133 umol/L (male); 1.4 mg/dL; 124 umol/L (female)

• Age: >= 16 years; Maximum serum creatinine: 1.7 mg/dL; 150 umol/L (male); 1.4mg/dL; 124 umol/L (female)

• PART 2: Bilirubin (sum of conjugated and unconjugated) =< 1.5 x upper limit ofnormal (ULN) for age

• PART 2: Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 135 U/L (i.e., 3 x ULN). For the purposes of this study, the ULN for ALT (SGPT) is 45 U/L

• PART 2: No evidence of dyspnea at rest, no exercise intolerance due to pulmonaryinsufficiency, and pulse oximetry >= 92% while breathing room air

• PART 2: No signs or symptoms of heart failure in a patient who has no history ofcongestive heart failure, no prior exposure to cardiotoxic drugs, and noradiotherapy to the heart; OR shortening fraction of >= 27% or ejection fraction of >= 50% by echocardiogram

• PART 2: Serum lipase =< ULN at screening

• PART 2: Patients with treated CNS metastasis are eligible if there is no evidence ofprogression for at least 4 weeks after CNS-directed treatment as ascertained byclinical examination and brain imaging (magnetic resonance imaging [MRI] or computedtomography [CT] scan) during screening

• Patients with new or progressive CNS metastasis (active metastasis) orleptomeningeal disease are eligible if the treating physician determines thatimmediate CNS-directed treatment is not required and is unlikely to be requiredfor at least 6 weeks after treatment initiation, and a risk-benefit analysis (discussion) by the patient and investigator favors participation in the trial

• PART 2: Human immunodeficiency virus (HIV): Infected patients on effectiveanti-retroviral therapy with undetectable viral load within 6 months prior totreatment initiation are eligible

• Note: Routine screening for HIV status prior to enrollment is not required

• PART 2: Hepatitis B virus (HBV): Patients with evidence of chronic infection withundetectable viral load are eligible. Suppressive therapy, if indicated, is allowed

• Note: Routine screening for HBV status prior to enrollment is not required

• PART 2: Hepatitis C virus (HCV): Infected patients currently on treatment withundetectable viral load are eligible. Patients with history of infection must havebeen treated and cured

• Note: Routine screening for HCV status prior to enrollment is not required

• PART 2: Patients must provide a pre-treatment tumor tissue specimen (baselinesample) for correlative exploratory biology studies. The specimen may be archival orprospective, from a medically necessary surgery, biopsy, or excision. Tissue willnot be obtained solely for this trial. A specimen from the time of most recentrelapse/progression is preferred, but not mandatory. Submission of a representativesample from all available lesions (archival and prospective) is strongly encouraged.If available, residual tissue from Part 1 may be used to fulfill the baseline tissuesample requirement; however additional tissue may be required if residual tissue isinsufficient

• PART 2: All patients and/or their parents or legally authorized representatives musthave the ability to understand and the willingness to sign a written informedconsent. Assent, where appropriate, will be obtained according to local policy.Patients with impaired decision-making capacity will not be excluded

Exclusion Criteria:

• PART 1: Patients with history of autoimmune disease

• PART 1: Patients with history of interstitial lung disease or pneumonitis are noteligible

• PART 1: Patients who have received solid organ transplant or allogenic stem celltransplant are not eligible

• PART 1: Patients who have been previously treated with a combination ofanti-PD-1/PD-L1 and anti-CTLA-4 inhibitors are not eligible

• PART 2: Patients requiring systemic corticosteroids or other forms ofimmunosuppressive therapy within 7 days prior to treatment initiation are noteligible

• Following treatment initiation, systemic corticosteroids or other forms ofimmunosuppressive therapy are permitted if administered for the treatment oftoxicity, tumor flare, or pseudo-progression and can be tapered. In most casesstudy treatment must be held until the dose is tapered to 10 mg/day prednisoneor equivalent. The protocol principal investigator must be consulted prior toresuming treatment

• Physiologic corticosteroids up to 5 mg/day prednisone or equivalent arepermitted

• Topical, ocular, intra-articular, intra-nasal, inhaled corticosteroids arepermitted

• Patients with CNS tumors receiving steroids for intracranial mass effect mustbe able to discontinue these at least 7 days prior to treatment initiation

• PART 2: Patients who are receiving other anticancer agent(s) are not eligible

• PART 2: Patients who are receiving or have received any other investigationalagent(s) within 14 days prior to treatment initiation are not eligible

• PART 2: Patients with CNS tumors with any of the following characteristics onimaging are not eligible:

• Tumor with any evidence of uncal herniation or mass effect leading to severemidline shift

• Tumor > 6 cm in single maximal dimension

• Tumor that in the opinion of the investigator shows significant mass effect

• PART 2: Patients with uncontrolled intercurrent illness/condition that would limitcompliance with the study requirements are not eligible. This includes, but is notlimited to, ongoing active infection, symptomatic congestive heart failure (New YorkHeart Association class III or IV), unstable angina pectoris, cardiac arrhythmia,psychiatric illness/social situations

• PART 2: The study agents have the potential for teratogenic or abortifacienteffects. Females of reproductive potential must have a negative serum pregnancy testwithin 72 hours prior to treatment initiation. Additional pregnancy tests (serum orurine) should be obtained during study participation in accordance with localstandards and guidelines

• Females of reproductive potential may not participate unless they have agreedto use an effective method of contraception (hormonal or barrier method ofbirth control; abstinence) prior to study entry, for the duration of treatment,and as follows:

• A period of 5 months after the last dose of nivolumab

• A period of 3 months after the last dose of ipilimumab

• Should a female patient become pregnant or suspect she is pregnant while she orher partner is participating in this study, she should inform the investigatorimmediately

• Due to the unknown but potential risk for adverse events (AEs) in nursinginfants secondary to treatment of the mother with the study agents,breastfeeding must be discontinued if the mother is treated on study

• Males will not be required to use contraceptive measures

• Note: Females of reproductive potential are defined as those who are past theonset of menarche and are not surgically sterile (i.e., bilateralsalpingectomy, bilateral oophorectomy, complete hysterectomy)

• PART 2: Patients with history of autoimmune disease (such as autoimmune thyroiddisease or inflammatory bowel disease) that has required systemic treatment within 2years prior to treatment initiation are not eligible

• Asymptomatic laboratory abnormalities (e.g., antinuclear antibody [ANA],rheumatoid factor, altered thyroid studies) are permitted in the absence of anautoimmune disorder diagnosis

• Atopy-related conditions (e.g., asthma, allergic rhinitis, atopic dermatitis)are permitted

• Replacement therapy (e.g., thyroxine, insulin, physiological corticosteroidreplacement therapy) is not considered a form of systemic treatment

• PART 2: Patients with history of interstitial lung disease or pneumonitis are noteligible

• PART 2: Patients who have received solid organ transplant or allogenic stem celltransplant are not eligible

• PART 2: Patients with previous grade 4 life-threatening reaction or other adversereaction that in the opinion of the investigator would preclude