B Cell Leukemias, B Cell Lymphomas
Conditions
Keywords
Biological: CART 22
Brief summary
This is a pilot study to determine the feasibility and safety of a single dose of autologous T cells expressing CD22 chimeric antigen receptors expressing tandem TCR-ζ and 4-1BB signaling domains (CART22/CART22-65s cells) in pediatric and young adult subjects with relapsed or refractory B cell acute lymphoblastic leukemia.
Interventions
BIOLOGICALCohort 1
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 CART22 cells/kg Day 2, 30% fraction: 0.3-1.5x10\^8 CART22 cells/kg Day 3, 60% fraction: 0.6-3x10\^8 CART22 cells/kg
BIOLOGICALCohorts 2
Subjects \<50kg will receive 0.2-1 x 10\^7 CART22-65s cells/kg as a split dose over three days as follows: Day 1, 10% fraction: 0.2-1x10\^6 CART22-65s cells/kg Day 2, 30% fraction: 0.6-3x10\^6 CART22-65s cells/kg Day 3, 60% fraction: 1.2-6x10\^6 CART22-65s cells/kg Subjects ≥50kg will receive 1-5x10\^8 CART22-65s cells as a split dose over three days as follows: Day 1, 10% fraction: 1-5x10\^7 CART22-65s cells/kg Day 2, 30% fraction: 0.3-1.5x10\^8 CART22-65s cells/kg Day 3, 60% fraction: 0.6-3x10\^8 CART22-65s cells/kg
BIOLOGICALCohort 3
Subjects \<50kg will receive 0.2-1 x 10\^7 CART22-65s cells as a split dose over two days as follows: Day 1, 25% fraction: 0.5-2.5x10\^6 CAR T cells/kg Day 2, 75% fraction: 1.5-7.5x10\^6 CAR T cells/kg Subjects ≥50kg will receive 1-5x10\^8 CART22-65s cells as a split dose over two days as follows: Day 1, 25% fraction: 0.25-1.25x10\^8 CART22-65s cells Day 2, 75% fraction: 0.75-3.75x10\^8 CART22-65s cells
BIOLOGICALCohort 3A
Subjects \<50kg will receive 0.2-2 x 10\^6 CART22-65s cells/kg as a split dose over two days as follows: Day 1, 25% fraction: 25% fraction: 0.05-0.5x10\^6 CAR T cells/kg Day 2, 75% fraction: 75% fraction: 0.15-1.5x10\^6 CAR T cells/kg Subjects ≥50kg will receive 0.1-1x10\^8 CART22-65s cells as a split dose over two days as follows: Day 1, 25% fraction: 0.25-2.5x10\^7 CART22-65s cells Day 2, 75% fraction: 0.75-7.5x10\^7 CART22-65s cells
Sponsors
University of Pennsylvania
Children's Hospital of Philadelphia
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 29 Years
Healthy volunteers
No
Inclusion criteria
1. Signed informed consent form must be obtained prior to any study procedure. 2. Relapsed or refractory B-cell ALL: 1. 2nd or greater relapse OR 2. Any marrow or extramedullary relapse after allogeneic HSCT and ≥ 6 months from SCT at infusion OR 3. Any marrow relapse after CAR-modified T cell therapy OR 4. Refractory disease defined as having not achieved a CR after \> 2 chemotherapy regimens OR 5. Patients with Ph+ ALL are eligible if they are intolerant to or have failed tyrosine kinase inhibitor therapy OR 6. 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 (at infusion, must meet criteria in Section 5.2) 3. Documentation of CD22 tumor expression in bone marrow, other tumor biopsy, CSF or peripheral blood by flow cytometry (or a recent marrow in the case of refractory disease). If the patient has received CD22-directed therapy (i.e., inotuzumab), then the marrow or other sample should be obtained after this therapy to show CD22 expression. 4. Adequate organ function defined as: 1. 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 2. 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. 5. Evidence of disease by standard morphologic or by MRD criteria. If the results of a historical biopsy (obtained at the time of the patient's most recent relapse) are available, this does not need to be repeated at screening. 6. Age 1-29 years. 7. Adequate performance status (Lansky or Karnofsky score ≥50). 8. Subjects of reproductive potential must agree to use acceptable birth control methods.
Exclusion criteria
1. Active hepatitis B or active hepatitis C. 2. HIV Infection. 3. Active acute or chronic graft-versus-host disease (GVHD) requiring systemic therapy. 4. Concurrent use of systemic steroids or immunosuppressant medications. Recent or current use of inhaled steroids or physiologic replacement with hydrocortisone is not exclusionary. 5. CNS3 disease that is progressive on therapy, or with CNS parenchymal lesions that might increase the risk of CNS toxicity. 6. Pregnant or nursing (lactating) women. 7. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The frequency and severity of adverse events. | From date of dosing ( day 1 ) up 15 years | Grade 3 and higher toxicity rate (toxicity possibly attributed to CART22 or CART22-65s) that is unmanageable, unexpected and unrelated to chemotherapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of manufacturing products that do not meet release criteria. | 3 months | Product must pass for vector transduction efficiency, T cell product purity, viability, sterility or due to tumor contamination. |
| Overall Complete Remission Rate (ORR) at Day 28. | 4 months | Includes CR and CR with incomplete blood count recovery (CRi) |
| 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) | From date of dosing ( day 1 ) up 15 years | — |
| Duration of remission (DOR) | 15 Years | — |
| Number of subjects with relapse free survival (RFS) | 15 years | — |
| Number of subjects with event free survival (EFS). | 15 years | — |
| Describe cause of death (COD) when appropriate | 15 years | — |
| Describe response in terms of minimal residual disease (MRD). | 1 year | Percentage of patients who achieve a CR associated with minimal residual disease (MRD) negative bone marrow as determined by high sensitivity flow cytometry. |
| Incidence of any acute GVHD | 15 year | — |
| Incidence of any grade II-IV aGVHD | 15 year | — |
| Incidence any chronic GVHD. | 15 year | — |
| Incidence any extensive, limited cGVHD. | 15 year | — |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORStephan Grupp, MD, PhD
Children's Hospital of Philadelphia
Outcome results
None listed