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

Study Overview
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Brief Summary
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This phase I trial investigates the side effects and determines the best dose of an immune cell therapy called GD2CART, as well as how well it works in treating patients with osteosarcoma or neuroblastoma that has come back (relapsed) or does not respond to treatment (refractory). T cells are infection fighting blood cells that can kill tumor cells. The T cells given in this trial will come from the patient and will have a new gene put in them that makes them able to recognize GD2, a protein on the surface of tumor cells. These GD2-specific T cells may help the body's immune system identify and kill GD2 positive tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the feasibility of producing T cells modified to express a GD2-specific chimeric antigen receptor (GD2-CAR-expressing autologous T-lymphocytes [GD2CART]) meeting established release criteria using a dasatinib containing culture platform and retroviral vector in the Miltenyi CliniMACS Prodigy (Registered Trademark) system. II. Determine the safety and maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) via administration of escalating doses of autologous GD2CART in children and young adults with relapsed/refractory osteosarcoma and neuroblastoma following cyclophosphamide-fludarabine based lymphodepletion. III. Determine clinical activity in a preliminary fashion of autologous GD2CART in children and young adults with relapsed, refractory osteosarcoma and neuroblastoma. SECONDARY OBJECTIVES: I. Measure persistence of adoptively transferred GD2CART and correlate this with antitumor effects. II. If unacceptable toxicity occurs that is possibly, probably, or likely related to GD2CART, assess the capacity for rimiducid (AP1903), a dimerizing agent, to mediate clearance of the genetically engineered cells and resolve toxicity. III. Describe the feasibility and tolerability of a second infusion of GD2CART in select patients. EXPLORATORY OBJECTIVES: I. Compare persistence of GD2CART administered in this trial to that observed in a previous trial using GD2.OX40.28.z.iCasp9 CAR T cells (NCI 14-C-0059) and assess features of the T cell product and the expanded T cells in vivo that correlate with persistence. II. Conduct exploratory studies measuring levels of circulating myeloid cells including myeloid derived suppressor cells (MDSCs) in patients treated on this trial and compare levels to those observed in NCI 14-C-0059. III. Explore GD2 expression in patients with neuroblastoma and osteosarcoma, including patients who have previously received anti-GD2 antibodies, from tissue and/or bone marrow samples at study entry and if available, after cell infusion. OUTLINE: This is a dose-escalation study of GD2CART followed by a dose-expansion study. LYMPHODEPLETION CHEMOTHERAPY: Patients receive fludarabine phosphate intravenously (IV) daily on days -5 to -2 and cyclophosphamide IV daily on days -4 to -2. GD2CART: Patients receive GD2CART cells IV on day 0. Patients also undergo echocardiogram (ECHO), multigated acquisition scan (MUGA) or cardiac magnetic resonance imaging (MRI) scan during screening, blood sample collection throughout the trial, and tumor biopsies as clinically indicated. In addition, patients undergo standard imaging scans throughout the trial. After completion of study treatment, patients are followed up three times weekly until day 14, twice weekly until day 28, at months 2, 3, 6, 9, and 12, every 3 months until the end of the second year, then annually for up to 10 years.

Official Title
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GD2-CAR PERSIST: Production and Engineering of GD2-Targeted, Receptor Modified T Cells (GD2CART) for Osteosarcoma or Neuroblastoma to Increase Systemic Tumor Exposure

Conditions
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Neuroblastoma, Osteosarcoma

Intervention / Treatment
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* Procedure: Biopsy
* Procedure: Biospecimen Collection
* Drug: Cyclophosphamide
* Procedure: Echocardiography
* Drug: Fludarabine Phosphate
* Biological: GD2-CAR-expressing Autologous T-lymphocytes
* Procedure: Imaging Technique
* Procedure: Magnetic Resonance Imaging of the Heart
* Procedure: Multigated Acquisition Scan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have histologically confirmed neuroblastoma or osteosarcoma that is recurrent or refractory and for which standard curative measures do not exist or are no longer effective. Must have histologic verification of their disease at diagnosis or at relapse Patients with osteosarcoma must have progressive, recurrent or refractory disease after all curative measures, including first line chemotherapy Patients with osteosarcoma in the dose escalation cohort, must have evaluable or measurable disease at enrollment Patients with osteosarcoma in the expansion cohort must have measurable disease by Response 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 must have: Prior progressive disease OR refractory disease present since diagnosis AND at least one of the following: Any amount of tumor in bone marrow (BM) At least one MIBG-avid soft tissue or skeletal site For metaiodobenzylguanidine (MIBG)-nonavid disease, at least one FDG-PET- positive soft tissue or skeletal site plus past histologic confirmation Progressive disease is defined as any disease progression occurring at any time after the diagnosis of high-risk neuroblastoma. Refractory disease is defined as an incomplete response of high-risk neuroblastoma to all treatments but without disease progression Must be <40 years of age There is no limit to the number of prior treatment regimens. The following washout periods prior to leukapheresis apply to patients undergoing leukapheresis on this study. If a patient has cryopreserved peripheral blood mononuclear cells (PBMCs) stored, the following washout periods are strongly recommended but not required and the product is useable if it meets the criteria established in this Investigational New Drug (IND) Myelosuppressive chemotherapy: Patients must not have received myelosuppressive chemotherapy within 3 weeks of leukapheresis (6 weeks if prior nitrosourea). Hematopoietic growth factors: At least 7 days must have elapsed since the completion of therapy with a growth factor. At least 14 days must have elapsed after receiving pegfilgrastim. Biological agent, tyrosine kinase inhibitor, targeted agent, metronomic chemotherapy: At least 7 days must have elapsed since the completion of therapy with a biologic agent, tyrosine kinase inhibitor, targeted agent, or metronomic non-myelosuppressive regimen. 131I-MIBG or other radioisotope therapy: At least 6 weeks must have elapsed since prior therapy with 131I-MIBG. At least 6 weeks or 10 half-lives (whichever is shorter) must have elapsed since prior therapy with any other radioisotope. Monoclonal antibodies and checkpoint inhibitors: At least 3 weeks or 5 half-lives (whichever is shorter) must have elapsed since prior therapy that included a monoclonal antibody or checkpoint inhibitor. Radiotherapy (XRT): 3 weeks must have elapsed since XRT, but at least 6 weeks if central nervous system (CNS) or lung fields, with the exception that there is no time restriction for palliative radiation with minimal bone marrow involvement and the patient has measurable/evaluable disease outside the radiation port or the site of radiation has documented progression. Vaccine therapy, anti-GD2 mAb therapy, or therapy with any genetically engineered T cells: Patients may have received previous vaccine therapy, anti-GD2 monoclonal antibody (mAb) therapy, or therapy with any genetically engineered T cells except prior GD2 CAR T cell therapy. At least 3 weeks or 5 half-lives, whichever is shorter, must have elapsed since any prior vaccine or monoclonal antibody therapy. At least 42 days must have elapsed since prior modified T cell, natural killer (NK) cell, or dendritic cell therapy. Allogeneic stem cell transplant/infusion: At least 12 weeks must have elapsed since allogeneic stem cell transplant and without evidence of active graft versus host disease (GVHD). Patients who received an autologous stem cell infusion following myeloablative therapy should be at least 6 weeks from their infusion. Patients who received an autologous stem cell infusion following non-myeloablative therapy do not have a wash-out period; they are eligible once they meet all other eligibility requirements, including recovery from acute side effects. This criterion does not apply to patients with apheresis product or usable T cell product available for use. Must meet parameters for apheresis per institutional guidelines. (This criterion does not apply to patients with apheresis product or usable T cell product available for use. Cryopreserved PBMCs stored from participation in other institutional cell therapy or cell collection studies or standard of care may be used to generate the cellular product on this study if they meet the criteria established in this IND Patients > 16 years of age must have Karnofsky ≥ 50%. Patients ≤ 16 years of age must have Lansky scale ≥ 50%; or Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 Leukocytes >= 750/mcL Cytopenias deemed to be disease-related and not therapy-related are exempt from this exclusion. Patients must not be refractory to transfusions Platelets >= 75,000/mcL Cytopenias deemed to be disease-related and not therapy-related are exempt from this exclusion. Patients must not be refractory to transfusions Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) (For the purpose of this study, the upper limit of normal [ULN] for SGOT is 50 U/L and the ULN for SGPT is 45 U/L) =< 5 x ULN Total bilirubin =< 2 x institutional upper limit of normal (ULN) for age. Patients with Gilbert's syndrome are excluded from the requirement of a normal bilirubin and patients 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 is characterized by mild, chronic unconjugated hyperbilirubinemia in the absence of liver disease or overt hemolysis). Note: Adult values will be used for calculating hepatic 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 glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 for patients with levels above institutional normal Cardiac ejection fraction >= 45% or shortening fraction >= 28%, no evidence of physiologically significant pericardial effusion as determined by an echocardiogram (ECHO). No clinically significant electrocardiogram (ECG) findings Pulmonary status: No clinically significant pleural effusion. Baseline oxygen saturation > 92% on room air at rest No acute neurotoxicity greater than grade 2 with the exception of decreased tendon reflex (DTR). Any grade of DTR is eligible Females of child-bearing potential and males of reproductive potential who are sexually active must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and 4 months after completion of chemotherapy preparative administration or until CAR is no longer detectable, whichever is later. Should a female become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately Note: Females of childbearing potential are defined as those who are past the onset of menarche and are not surgically sterile (i.e., bilateral salpingectomy, bilateral oophorectomy, complete hysterectomy) or post menopausal All patients >= 18 years of age must be able to give informed consent or if unable to give consent have a legal authorized representative (LAR) who can give consent for the patient. For patients < 18 years old their LAR (i.e., parent or legal guardian) must give informed consent. Pediatric patients will be included in age appropriate discussion and verbal assent will be obtained for those > 7 years of age, 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 compounds of similar chemical or biologic composition to GD2CART, cyclophosphamide, fludarabine, or other agents used in this study. History of hypersensitivity to dornase alfa, Chinese hamster ovary cell products, or any of the components of pulmozyme Patients who require systemic corticosteroid or other immunosuppressive therapy. (A one-week washout from systemic corticosteroid or other immunosuppressive therapy is permitted.) Use of physiologic doses of corticosteroids (up to 3 mg/m^2/day prednisone equivalent) are permitted. Use of topical, ocular, intra-articular, intra-nasal, or inhaled corticosteroids are permitted Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements History of additional malignancy other than non-melanoma skin cancer or carcinoma in situ (e.g., cervix, bladder, breast) unless untreated and stable or disease free for at least 3 years Untreated central nervous system (CNS) metastasis. Patients with previous CNS tumor involvement that has been treated and is stable for at least 6 weeks following completion of therapy are permitted. Patients who are clinically stable as evidenced by no requirements for corticosteroids, no evolving neurologic deficits, and no progression of residual brain abnormalities without specific therapy, are permitted. Patients with asymptomatic subcentemeric CNS lesions are permitted if no immediate radiation or surgery is indicated CNS disorder such as cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or autoimmune disease with CNS involvement that in the judgement of the investigator 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 B surface antigen [HBsAg] positive), or hepatitis C virus (anti-HCV positive) as the immunosuppression contained in this study will pose unacceptable risk. A history of HIV, hepatitis B, or hepatitis C is permitted if the viral load is undetectable per quantitative 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/systemic disease modifying agents within the last 2 years Females of childbearing potential must have a negative serum or urine pregnancy test. Pregnant females are excluded from this study because the effects of autologous GD2CART on the developing human fetus are unknown and because the chemotherapy agents used in this trial (cyclophosphamide and fludarabine) are category 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 with cyclophosphamide/fludarabine, breastfeeding should be discontinued if the mother is treated with cyclophosphamide/fludarabine. These potential risks may also apply to other agents used in this study. Patients with known GD2 negative tumors by validated immunohistochemistry (IHC) will be excluded from enrollment given the change in risk profile In the investigator's judgment, unlikely to complete protocol-required study visits or procedures, including follow-up visits, or comply with the study requirements for participation. Or in the investigator's judgment, if the patient is likely to develop significant toxicity and morbidity from CAR-T cell expansion mediated inflammation based on location of tumor site.

Ages Eligible for Study
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Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (GD2 CAR T)<br>LYMPHODEPLETION CHEMOTHERAPY: Patients receive fludarabine phosphate IV daily on days -5 to -2 and cyclophosphamide IV daily on days -4 to -2. GD2CART: Patients receive GD2CART cells IV on day 0. Patients also undergo ECHO, MUGA or cardiac MRI scan during screening, blood sample collection throughout the trial, and tumor biopsies as clinically indicated. In addition, patients undergo standard imaging scans throughout the trial. | Procedure: Biopsy<br>* Undergo biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo collection of blood<br>* Other names: Specimen Collection;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR-138719;Procedure: Echocardiography<br>* Undergo ECHO<br>* Other names: EC;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Biological: GD2-CAR-expressing Autologous T-lymphocytes<br>* Given IV<br>* Other names: tvs-CTL Vaccine;Procedure: Imaging Technique<br>* Undergo standard imaging scans<br>* Other names: Type of imaging;Procedure: Magnetic Resonance Imaging of the Heart<br>* Undergo cardiac MRI<br>* Other names: Heart MRI;Procedure: Multigated Acquisition Scan<br>* Undergo MUGA<br>* Other names: Synchronized Multigated Acquisition Scanning;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of producing GD2-CAR-expressing autologous T-lymphocytes (GD2CART) cells | Success will be defined by manufacturing and expansion of GD2CART to satisfy the targeted dose level and meet the requirements of the Certificate of Analysis. Specifically, dose escalation will proceed if 3 or more of the first 3 to 6 patients in a dose level are able to produce adequate cells for evaluation. | Up to day 28 days after cell infusion | 
| Incidence of adverse events (AEs) | Safety of GD2CART will be by the incidence and severity of dose limiting toxicities (DLTs), treatment emergent AEs (TEAEs), serious adverse events (SAEs), laboratory abnormalities, changes in vital signs, and changes in physical examination following infusion of GD2CART cells. | Up to 15 years | 
| Maximum tolerated dose (MTD) |  | Up to day 28 days after cell infusion | 
| Best response to GD2CART cells | Simon's two stage design will be used to evaluate the clinical benefit of GD2CART after conditioning lymphodepletion chemotherapy in two groups of patients: children and young adults with recurrent, refractory osteosarcoma and neuroblastoma. | Up to day 28 days after cell infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Persistence of GD2CART cells | Persistence of GD2CART and correlation with tumor regression and sustained clinical benefit will be assessed. Persistence will be defined as the duration of time that GD2CART cells can be detected above the background rate (baseline measure) as measured by polymerase chain reaction (PCR). The persistence will be compared between the different response statuses (responders versus non-responders) using a t-test allowing for unequal variance. | Up to 5 years | 
| Capacity for rimiducid (AP1903) to reverse unacceptable toxicity related to GD2CART administration | The toxicity is defined to be reversed or resolved when the toxicity grading has resolved to grade 2 or below. The resolution of toxicity will be summarized descriptively. | Up to 28 days after cell infusion | 
| Feasibility and tolerability of a second infusion of GD2CART cells |  | After a 2nd infusion of GD2CART cells |