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Co-administration of CART22-65s and huCART19 for B-ALL

Primary Purpose

B-cell Acute Lymphoblastic Leukemia, B Lineage Lymphoblastic Lymphoma

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Autologous, humanized anti-CD22 CAR T cell therapy (CART22-65s)
Autologous, humanized anti-CD19 CAR T cell therapy (huCART19)
Sponsored by
Stephan Grupp MD PhD
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for B-cell Acute Lymphoblastic Leukemia

Eligibility Criteria

undefined - 29 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Signed informed consent form Patients with documented CD19+ and/or CD22+ ALL/LLy: Cohort A: Patients with relapsed or refractory ALL/LLy: Cohort B: Patients with poor response to prior B cell directed engineered cell therapy Patients with prior or current history of Central Nervous System 3 disease will be eligible if Central Nervous System disease is responsive to therapy Documentation of CD19 and/or CD22 tumor expression in bone marrow, peripheral blood, Cerebrospinal fluid, or tumor tissue by flow cytometry at the time of last detectable disease. If the patient has experienced a relapse after CD19-directed and/or CD22-directed therapy, flow cytometry should be evaluated after this therapy to demonstrate CD19 and/or CD22 expression. Age 0-29 years Adequate organ function Adequate performance status defined as Lanksy or Karnofsky performance 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 Vs. Host Disease requiring systemic therapy Concurrent use of systemic steroids or immunosuppression at the time of cell infusion or cell collection, or a condition, in the treating physician's opinion, that is likely to require steroid therapy or immunosuppression during collection or after infusion. Steroids for disease treatment at times other than cell collection or at the time of infusion are permitted. Use of physiologic replacement hydrocortisone or inhaled steroids is permitted as well. Central nervous system disease that is progressive on therapy, or with Central nervous system parenchymal lesions that might increase the risk of central nervous system toxicity. Pregnant or nursing (lactating) women Uncontrolled active infection

Sites / Locations

  • Children's Hospital of PhiladelphiaRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Dose Finding Arm

Expansion Arm

Arm Description

Phase 1 will evaluate the safety of co-administration of CART22-65s with huCART19 in patients who experienced a disease relapse after prior CAR T cell therapy. There is no planned dose escalation but a dose-deescalation will be made based on the incidence of Dose Limiting Toxicities

If at least one dose level of phase 1 is determined to be safe, the phase 2 dose expansion phase of the trial will be opened to enrollment. Subjects will receive the highest dose of CART 22-65s and huCART19 cells that were determined to be safe. 2 cohorts are planned: Cohort A (relapsed/refractory, CAR T cell naïve) & Cohort B (prior treatment with a prior CAR T cell product).

Outcomes

Primary Outcome Measures

Safety of CART22-65s and huCART19 co-administration
The safety of the administering CART22-65s and huCART19 will be measured by the monitoring the frequency and severity of adverse events in patients with advanced or refractory B-Cell Acute Lymphoblastic Leukemia or B Cell Lymphoblastic Lymphoma (B-LLy), including those previously treated with cell therapy.
Efficacy of CART22-65s and huCART19 co-administration
The efficacy of CART22-65s and huCART19 co-administration will be measured by the evaluating the overall response rate in patients with advanced or refractory B cell hematologic malignancies, including those previously treated with cell therapy.

Secondary Outcome Measures

Manufacturing Feasibility
The manufacturing feasibility of manufacturing both CART22-65s and huCART19 will be measured by the percentage of manufactured products that do not meet release criteria for vector transduction efficiency, T cell product purity, viability, sterility or due to tumor contamination.
Anti-tumor response due to CART22-65s and huCART19 co-administration
Anti-tumor response due to CART22-65s and huCART19 co-administration will be measured by negative minimal residual disease (MRD) as measured by multiparameter flow cytometry at day 28.
Event Free Survival
1-year Event-Free Survival (EFS) in subjects with relapsed/refractory B-ALL (Cohort A) and in subjects with poor response to prior B cell directed engineered cell therapy (Cohort B)
Relapse Free Survival
1-year relapse-free survival (RFS) rate in CAR-naïve subjects with relapsed/refractory B-ALL (Cohort A) and in CAR-exposed subjects with poor response to prior B cell directed engineered cell therapy (Cohort B)
Overall Survival
1-year overall survival (OS) rate in CAR-naïve subjects with relapsed/refractory B-ALL (Cohort A) and in CAR-exposed subjects with poor response to prior B cell directed engineered cell therapy (Cohort B).
CAR T Cell Therapy Persistence
CART22-65s and huCART19 persistence polymerase chain reaction (or flow cytometry) analysis of whole blood to detect and quantify survival of CART2265s and huCART19 over time.
Bioreactivity of CART22-65s and huCART19 when co-administered
The bioreactivity of CART22-65s and huCART19 when co-administered, as measured by elevations level in any of; Uric Acid, Lactate Dehydrogenase (LDH), c-reactive protein (CRP), and cytokines (e.g.IL -10) before and after CART T cell infusions.

Full Information

First Posted
December 6, 2022
Last Updated
January 25, 2023
Sponsor
Stephan Grupp MD PhD
Collaborators
University of Pennsylvania
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1. Study Identification

Unique Protocol Identification Number
NCT05674175
Brief Title
Co-administration of CART22-65s and huCART19 for B-ALL
Official Title
Use of Autologous Anti-CD22 CAR T Cells (CART22-65s) Co-administered With Humanized Anti-CD19 CAR T Cells (huCART19) in Children and Young Adults With Relapsed or Refractory B-ALL
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 25, 2023 (Actual)
Primary Completion Date
January 15, 2025 (Anticipated)
Study Completion Date
January 15, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Stephan Grupp MD PhD
Collaborators
University of Pennsylvania

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study will evaluate the safety and efficacy of administering two CAR T cell products, huCART19 and CART22-65s, in children with advanced B cell Acute Lymphoblastic Leukemia (B-ALL).
Detailed Description
CD19-targeted CAR T cell therapy has transformed the treatment landscape for children and young adults with chemo-refractory or relapsed B cell Acute Lymphoblastic Leukemia (B-ALL). Despite remarkable initial response rates, approximately 50% of pediatric patients experience a subsequent disease relapse. The prognosis for these patients is dismal with a median survival of less than one year from the time of post-CART19 relapse. The primary mechanisms contributing to CART19 failure include CD19-antigen escape and loss of CAR T cell surveillance due to short CART persistence. This study aims to counter each driver of relapse by co-administering two next-generation CAR T cell products: an anti-CD22 CART (CART22-65s), designed to overcome CD19-antigen escape; and a humanized anti-CD19 CART (huCART19), designed to overcome immune-mediated rejection of murine CART19.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
B-cell Acute Lymphoblastic Leukemia, B Lineage Lymphoblastic Lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
93 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Dose Finding Arm
Arm Type
Experimental
Arm Description
Phase 1 will evaluate the safety of co-administration of CART22-65s with huCART19 in patients who experienced a disease relapse after prior CAR T cell therapy. There is no planned dose escalation but a dose-deescalation will be made based on the incidence of Dose Limiting Toxicities
Arm Title
Expansion Arm
Arm Type
Experimental
Arm Description
If at least one dose level of phase 1 is determined to be safe, the phase 2 dose expansion phase of the trial will be opened to enrollment. Subjects will receive the highest dose of CART 22-65s and huCART19 cells that were determined to be safe. 2 cohorts are planned: Cohort A (relapsed/refractory, CAR T cell naïve) & Cohort B (prior treatment with a prior CAR T cell product).
Intervention Type
Biological
Intervention Name(s)
Autologous, humanized anti-CD22 CAR T cell therapy (CART22-65s)
Other Intervention Name(s)
CART22-65s
Intervention Description
CART22-65s are autologous T cells that have been engineered to express an extracellular single chain antibody (scFv) with specificity for CD22 linked to an intracellular signaling molecule consisting of a tandem signaling domain comprised of the TCRζ signaling module linked to the 4-1BB costimulatory domain
Intervention Type
Biological
Intervention Name(s)
Autologous, humanized anti-CD19 CAR T cell therapy (huCART19)
Other Intervention Name(s)
huCART19
Intervention Description
HuCART19 cells are autologous T cells that have been engineered to express an extracellular single chain antibody (scFv) with specificity for CD19 linked to an intracellular signaling molecule consisting of a tandem signaling domain comprised of the TCRζ signaling module linked to the 4-1BB costimulatory domain
Primary Outcome Measure Information:
Title
Safety of CART22-65s and huCART19 co-administration
Description
The safety of the administering CART22-65s and huCART19 will be measured by the monitoring the frequency and severity of adverse events in patients with advanced or refractory B-Cell Acute Lymphoblastic Leukemia or B Cell Lymphoblastic Lymphoma (B-LLy), including those previously treated with cell therapy.
Time Frame
1 year
Title
Efficacy of CART22-65s and huCART19 co-administration
Description
The efficacy of CART22-65s and huCART19 co-administration will be measured by the evaluating the overall response rate in patients with advanced or refractory B cell hematologic malignancies, including those previously treated with cell therapy.
Time Frame
1 year
Secondary Outcome Measure Information:
Title
Manufacturing Feasibility
Description
The manufacturing feasibility of manufacturing both CART22-65s and huCART19 will be measured by the percentage of manufactured products that do not meet release criteria for vector transduction efficiency, T cell product purity, viability, sterility or due to tumor contamination.
Time Frame
5 years
Title
Anti-tumor response due to CART22-65s and huCART19 co-administration
Description
Anti-tumor response due to CART22-65s and huCART19 co-administration will be measured by negative minimal residual disease (MRD) as measured by multiparameter flow cytometry at day 28.
Time Frame
Day 28
Title
Event Free Survival
Description
1-year Event-Free Survival (EFS) in subjects with relapsed/refractory B-ALL (Cohort A) and in subjects with poor response to prior B cell directed engineered cell therapy (Cohort B)
Time Frame
1 year
Title
Relapse Free Survival
Description
1-year relapse-free survival (RFS) rate in CAR-naïve subjects with relapsed/refractory B-ALL (Cohort A) and in CAR-exposed subjects with poor response to prior B cell directed engineered cell therapy (Cohort B)
Time Frame
1 year
Title
Overall Survival
Description
1-year overall survival (OS) rate in CAR-naïve subjects with relapsed/refractory B-ALL (Cohort A) and in CAR-exposed subjects with poor response to prior B cell directed engineered cell therapy (Cohort B).
Time Frame
1 year
Title
CAR T Cell Therapy Persistence
Description
CART22-65s and huCART19 persistence polymerase chain reaction (or flow cytometry) analysis of whole blood to detect and quantify survival of CART2265s and huCART19 over time.
Time Frame
1 year
Title
Bioreactivity of CART22-65s and huCART19 when co-administered
Description
The bioreactivity of CART22-65s and huCART19 when co-administered, as measured by elevations level in any of; Uric Acid, Lactate Dehydrogenase (LDH), c-reactive protein (CRP), and cytokines (e.g.IL -10) before and after CART T cell infusions.
Time Frame
1 year

10. Eligibility

Sex
All
Maximum Age & Unit of Time
29 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Signed informed consent form Patients with documented CD19+ and/or CD22+ ALL/LLy: Cohort A: Patients with relapsed or refractory ALL/LLy: Cohort B: Patients with poor response to prior B cell directed engineered cell therapy Patients with prior or current history of Central Nervous System 3 disease will be eligible if Central Nervous System disease is responsive to therapy Documentation of CD19 and/or CD22 tumor expression in bone marrow, peripheral blood, Cerebrospinal fluid, or tumor tissue by flow cytometry at the time of last detectable disease. If the patient has experienced a relapse after CD19-directed and/or CD22-directed therapy, flow cytometry should be evaluated after this therapy to demonstrate CD19 and/or CD22 expression. Age 0-29 years Adequate organ function Adequate performance status defined as Lanksy or Karnofsky performance 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 Vs. Host Disease requiring systemic therapy Concurrent use of systemic steroids or immunosuppression at the time of cell infusion or cell collection, or a condition, in the treating physician's opinion, that is likely to require steroid therapy or immunosuppression during collection or after infusion. Steroids for disease treatment at times other than cell collection or at the time of infusion are permitted. Use of physiologic replacement hydrocortisone or inhaled steroids is permitted as well. Central nervous system disease that is progressive on therapy, or with Central nervous system parenchymal lesions that might increase the risk of central nervous system toxicity. Pregnant or nursing (lactating) women Uncontrolled active infection
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Melissa Varghese
Phone
8455535358
Email
Varghesem@chop.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Laura Shinehouse
Email
shinehous1@chop.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Regina Myers, MD
Organizational Affiliation
Children's Hospital of Philadelphia
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Melissa Varghese
Phone
845-553-5358
Email
Varghesem@chop.edu

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Co-administration of CART22-65s and huCART19 for B-ALL

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