A Pediatric Trial of Genetically Modified Autologous T Cells Directed Against CD19 for Relapsed CD19+ Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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Patients with relapsed leukemia often develop resistance to chemotherapy. For this reason, we are attempting to use a patient's own T cells, which can be genetically modified to expresses a chimeric antigen receptor(CAR). The CAR enables the T cell to recognize and kill the leukemic cells though the recognition of CD19, a protein expressed on the surface of the majority of pediatric ALL. This is a phase I study designed to determine the maximum tolerated dose of the CAR+ T cells and define the toxicity of the treatment. As a secondary aim, we will be looking at the efficacy of the T cells on eradicating the patient's leukemic cells.

Detailed Description
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Upon meeting the eligibility requirements and enrolling on study, subjects will undergo a blood draw to obtain the T cells for the generation of the CD19 CAR+ T cells. The T cells are isolated from the blood, transduced with a lentivirus to express the CD19 CAR, and expanded in culture over a three week period. During the process of cell generation, subjects will continue to be cared for by their primary oncologist and may undergo additional treatment directed at the leukemia during this time. After the CAR+ T cells have been generated, the subject undergoes a disease assessment and will be admitted to the hospital to receive 2 days of cyclophosphamide for lymphodepletion and reduction of disease burden. Several days later, the subject will receive an infusion of the CAR+ T cells. Following treatment with the CAR+ T cells, subjects will be intensely followed for 6 weeks with serial blood testing and re-evaluation of disease status with bone marrow aspirates. After 6 weeks, the subjects clinical care will be resumed by their primary oncologist, and it is possible that they would receive additionally chemotherapy or a stem cell transplant. Upon completion of the study, subjects will be followed at least annually with a either a medical history, physical exam and blood tests or a phone call/questionnaire for 15 years. This follow up will help to determine if the subject develops any long-term health problems related to the CAR+ T cells including a new cancer.

Official Title
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Pediatric Leukemia Adoptive Therapy (PLAT)-01: A Phase 1 Feasibility and Safety Study of Cellular Immunotherapy for Relapsed Pediatric CD19+ Acute Lymphoblastic Leukemia Using Autologous T-cells Lentivirally Transduced To Express a CD19-Specific Chimeric Antigen Receptor

Conditions
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B Cell Leukemia

Intervention / Treatment
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* Biological: Autologous CD19 CAR+ EGFTt + T cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: CD19+ Leukemia in 1st marrow relapse with MRD at the end of 1st month of re-induction CD19+ Leukemia in 2nd or greater relapse CD19+ Leukemia with indication for HCT, but has contraindication Age between 1 and 26 years of age Karnofsky of >50 or Lansky >50 Life Expectancy >12 weeks Able to tolerate a blood draw of 4-6mL/kg Recovered from acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy absolute lymphocyte count of >/=750 cell/mm3 or >/=500 is >20kg creatinine clearance or radioisotope GFR >/= 70mL/min/1.73m2 OR normal serum creatinine based on age/gender total bilirubin </= 1.5x upper limit normal OR direct bilirubin </= 1.5mg/dl ALT </= 3x upper limit normal corrected QTc <450msec of ECG Shortening Fraction >28% by ECHO or Ejection Fraction >50% by MUGA Documented negative HIV, Hep B and Hep C Agree to long-term follow up for up to 15 years if they receive T cell infusion Exclusion Criteria: Philadelphia Positive Leukemia Prior Allogeneic Stem Cell Transplant CNS 2 or 3 prior cellular immunotherapy with chimeric antigen receptor modified T cells fully humanized antibodies within three half lives systemic corticosteroids within 7 days of enrollment requires supplemental oxygen or has a chest X-ray with an infectious process CNS pathology (seizure disorder, paresis, aphasia, cerebrovascular ischemia/hemorrhage, severe brain injuries, dementia, cerebellar disease, organic brain syndrome, psychosis, coordination or movement disorder) Pregnant or breastfeeding women. Female participant of reproductive age must have a negative pregnancy test and agree to contraception for 1 year after T cell infusion. Active Malignancy other than CD19+ Leukemia Active severe infection defined as a positive blood culture within 48 hours of study enrollment or a fever >38.2C AND clinical signs of infection within 48 hours of study enrollment Patient has a concurrent medical condition, that in the opinion of the protocol PI or designee, would prevent the patient from undergoing protocol-based therapy. Trisomy 21 Primary immunodeficiency/bone marrow failure syndrome

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 26 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: CAR+ T cells<br>Subjects will receive two days of cyclophosphamide for a total of 3g/m^2 followed several days later by a single dose of Autologous CD19 CAR+ EGFTt + T cells | Biological: Autologous CD19 CAR+ EGFTt + T cells<br>* Autologous T cell modified to express a CD19 specific CAR and a truncated EGFRt tag<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participant with Adverse Events | The safety of the T cell infusion will be described and the maximum tolerated dose determined. | 42 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Persistence of the CD19 CAR+ T cells | Patients will be followed for 42 days to determine if the transferred T cells remain detectable in the blood and bone marrow | 42 days | 
| Determine if there is anti-leukemic activity of the CD19 CAR+ T cells | Patients will have their bone marrow assessed following the T cell infusion to determine if their disease responded to the treatment | 42 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pediatric, acute lymphoblastic leukemia, CD19, Chimeric Antigen Receptor