CD22 Redirected Autologous T Cells for ALL

Study Overview
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Brief Summary
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This is a single center, single arm, open-label pilot study to determine the feasibility and safety of a single dose administered as spilt fractions of autologous T cells expressing CD22 chimeric antigen receptors expressing tandem TCRζ and 4-1BB (TCRζ/4-1BB) co-stimulatory domains (referred to as CART22 cells) in pediatric patients with relapsed or refractory B-cell acute lymphoblastic leukemia.

Detailed Description
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The study will consist of three sequential phases: 1) a screening phase, 2) a manufacturing and pre- treatment phase, consisting of apheresis (if applicable) and chemotherapy (if applicable), and 3) a treatment phase, consisting of a CART22 transfused cell infusion and follow up evaluations. After signing informed consent, patients will undergo screening tests and procedures to determine eligibility. Once patient eligibility is confirmed, patients will have cells collected by leukapheresis to obtain peripheral blood mononuclear cells (PBMC) for CART22 manufacturing, unless adequate numbers of cells are available from a prior apheresis. Cells will be transduced with the anti-CD22 TCRζ/4-1BB lentiviral vector, expanded in vitro and then frozen for future administration. Cryopreserved historical apheresis products collected from the patient prior to study entry are usable for CART22 manufacturing if collected at an appropriately certified apheresis center and the product meets adequate mononuclear cell yields. If a historical apheresis product is not available, an apheresis procedure will be scheduled for cell procurement after study entry. Unless contraindicated and medically not advisable based on previous chemotherapy, patients will be given conditioning chemotherapy prior to CART22 cell infusion with the intent of lymphodepletion. Additionally, if the patient's white blood cell (WBC) count is ≤ 1,000 /uL, conditioning/lymphodepleting chemotherapy is NOT required. The chemotherapy will be planned so that the last dose is completed 1-4 days BEFORE the planned infusion of CART22 cells. The chemotherapy start date will vary based on the duration of the selected chemotherapy regimen. If the period from chemotherapy to CART22 infusion is delayed 4 or more weeks, the patient will need to be re-treated with lymphodepleting chemotherapy prior to CART22 infusion. We will enroll 15 evaluable patients for the primary safety endpoint analysis. Primary safety evaluable patients are those who have received any CART22 cells. The first three subjects infused with CART22 will be staggered by 14 days to allow for monitoring of adverse events, including CRS. Subjects with a manufactured cell dose that is less than the protocol-specified dose will be scored as a manufacturing failure. These subjects will receive their cell infusion, provided that all other manufacturing release criteria are met. All patients will have blood tests to assess CART22 safety, engraftment and persistence at regular intervals throughout the study (Visit Evaluation Schedule in Appendix 1). Circulating CART22 T cells subsets will be assessed at various times after infusion. CART22 trafficking will be assessed in bone marrow aspirates, and other tissues, if available. Follow up is planned at a minimum of weekly for 4 weeks, monthly for 6 months, then patients will be followed quarterly for the remainder of the year to obtain a medical history, undergo a physical examination, and blood tests. Additional samples collections and assessments between schedule visits after CART22 cell infusion will be performed as clinically indicated. Following these evaluations, patients will enter a roll-over study for long term follow-up for up to an additional fourteen years to assess for safety assessments per the FDA guidelines.

Official Title
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Pilot Study of Autologous Anti-CD22 Chimeric Antigen Receptor Redirected T Cells in Pediatric Patients With Chemotherapy Resistant Or Refractory Acute Lymphoblastic Leukemia

Conditions
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B Cell Leukemias, B Cell Lymphomas

Intervention / Treatment
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* Biological: CART22 cells transduced with a lentiviral vector to express anti-CD22 scFv TCRz:41BB


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent form must be obtained prior to any study procedure. Relapsed or refractory B-cell ALL: 2nd or greater BM relapse OR Any marrow relapse after allogeneic HSCT and ≥ 6 months from SCT at infusion OR Any marrow relapse after CAR-modified T cell therapy OR Refractory disease defined as having not achieved a CR after > 2 chemotherapy regimens OR Patients with Ph+ ALL are eligible if they are intolerant to or have failed tyrosine kinase inhibitor therapy OR Ineligible for allogeneic SCT because of: i. Comorbid disease ii. Other contraindications to allogeneic SCT conditioning regimen iii. Lack of suitable donor iv. Prior SCT v. Declines allogeneic SCT as a therapeutic option after documented discussion, with expected outcomes, about the role of SCT with a BMT physician not part of the study team g. Patients with CNS3 disease will be eligible if CNS disease is responsive to therapy. Documentation of CD22 tumor expression in bone marrow or peripheral blood by flow cytometry at relapse. Adequate organ function defined as: A serum creatinine based on age/gender as follows: Maximum Serum Creatinine (mg/dL) Age 1 to < 2 years Male 0.6 Female 0.6 Age 2 to < 6 years Male 0.8 Female 0.8 Age 6 to < 10 years Male 1.0 Female 1.0 Age 10 to < 13 years Male 1.2 Female 1.2 Age 13 to < 16 years Male 1.5 Female 1.4 Age ≥ 16 years Male 1.7 Female 1.4 Adequate liver function i. ALT < 500 U/L ii. Bilirubin <3x upper limit of normal iii. ALT and/or bilirubin that exceed these ranges is acceptable if, in the opinion of the investigator (or by liver biopsy), the abnormalities are directly related to ALL infiltration of the liver c. Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea, pulse oxygen > 92% on room air; DLCO > 40% (corrected for anemia) if PFTs are clinically appropriate as determined by the treating investigator d. Left Ventricle Shortening Fraction (LVSF) ≥ 28% or Ejection Fraction (LVEF) ≥ 40% confirmed by ECHO/MUGA; in cases where quantitative assessment of LVEF is not possible, a statement by the cardiologist that the ECHO shows qualitatively normal ventricular function will suffice. Evidence of disease by standard morphologic or by MRD criteria. A clinical marrow showing disease may be performed at enrollment or within 12 weeks of enrollment. Age 1-29 years. Adequate performance status (Lansky or Karnofsky score ≥50) Subjects of reproductive potential must agree to use acceptable birth control methods. Exclusion Criteria: Active hepatitis B or active hepatitis C. HIV Infection. Active acute or chronic graft-versus-host disease (GVHD) requiring systemic therapy. Concurrent use of systemic steroids or immunosuppressant medications. Recent or current use of inhaled steroids or physiologic replacement with hydrocortisone is not exclusionary. For additional details regarding the use of steroids and immunosuppressant medication. CNS3 disease that is progressive on therapy, or with CNS parenchymal lesions that might increase the risk of CNS toxicity. Pregnant or nursing (lactating) women. Receipt of a prior investigational study agent within 4 weeks prior to screening visit. *Note- patients who have received anti-CD19 CART cells (e.g. CART19/CTL019) on an investigational study where cell infusion occurred greater than 4 weeks before the screening visit are NOT excluded.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 29 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: CART22 cells<br>Subjects <50kg will receive 0.2-1 x 10^7 CART22 cells/kg as a split dose over three days as follows: Day 1, 10% fraction: 0.2-1x10^6 CART22 cells/kg Day 2, 30% fraction: 0.6-3x10^6 CART22 cells/kg Day 3, 60% fraction: 1.2-6x10^6 CART22 cells/kg Subjects ≥50kg will receive 1-5x10^8 CART22 cells as a split dose over three days as follows: Day 1, 10% fraction: 1-5x10^7 Day 2, 30% fraction: 0.3-1.5x10^8 Day 3, 60% fraction: 0.6-3x10^8 | Biological: CART22 cells transduced with a lentiviral vector to express anti-CD22 scFv TCRz:41BB<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency and severity of adverse events, including, but not limited to, cytokine release syndrome (CRS) | grade 3 and higher toxicity rate (toxicity possibly attributed to CART22) | From date of dosing ( day 1 ) up to 50 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of manufacturing products that do not meet release criteria. | Product must pass for vector transduction efficiency, T cell product purity, viability, sterility or due to tumor contamination. | 3 months | 
| Overall Complete Remission Rate (ORR) at Day 28. | Includes CR and CR with incomplete blood count recovery (CRi) | 4 months | 
| Evaluate overall response rate (CR/CRi by or at Month 6) at Month 6. |  | 9 months | 
| Evaluate disease status at Month 6. |  | 9 months | 
| Overall survival (OS) |  | at 50 weeks | 
| Duration of remission (DOR) |  | at 50 weeks | 
| Number of subjects with relapse free survival (RFS) |  | at 50 weeks | 
| Number of subjects with event free survival (EFS). |  | at 50 weeks | 
| Describe cause of death (COD) when appropriate |  | 15 years | 
| Describe response in terms of minimal residual disease (MRD). | Percentage of patients who achieve a CR associated with minimal residual disease (MRD) negative bone marrow as determined by high sensitivity flow cytometry. | 1 year | 
| Incidence of any acute GVHD |  | 15 year | 
| Incidence of any grade II-IV GVHD |  | 15 year | 
| Incidence any chronic GVHD. |  | 15 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Biological: CART 22