Testing a New Immune Cell Therapy, GD2-Targeted Modified T-cells (GD2CART), in Children, Adolescents, and Young Adults With Relapsed/Refractory Osteosarcoma and Neuroblastoma, The GD2-CAR PERSIST Trial

Inclusion Criteria:

• Must have histologically confirmed neuroblastoma or osteosarcoma that is recurrentor refractory and for which standard curative measures do not exist or are no longereffective. Must have histologic verification of their disease at diagnosis or atrelapse

• Patients with osteosarcoma in the dose escalation cohort, must have evaluable ormeasurable disease at enrollment

• Patients with osteosarcoma in the expansion cohort must have measurable disease byResponse Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) at enrollment

• Patients with neuroblastoma in the dose escalation or dose the expansion cohort musthave:

• Prior progressive disease OR refractory disease present since diagnosis AND atleast one of the following:

• Evidence of tumor in the bone marrow (BM)

• At least one metaiodobenzylguanidine (MIBG)-avid soft tissue or skeletalsite

• For MIBG-nonavid disease, at least one FDG-PET- positive soft tissue orskeletal site plus past histologic confirmation

• Progressive disease is defined as any disease progression occurring at any timeafter the diagnosis of high-risk neuroblastoma. Refractory disease is definedas an incomplete response of high-risk neuroblastoma to all treatments butwithout disease progression

• Must be < 40 years of age

• There is no limit to the number of prior treatment regimens. The following washoutperiods prior to leukapheresis apply to patients undergoing leukapheresis on thisstudy. If a patient has cryopreserved peripheral blood mononuclear cells (PBMCs)stored, the following washout periods are strongly recommended but not required andthe product is useable if it meets the criteria established in this InvestigationalNew Drug (IND)

• Myelosuppressive chemotherapy: Patients must not have received myelosuppressivechemotherapy within 3 weeks of leukapheresis (6 weeks if prior nitrosourea)

• Hematopoietic growth factors: At least 7 days must have elapsed since thecompletion of therapy with a short-acting growth factor. At least 14 days musthave elapsed after receiving pegfilgrastim

• Biological agent, tyrosine kinase inhibitor, targeted agent, metronomicchemotherapy: At least 7 days must have elapsed since the completion of therapywith a biologic agent, tyrosine kinase inhibitor, targeted agent, or metronomicnon-myelosuppressive regimen

• 131I-MIBG or other radioisotope therapy: At least 6 weeks must have elapsedsince prior therapy with 131I-MIBG. At least 6 weeks or 10 half-lives (whichever is shorter) must have elapsed since prior therapy with any otherradioisotope

• Monoclonal antibodies and checkpoint inhibitors: At least 3 weeks or 5half-lives (whichever is shorter) must have elapsed since prior therapy thatincluded a monoclonal antibody or checkpoint inhibitor

• Radiotherapy (XRT): 3 weeks must have elapsed since XRT; at least 6 weeks ifXRT involved central nervous system (CNS) or lung fields; and at least 12 weeksfrom total-body irradiation (TBI), craniospinal XRT, or XRT involving ≥ 50%bony pelvis, with the exception that there is no time restriction forpalliative radiation with minimal bone marrow involvement and the patient hasmeasurable/evaluable disease outside the radiation port or the site ofradiation has documented progression

• Vaccine therapy, anti-GD2 mAb therapy, or therapy with any geneticallyengineered T cells: Patients may have received previous vaccine therapy,anti-GD2 monoclonal antibody (mAb) therapy, or therapy with any geneticallyengineered T cells except prior GD2 CAR T cell therapy. At least 3 weeks or 5half-lives, whichever is shorter, must have elapsed since any prior vaccine ormonoclonal antibody therapy. At least 42 days must have elapsed since priormodified T cell, natural killer (NK) cell, or dendritic cell therapy

• Allogeneic stem cell transplant/infusion: At least 12 weeks must have elapsedsince allogeneic stem cell transplant and without evidence of active graftversus host disease (GVHD)

• Autologous stem cell transplant/infusion: Patients who received an autologousstem cell infusion following myeloablative therapy should be at least 6 weeksfrom their infusion. Patients who received an autologous stem cell infusionfollowing non-myeloablative therapy do not have a wash-out period; they areeligible once they meet all other eligibility requirements, including recoveryfrom acute side effects

• Must meet parameters for apheresis per institutional guidelines. (This criteriondoes not apply to patients with apheresis product or usable T cell product availablefor use). Cryopreserved PBMCs stored from participation in other institutional celltherapy or cell collection studies or standard of care may be used to generate thecellular product on this study if they meet the criteria established in this IND

• Patients > 16 years of age must have Karnofsky ≥ 60%. Patients ≤ 16 years of agemust have Lansky scale ≥ 60%; corresponding to Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

• Leukocytes >= 750/mcL (For patients without bone marrow involvement. Patients whohave bone marrow involvement with tumor are exempt from the platelet requirement andwill not be evaluable for hematological toxicities. Patients must not be refractoryto transfusions)

• Absolute neutrophil count (ANC) ≥ 500/mcL (For patients without bone marrowinvolvement. Patients who have bone marrow involvement with tumor are exempt fromthe platelet requirement and will not be evaluable for hematological toxicities.Patients must not be refractory to transfusions.)

• Platelets >= 75,000/mcL (transfusion independent defined as no transfusion in prior 7 days) (For patients without bone marrow involvement. Patients who have bone marrowinvolvement with tumor are exempt from the platelet requirement and will not beevaluable for hematological toxicities. Patients must not be refractory totransfusions.)

• Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 5 x upper limit of normal (ULN) (For the purpose of this study, the ULN for SGOTis 50 U/L and the ULN for SGPT is 45 U/L)

• Albumin >= 2 g/dL

• Total bilirubin =< 2 x institutional upper limit of normal (ULN) for age. Patientswith Gilbert's syndrome are excluded from the requirement of a normal bilirubin andpatients will not be excluded if bilirubin elevation is due to tumor involvement. (Gilbert's syndrome is found in 3-10% of the general population, and ischaracterized by mild, chronic unconjugated hyperbilirubinemia in the absence ofliver disease or overt hemolysis). Note: Adult values will be used for calculatinghepatic toxicity and determining eligibility

• Age, maximum serum creatinine (mg/dL):

• 1 month to < 6 months: 0.4 (male), 0.4 (female)

• 6 months to < 1 year: 0.5 (male), 0.5 (female)

• 1 to < 2 years: 0.6 (male), 0.6 (female)

• 2 to < 6 years: 0.8 (male), 0.8 (female)

• 6 to < 10 years: 1 (male), 1 (female)

• 10 to < 13 years: 1.2 (male), 1.2 (female)

• 13 to < 16 years: 1.5 (male), 1.2 (female)

• >= 16 years: 1.7 (male), 1.4 (female) OR Creatinine clearance or glomerularfiltration rate (GFR) >= 60 mL/min/1.73 m^2 for patients with levels aboveinstitutional normal

• Cardiac ejection fraction >= 45% or shortening fraction >= 28%, no evidence ofphysiologically significant pericardial effusion as determined by an echocardiogram (ECHO). No clinically significant electrocardiogram (ECG) findings

• Pulmonary status: No clinically significant pleural effusion. Baseline oxygensaturation > 92% on room air at rest

• No acute neurotoxicity greater than grade 2 with the exception of decreased tendonreflex (DTR). Any grade of DTR is eligible

• Females of child-bearing potential and males of reproductive potential who aresexually active must agree to use adequate contraception (hormonal or barrier methodof birth control; abstinence) from the start of study enrollment until 6 monthsafter GD2 CAR T cell infusion (or until the duration of study participation, in thecase of patients who start lymphodepleting chemotherapy but do not receive the GD2CART infusion). Should a female become pregnant or suspect she is pregnant while sheor her partner is participating in this study, she should inform her treatingphysician immediately

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

• All patients >= 18 years of age must be able to give informed consent or if unableto give consent have a legal authorized representative (LAR) who can give consentfor the patient. For patients < 18 years old their LAR (i.e., parent or legalguardian) must give informed consent. Pediatric patients will be included in ageappropriate discussion and verbal assent will be obtained for those > 7 years ofage, when appropriate, according to local policy

Exclusion Criteria:

• Receiving any other current investigational agents

• History of anaphylactic reactions attributed to anti-GD2 antibodies or to compoundsof similar chemical or biologic composition to GD2CART, cyclophosphamide,fludarabine, or other agents used in this study. History of hypersensitivity todornase alfa, Chinese hamster ovary cell products, or any of the components ofpulmozyme

• Patients who require systemic corticosteroid or other immunosuppressive therapy. (Aone-week washout from systemic corticosteroid or other immunosuppressive therapy ispermitted.) Use of physiologic doses of corticosteroids (up to 3 mg/m^2/dayprednisone equivalent) are permitted. Use of topical, ocular, intra-articular,intra-nasal, or inhaled corticosteroids are permitted

• Uncontrolled intercurrent illness including, but not limited to, symptomaticcongestive heart failure, unstable angina pectoris, cardiac arrhythmia, orpsychiatric illness/social situations that would limit compliance with studyrequirements

• History of additional malignancy other than non-melanoma skin cancer or carcinoma insitu (e.g., cervix, bladder, breast) unless untreated and stable or disease free forat least 3 years

• Untreated central nervous system (CNS) metastasis. Patients with previous CNS tumorinvolvement that has been treated and is stable for at least 6 weeks followingcompletion of therapy are permitted. Patients who are clinically stable as evidencedby no requirements for corticosteroids, no evolving neurologic deficits, and noprogression of residual brain abnormalities without specific therapy, are permitted.Patients with asymptomatic subcentemeric CNS lesions are permitted if no immediateradiation or surgery is indicated

• CNS disorder such as cerebrovascular ischemia/hemorrhage, dementia, cerebellardisease, or autoimmune disease with CNS involvement that in the judgement of theinvestigator may impair the ability to evaluate neurotoxicity

• Presence of fungal, bacterial, viral, or other infection that is uncontrolled

• Ongoing infection with human immunodeficiency virus (HIV), hepatitis B (hepatitis Bsurface antigen [HBsAg] positive), or hepatitis C virus (anti-HCV positive) as theimmunosuppression contained in this study will pose unacceptable risk. A history ofHIV, hepatitis B, or hepatitis C is permitted if the viral load is undetectable perquantitative polymerase chain reaction (PCR) and/or nucleic acid testing

• Primary immunodeficiency or history of systemic autoimmune disease (e.g., Crohns,rheumatoid arthritis, systemic lupus) requiring systemic immunosuppression/systemicdisease modifying agents within the last 2 years

• Females of childbearing potential must have a negative serum or urine pregnancytest. Pregnant females are excluded from this study because the effects ofautologous GD2CART on the developing human fetus are unknown and because thechemotherapy agents used in this trial (cyclophosphamide and fludarabine) arecategory D agents with the potential for teratogenic or abortifacient effects.Additionally, because there is an unknown but potential risk for adverse events (AEs) in nursing infants secondary to treatment of the mother withcyclophosphamide/fludarabine, breastfeeding should be discontinued if the mother istreated with cyclophosphamide/fludarabine. These potential risks may also apply toother agents used in this study

• In the investigator's judgment, unlikely to complete protocol-required study visitsor procedures, including follow-up visits, or comply with the study requirements forparticipation. Or in the investigator's judgment, if the patient is likely todevelop significant toxicity and morbidity from CAR-T cell expansion mediatedinflammation based on location of tumor site