Precursor B Cell Acute Lymphoblastic Leukemia (B-ALL) Treated With Autologous T Cells Genetically Targeted to the B Cell Specific Antigen CD19

Study Overview
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Brief Summary
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This study is an investigational approach that uses immune cells, called T cells, to kill leukemia. These T cells are removed from blood, modified in a laboratory, and then put back in the body. T cells fight infections and can also kill cancer cells in some cases. However, right now T cells are unable to kill the cancer cells. For this reason we will put one gene into the T cells that allows them to recognize and kill the leukemia cells. This gene will be put in the T cells by a weakened virus. The gene will produce proteins in the T cells that help the T cells recognize the leukemia cells and possibly kill them. The doctors have found that T cells modified in this way can cure an ALL-like cancer in mice. The main goals of this study is to determine the safety and appropriate dose of these modified T cells in patients with ALL. This will be done in a clinical trial. The dose of modified T-cells will depend on if you have disease present in your bone marrow or not. The patient will also receive chemotherapy before the T cells. We will use normally chemotherapy that is used in patients with leukemia. The chemotherapy is given to reduce leukemia and to allow the T cells to live longer.

Official Title
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A Phase I Trial of Precursor B Cell Acute Lymphoblastic Leukemia (B-ALL) Treated With Autologous T Cells Genetically Targeted to the B Cell Specific Antigen CD19

Conditions
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Leukemia, Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Biological: gene-modified T cells targeted


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients are eligible (> or = to 18 year old). Patients must have B- ALL refractory, relapsed, MRD, or in first CR as described below. Complete remission is defined as restoration of normal hematopoiesis with a neutrophil count > 1,000 x 106/L, a platelet count > 100,000 x 106/L, and hemoglobin > 10 g/dL. Blasts should be < 5% in a post-treatment bone marrow differential. Furthermore, there should be no clinical evidence of leukemia for a minimum of four weeks. MRD is defined as patients meeting the criteria for CR above, but with residual disease measured by a quantitative PCR, or by flow or by deep-sequencing of the IgH rearrangements . The assay from blood and/or bone marrow defines MRD by qPCR as a cycle threshold (CT) that is at least 1 CT value < than the lowest CT value from the background. Outside laboratory tests may suffice for this assessment at the discretion of the Principal Investigator. Relapsed B-ALL will be defined as patients that meet the above criteria for a CR before developing recurrent disease (increased bone marrow blasts). Refractory patients will be defined as patients that have not achieved a CR after 1 cycle of induction chemotherapy Patients must have a diagnosis of B-ALL by flow cytometry, or bone marrow histology, and/or cytogenetics. Patients must have CD19+ ALL as confirmed by flow cytometry and/or immunohistochemistry. Creatinine < 2.0 mg/100 ml, bilirubin < 2.0 mg/100 ml, AST and ALT < 3x normal, PT and PTT < 2x normal outside the setting of stable chronic anticoagulation therapy. LFTs (Bilirubin, AST, and/or ALT) may be acceptable if the elevation is secondary to leukemia infiltration or leukemia therapy with tyrosine kinase inhibitors. Adequate cardiac function (LVEF ≥ 40%) as assessed by ECHO or MUGA or other similar cardiac imaging performed within 1 month of enrollment. Adequate pulmonary function as assessed by ≥ 92% oxygen saturation on room air by pulse oximetry. Patients must have adequate access for leukapheresis procedure as assessed by staff from the MSKCC Donor Room. Life expectancy > 3 months Exclusion Criteria: Karnofsky performance status < 70. Active central nervous system (CNS) leukemia, as defined by unequivocal morphologic evidence of lymphoblasts in the cerebrospinal fluid (CSF) or symptomatic CNS leukemia (i.e. cranial nerve palsies or other significant neurologic dysfunction) within 28 days of enrollment. Prophylactic intrathecal medication is not a reason for exclusion. Patients previously treated with an allogeneic SCT that is currently complicated by active GVHD requiring T cell suppressive therapy. Patients with following cardiac conditions will be excluded: New York Heart Association (NYHA) stage III or IV congestive heart failure Myocardial infarction ≤6 months prior to enrollment History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration History of severe non-ischemic cardiomyopathy with EF ≤20% Patients with HIV, hepatitis B or hepatitis C infection. Patients with any concurrent active malignancies as defined by malignancies requiring any therapy other than expectant observation.

Ages Eligible for Study
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Minimum Age: 18 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: Pts with B Cell Acute Lymphoblastic Leukemia<br>This is a phase I study. Patients with CD19+ ALL (CR, relapsed, MRD, or refractory) are eligible for enrollment. B-ALL patients in first CR will be enrolled but only treated if they develop MRD or a frank relapse, while patients with MRD or with documented relapsed/refractory disease are eligible for immediate treatment. The T cell doses originally proposed in this study were based on doses administered safely in prior autologous T cell adoptive therapy trials but the dose has been modified based on the toxicities observed in patients with morphologic evidence of disease. Patients will be treated with different doses of T cells depending on the amount of disease at the time of T cell infusion. Patients in Cohort 1 (<5% blasts in the BM) will continue to receive 10^6 19-28z+ T cells/kg as previously. Patients in Cohort 2 (≥5% blasts in the BM) will receive the reduced dose of 1x106 19-28z+ T cells/kg). | Biological: gene-modified T cells targeted<br>* Pts will undergo leukapheresis. The leukapheresis product will be washed & frozen until the GTF is directed to start T cell production by the PI. CD3+ T cells will be isolated from the leukapheresis, & transduced with the 19-28z chimeric receptor & expanded. All relapsed (either MRD+ or morphologic) & refractory pts get re-induction chemo whenever feasible to optimally reduce the tumor burden prior to the T cell infusion. The re-induction chemo regimen will be selected by the treating dr. based on prior therapy, adverse reactions to chemo & highest likelihood to achieve an optimal response. Once pts recover from the toxicities of the re-induction chemo the disease status will be re-evaluated by repeating bone marrow aspirate or biopsy. Pts get conditioning chemo (min 2 weeks from end of re-induction chemo) followed 2-7 days later by the 19-28z+ T cells. Pts will be tx in 2 cohorts with diff doses of T cells according to the amount of disease immediately prior to the T cell infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the safety of adoptive transfer of gene-modified autologous CD19-specific T cells in adult patients with B-ALL. |  | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the anti-leukemic effect of adoptively transferred anti-CD19 T cells. |  | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cyclophosphamide, T cell, leukapheresis, stem cell transplant, bone marrow transplant, 09-114