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Study of CD19-directed Allogeneic Memory T-cell Therapy for Relapsed/Refractory CD19+ Leukemia

Primary Purpose

Acute Lymphoblastic Leukemia, in Relapse, Acute Lymphoblastic Leukemia, Refractory, Pediatric ALL

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
CD19-CAR(Mem) T-cells
Cyclophosphamide
Fludarabine
Mesna
CliniMACS
Leukapheresis
Sponsored by
St. Jude Children's Research Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Lymphoblastic Leukemia, in Relapse

Eligibility Criteria

undefined - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria Eligibility Criteria for Donors: Apheresis and Manufacturing

  • Age ≥ 18 years old
  • At least single haplotype matched (≥ 3/6) family member
  • HIV negative
  • For females of child bearing age: Not pregnant as confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment AND Not lactating with intent to breastfeed
  • Completed the process of donor eligibility determination as outlined in 21 CFR 1271 and agency guidance
  • Identified recipient with relapsed and/or refractory CD19-positive leukemia who is not suitable to receive autologous CD19-CAR T-cell therapy as defined by the following:

    • Relapsed and/or refractory disease despite prior treatment with autologous CD19-CAR T-cell therapy
    • History of prior autologous leukapheresis failure
    • History of prior autologous CAR T-cell manufacturing failure
    • Unable to undergo autologous leukapheresis in the opinion of the study PI(s): examples may include - patient small size/low weight, inadequate T-cell counts, rapidly progressive leukemia, clinical status not amenable to apheresis

Eligibility Criteria for Patients: Treatment

  • Age ≤ 21 years old
  • Not suitable to receive autologous CD19-CAR T-cell therapy as defined above
  • Relapsed and/or refractory CD19-positive leukemia*:

    • CD19-positivity confirmed within 2 months and after receipt of any CD19-directed therapy

      • Refractory disease (defined as any of the following):

        • Primary refractory disease despite at least 2 cycles of an intensive chemotherapy regimen designed to induce remission
        • Refractory disease despite salvage therapy
      • Relapsed disease (defined as any of the following):

        • 2nd or greater relapse
        • Any relapse after allogeneic hematopoietic cell transplantation (HCT)
        • 1st relapse if patient requires an allogeneic HCT as part of standard of care relapse therapy, but is found to be ineligible and/or unsuitable for HCT
  • Patient cohorts:

    • Cohort A: patient has previously received a HCT from the selected CAR T-cell donor
    • Cohort B - patient has NOT previously received a HCT from the selected CAR T-cell donor.
  • Detectable medullary CD19-positive leukemia
  • Estimated life expectancy of ≥ 8 weeks
  • Karnofsky or Lansky performance score ≥ 50
  • No CNS-3 disease or any level of detectable leukemia in CNS with associated neurologic symptoms
  • If history of allogeneic HCT (regardless of donor type), prior to planned CAR T-cell infusion, must meet the following criteria:

    • ≥ 3 months from HCT
    • have recovered from prior HCT therapy
    • have no evidence of active GVHD within prior 2 months
    • have not received a donor lymphocyte infusion (DLI) within the 28 days prior to planned CAR T-cell infusion
  • Adequate cardiac function: left ventricular ejection fraction ≥ 40% or shortening fraction ≥ 25% (function may be supported by pharmacologic therapy)
  • EKG without evidence of clinically significant arrhythmia
  • Adequate renal function: creatinine clearance or radioisotope GFR 50 ml/min/1.73m2 (GFR 40 ml/min/1.73m2 if < 2 years of age)
  • Adequate pulmonary function: forced vital capacity (FVC) ≥ 50% of predicted value; or pulse oximetry ≥ 92% on room air if patient is unable to perform pulmonary function testing
  • Total bilirubin ≤ 3 times the upper limit of normal for age, except in subjects with Gilbert's syndrome
  • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 5 times the upper limit of normal for age
  • No history of HIV infection
  • No evidence of severe, uncontrolled bacterial, viral or fungal infection
  • Has recovered from all NCI CTAE grade III-IV, non-hematologic acute toxicities from prior therapy
  • For females of child bearing age:

    • Not pregnant with negative serum or urine pregnancy test ≤ 7 days prior to enrollment AND Not lactating with intent to breastfeed
  • If sexually active, agreement to use birth control until 6 months after CAR T-cell infusion
  • No history of hypersensitivity reactions to murine protein-containing products
  • Not receiving systemic steroids therapy exceeding the equivalent of 0.5 mg/kg/day of methylprednisolone ≤ 7 days prior to CAR T-cell infusion
  • Not receiving systemic therapy ≤ 14 days prior to CAR T-cell infusion, which will interfere with the activity of the CAR T-cell product in vivo (in the opinion of the study PI(s))
  • Not receiving intrathecal chemotherapy ≤ 7 days prior to CAR T-cell infusion

Exclusion Criteria:

• NA

Sites / Locations

  • St. Jude Children's Research HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Group A

Group B

Arm Description

Participants in group A have received a prior stem cell transplant from their CAR T-cell donor.

Participants in group B have not received a prior stem cell transplant from their CAR T-cell donor.

Outcomes

Primary Outcome Measures

Maximum tolerated dose of allogeneic, CD19-CAR.CD45RA-negative cells
This phase I study includes dose escalation/de-escalation based on dose limiting toxicity (DLT) assessment to determine the maximum tolerated dose (MTD) of allogeneic, CD19-CAR.CD45RA-negative cells.

Secondary Outcome Measures

Full Information

First Posted
April 27, 2021
Last Updated
September 6, 2023
Sponsor
St. Jude Children's Research Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT04881240
Brief Title
Study of CD19-directed Allogeneic Memory T-cell Therapy for Relapsed/Refractory CD19+ Leukemia
Official Title
A Phase I Study Evaluating Allogeneic Memory T Cells Engineered to Express Chimeric Antigen Receptors Specific for CD19 for the Treatment of Pediatric and Young Adult Patients ≤ 21 Years of Age With Relapsed or Refractory CD19-Positive Leukemia
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
October 2023 (Anticipated)
Primary Completion Date
January 2025 (Anticipated)
Study Completion Date
January 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
St. Jude Children's Research Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
No

5. Study Description

Brief Summary
This is a Phase I clinical study evaluating the safety and maximum tolerated dose of a novel CAR T-cell product: allogeneic memory (CD45RA- negative) T-cells expressing a CD19-specific CAR 41BBz (CD19-CAR.CD45RA- negative T-cells) for the treatment of patients ≤ 21 years old with relapsed and/ or refractory CD19-positive leukemia. Primary Objective To determine the maximum tolerated dose (MTD) and characterize the safety profile and dose-limiting toxicities (DLTs) of treatment with allogeneic CD19-CAR.CD45RA-negative T-cells in pediatric, adolescent and young adult patients ≤ 21 years of age, with relapsed and/or refractory CD19-positive leukemia. Secondary Objectives To evaluate the anti-leukemic activity of allogeneic CD19-CAR.CD45RA-negative T-cells. To determine rates and severity of graft-versus-host-disease (GVHD) after treatment with allogeneic CD19-CAR.CD45RA-negative T-cells. Exploratory Objectives To study the expansion, persistence and phenotype of allogeneic CD19-CAR.CD45RA-negative T-cells. To characterize the cytokine profile in the peripheral blood and CSF after treatment with allogeneic CD19-CAR.CD45RA-negative T-cells. To assess whether allogeneic CD19-CAR.CD45RA-negative T-cells acquire functional versus exhaustion-associated epigenetic programs. To determine immune reconstitution post treatment, and the clonal structure and endogenous repertoire of allogeneic CD19-CAR.CD45RA-negative T-cells and relate inferred specificity to CAR response profiles. To characterize incidence and mechanisms of relapse post-therapy with allogeneic CD19-CAR.CD45RA-negative T-cells.
Detailed Description
This is a Phase I dose escalation study using a 3+3 study design. Two groups of patients will be evaluated in this study: group A - patients have received a prior stem cell transplant from their CAR T-cell donor; group B - patients have not received a prior stem cell transplant from their CAR T-cell donor. There will be up to 30 participants per group and a donor/ family member for each patient. .

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Lymphoblastic Leukemia, in Relapse, Acute Lymphoblastic Leukemia, Refractory, Pediatric ALL

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Group A
Arm Type
Experimental
Arm Description
Participants in group A have received a prior stem cell transplant from their CAR T-cell donor.
Arm Title
Group B
Arm Type
Experimental
Arm Description
Participants in group B have not received a prior stem cell transplant from their CAR T-cell donor.
Intervention Type
Biological
Intervention Name(s)
CD19-CAR(Mem) T-cells
Intervention Description
Allogeneic CD19-CAR.CD45RA-negative T-cells Intravenous infusion
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
Cytoxan
Intervention Description
Cyclophosphamide is a nitrogen mustard derivative. It acts as an alkylating agent that causes cross-linking of DNA strands by binding with nucleic acids and other intracellular structures, thus interfering with the normal function of DNA.
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Other Intervention Name(s)
Fludara
Intervention Description
Fludarabine phosphate is a synthetic purine nucleoside analog. It acts by inhibiting DNA polymerase, ribonucleotide reductase and DNA primase by competing with the physiologic substrate, deoxyadenosine triphosphate, resulting in inhibition of DNA synthesis.
Intervention Type
Drug
Intervention Name(s)
Mesna
Other Intervention Name(s)
Mesnex
Intervention Description
Mesna is a synthetic sulfhydryl (thiol) compound. Mesna contains free sulfhydryl groups that interact chemically with urotoxic metabolites of oxaza-phosphorine derivatives such as cyclophosphamide and ifosfamide.
Intervention Type
Device
Intervention Name(s)
CliniMACS
Intervention Description
A CliniMACS device is used to select donor T-cells for manufacturing of the memory CAR T-cell product.
Intervention Type
Procedure
Intervention Name(s)
Leukapheresis
Intervention Description
Leukapheresis is performed to collect the T cells that are needed to generate the CD19-CAR.CD45RA-negative T-cells product for the clinic study.
Primary Outcome Measure Information:
Title
Maximum tolerated dose of allogeneic, CD19-CAR.CD45RA-negative cells
Description
This phase I study includes dose escalation/de-escalation based on dose limiting toxicity (DLT) assessment to determine the maximum tolerated dose (MTD) of allogeneic, CD19-CAR.CD45RA-negative cells.
Time Frame
4 weeks after CAR T-cell infusion

10. Eligibility

Sex
All
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria Eligibility Criteria for Donors: Apheresis and Manufacturing Age ≥ 18 years old At least single haplotype matched (≥ 3/6) family member HIV negative For females of child bearing age: Not pregnant as confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment AND Not lactating with intent to breastfeed Completed the process of donor eligibility determination as outlined in 21 CFR 1271 and agency guidance For Cohort A only, identified recipient with relapsed and/or refractory CD19-positive leukemia For Cohort B only, iIdentified recipient with relapsed and/or refractory CD19-positive leukemia who is not suitable to receive autologous CD19-CAR T-cell therapy as defined by the following: Relapsed and/or refractory disease despite prior treatment with autologous CD19- CAR T-cell therapy History of prior autologous leukapheresis failure History of prior autologous CAR T-cell manufacturing failure Unable to undergo autologous leukapheresis in the opinion of the study PI(s): examples may include - patient small size/low weight, inadequate T-cell counts, rapidly progressive leukemia, clinical status not amenable to apheresis Eligibility Criteria for Patients: Treatment Age ≤ 21 years old Relapsed and/or refractory CD19-positive leukemia*: Refractory disease (defined as any of the following): Primary refractory disease despite at least 2 cycles of an intensive chemotherapy regimen designed to induce remission Refractory disease despite salvage therapy Relapsed disease (defined as any of the following): 2nd or greater relapse Any relapse after allogeneic hematopoietic cell transplantation (HCT) 1st relapse if patient requires an allogeneic HCT as part of standard of care relapse therapy, but is found to be ineligible and/or unsuitable for HCT CD19-positivity confirmed within 2 months and after receipt of any CD19-directed therapy Patient cohorts: Cohort A: patient has previously received a HCT from the selected CAR T-cell donor Cohort B - patient has NOT previously received a HCT from the selected CAR T-cell donor. For Cohort B only, not suitable to receive autologous CD19-CAR T-cell therapy as defined above in Criteria: Eligibility Criteria for Donors: Apheresis and Manufacturing Detectable medullary CD19-positive leukemia Estimated life expectancy of ≥ 8 weeks Karnofsky or Lansky performance score ≥ 50 No CNS-3 disease or any level of detectable leukemia in CNS with associated neurologic symptoms If history of allogeneic HCT (regardless of donor type), prior to planned CAR T-cell infusion, must meet the following criteria: ≥ 3 months from HCT have recovered from prior HCT therapy have no evidence of active GVHD within prior 2 months have not received a donor lymphocyte infusion (DLI) within the 28 days prior to planned CAR T-cell infusion Adequate cardiac function: left ventricular ejection fraction ≥ 40% or shortening fraction ≥ 25% (function may be supported by pharmacologic therapy) EKG without evidence of clinically significant arrhythmia Adequate renal function: creatinine clearance or radioisotope GFR 50 ml/min/1.73m2 (GFR 40 ml/min/1.73m2 if < 2 years of age) Adequate pulmonary function: forced vital capacity (FVC) ≥ 50% of predicted value; or pulse oximetry ≥ 92% on room air if patient is unable to perform pulmonary function testing Total bilirubin ≤ 3 times the upper limit of normal for age, except in subjects with Gilbert's syndrome Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 5 times the upper limit of normal for age No history of HIV infection No evidence of severe, uncontrolled bacterial, viral or fungal infection Has recovered from all NCI CTAE grade III-IV, non-hematologic acute toxicities from prior therapy For females of child bearing age: Not pregnant with negative serum or urine pregnancy test ≤ 7 days prior to enrollment AND Not lactating with intent to breastfeed If sexually active, agreement to use birth control until 6 months after CAR T-cell infusion No history of hypersensitivity reactions to murine protein-containing products Not receiving systemic steroids therapy exceeding the equivalent of 0.5 mg/kg/day of methylprednisolone ≤ 7 days prior to CAR T-cell infusion Not receiving systemic therapy ≤ 14 days prior to CAR T-cell infusion, which will interfere with the activity of the CAR T-cell product in vivo (in the opinion of the study PI(s)) Not receiving intrathecal chemotherapy ≤ 7 days prior to CAR T-cell infusion Exclusion Criteria: NA
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Aimee C. Talleur, MD
Phone
866-278-5833
Email
referralinfo@stjude.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Aimee C. Talleur, MD
Organizational Affiliation
St. Jude Children's Research Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Stephen Gottschalk, MD
Organizational Affiliation
St. Jude Children's Research Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
St. Jude Children's Research Hospital
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38105
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Aimee C. Talleur, MD
Phone
866-278-5833
Email
referralinfo@stjude.org
First Name & Middle Initial & Last Name & Degree
Aimee C. Talleur, MD
First Name & Middle Initial & Last Name & Degree
Stephen Gottschalk, MD

12. IPD Sharing Statement

Links:
URL
http://www.stjude.org
Description
St. Jude Children's Research Hospital
URL
http://www.stjude.org/protocols
Description
Clinical Trials Open at St. Jude

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Study of CD19-directed Allogeneic Memory T-cell Therapy for Relapsed/Refractory CD19+ Leukemia

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