CD22 Redirected Autologous T Cells for ALL

February 2, 2024 updated by: University of Pennsylvania

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

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.

Study Overview

Detailed Description

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.

Study Type

Interventional

Enrollment (Estimated)

15

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
        • Recruiting
        • Children's Hospital of Philadelphia
        • Principal Investigator:
          • Stephan Grupp, MD, PhD
        • Contact:
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 year to 29 years (Child, Adult)

Accepts Healthy Volunteers

No

Description

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 BM relapse OR
    2. Any marrow 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.

  3. Documentation of CD22 tumor expression in bone marrow or peripheral blood by flow cytometry at relapse.
  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. A clinical marrow showing disease may be performed at enrollment or within 12 weeks of enrollment.
  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. For additional details regarding the use of steroids and immunosuppressant medication.
  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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: CART22 cells

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Frequency and severity of adverse events, including, but not limited to, cytokine release syndrome (CRS)
Time Frame: From date of dosing ( day 1 ) up to 50 weeks
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.
Time Frame: 3 months
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.
Time Frame: 4 months
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.
Time Frame: 9 months
9 months
Evaluate disease status at Month 6.
Time Frame: 9 months
9 months
Overall survival (OS)
Time Frame: at 50 weeks
at 50 weeks
Duration of remission (DOR)
Time Frame: at 50 weeks
at 50 weeks
Number of subjects with relapse free survival (RFS)
Time Frame: at 50 weeks
at 50 weeks
Number of subjects with event free survival (EFS).
Time Frame: at 50 weeks
at 50 weeks
Describe cause of death (COD) when appropriate
Time Frame: 15 years
15 years
Describe response in terms of minimal residual disease (MRD).
Time Frame: 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.
1 year
Incidence of any acute GVHD
Time Frame: 15 year
15 year
Incidence of any grade II-IV GVHD
Time Frame: 15 year
15 year
Incidence any chronic GVHD.
Time Frame: 15 year
15 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Stephan Grupp, MD, PhD, Children's Hospital of Philadelphia

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 13, 2016

Primary Completion (Estimated)

December 1, 2037

Study Completion (Estimated)

December 1, 2037

Study Registration Dates

First Submitted

December 22, 2015

First Submitted That Met QC Criteria

January 7, 2016

First Posted (Estimated)

January 8, 2016

Study Record Updates

Last Update Posted (Estimated)

February 5, 2024

Last Update Submitted That Met QC Criteria

February 2, 2024

Last Verified

February 1, 2024

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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