Phase I Dose Escalation Study of CD19/CD22 Chimeric Antigen Receptor (CAR) T Cells in Children and Young Adults With Recurrent or Refractory B Cell Malignancies

Phase 1

Recruiting

• Conditions: B Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Philadelphia Chromosome Positive; Recurrent Adult Acute Lymphoblastic Leukemia; Minimal Residual Disease; Refractory Acute Lymphoblastic Leukemia; CD19 Positive
• Interventions: Biological: Chimeric Antigen Receptor T-Cell Therapy; Drug: Cyclophosphamide; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Other: Questionnaire Administration

• Registration Number: NCT03241940
• Lead Sponsor: Crystal Mackall, MD

Brief Summary

This phase I trial studies the best dose and side effects of CD19/CD22 chimeric antigen receptor (CAR) T cells when given together with chemotherapy, and to see how well they work in treating children or young adults with CD19 positive B acute lymphoblastic leukemia that has come back or does not respond to treatment. A CAR is a genetically-engineered receptor made so that immune cells (T cells) can attack cancer cells by recognizing and responding to the CD19/CD22 proteins. These proteins are commonly found on B acute lymphoblastic leukemia. Drugs used in chemotherapy, such as fludarabine phosphate and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving CD19/CD22-CAR T cells and chemotherapy may work better in treating children or young adults with B acute lymphoblastic leukemia.

Detailed Description

PRIMARY OBJECTIVES:

I. Determine the feasibility of producing CD19/CD22-CAR T cells meeting the established release criteria.

II.Assess the safety of administering escalating doses of autologous CD19/CD22-CAR T cells that meet established release specifications in children and young adults with B-cell hematologic malignancies following a cyclophosphamide/fludarabine conditioning regimen. The following dose escalation will be used in two disease groups: 1) children and young adults with relapsed/refractory low disease burden ALL (\< 5% blasts), and 2) children and young adults with relapsed/refractory high disease burden ALL (≥5% blasts) or lymphoma:

1. Dose Level -1: 3 x 105 transduced T cells/kg (± 20%)

2. Dose Level 1: 1 x 106 transduced T cells/kg (± 20%)

3. Dose Level 2: 3 x 106 transduced T cells/kg (± 20%)

4. Dose Level 3: 1 x 107 transduced T cells/kg (± 20%)

SECONDARY OBJECTIVES:

I. Evaluate the ability of CD19/CD22-CAR T cells to mediate clinical activity in children and young adults with B-acute lymphoblastic leukemia (ALL).

TERTIARY OBJECTIVES:

I. Analyze alterations in early B cell development induced by immune pressure exerted via CD19/CD22-CAR T cells.

II. Evaluate whether subjects receiving CD19/CD22-CAR T cells relapse with loss or diminished expression of CD19 and/or CD22, when feasible.

III. Measure persistence of CD19/CD22-CAR T cells in the blood, bone marrow and cerebral spinal fluid (CSF), and explore correlations between CD19/CD22-CAR T cell properties and CAR T cell efficacy and persistence.

IV. Establish the utility of chromatin structure and epigenomic technology to characterize CAR T cell therapies.

V. Explore the ability of CD19/CD22-CAR T cells to mediate clinical activity in children and young adults with refractory B cell lymphoma in a non-statistical cohort due to expectations of low accrual.

OUTLINE: This is a dose-escalation study of CD19/CD22-CAR T cells.

Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -4 to -2 and cyclophosphamide IV over 60 minutes on day -2. Patients then receive CD19/CD22-CAR T cells IV over 10-20 minutes on day 0. Patients that benefited from the first dose of CD19/CD22-CAR T cells, had no unacceptable side effects, and have enough cells left over may receive 2 or 3 additional doses of CD19/CD22-CAR T cells.

After completion of study treatment, patients are followed up daily until day 14, twice weekly until day 28, at 2 and 3 months, every 3 months until month 12, every 6-12 months up to year 5, and then annually for years 6-15.

Study Timeline

• Study First Submitted: 2017-08-03
• Study First Submitted QC: 2017-08-03
• Study First Posted: 2017-08-08
• Study Start: 2017-10-20
• Status Verified: 2024-07
• Last Update Submitted: 2024-07-10
• Last Update Posted: 2024-07-11
• Primary Completion: 2025-08-01
• Study Completion: 2035-08-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 50

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (CD19/CD22-CAR T cells, chemotherapy)	Chimeric Antigen Receptor T-Cell Therapy	Patients receive fludarabine phosphate IV over 30 minutes on days -4 to -2 and cyclophosphamide IV over 60 minutes on day -2. Patients then receive CD19/CD22-CAR T cells IV over 10-20 minutes on day 0. Patients that benefited from the first dose of CD19/CD22-CAR T cells, had no unacceptable side effects, and have enough cells left over may receive 2 or 3 additional doses of CD19/CD22-CAR T cells.
Treatment (CD19/CD22-CAR T cells, chemotherapy)	Questionnaire Administration	Patients receive fludarabine phosphate IV over 30 minutes on days -4 to -2 and cyclophosphamide IV over 60 minutes on day -2. Patients then receive CD19/CD22-CAR T cells IV over 10-20 minutes on day 0. Patients that benefited from the first dose of CD19/CD22-CAR T cells, had no unacceptable side effects, and have enough cells left over may receive 2 or 3 additional doses of CD19/CD22-CAR T cells.
Treatment (CD19/CD22-CAR T cells, chemotherapy)	Laboratory Biomarker Analysis	Patients receive fludarabine phosphate IV over 30 minutes on days -4 to -2 and cyclophosphamide IV over 60 minutes on day -2. Patients then receive CD19/CD22-CAR T cells IV over 10-20 minutes on day 0. Patients that benefited from the first dose of CD19/CD22-CAR T cells, had no unacceptable side effects, and have enough cells left over may receive 2 or 3 additional doses of CD19/CD22-CAR T cells.
Treatment (CD19/CD22-CAR T cells, chemotherapy)	Fludarabine Phosphate	Patients receive fludarabine phosphate IV over 30 minutes on days -4 to -2 and cyclophosphamide IV over 60 minutes on day -2. Patients then receive CD19/CD22-CAR T cells IV over 10-20 minutes on day 0. Patients that benefited from the first dose of CD19/CD22-CAR T cells, had no unacceptable side effects, and have enough cells left over may receive 2 or 3 additional doses of CD19/CD22-CAR T cells.
Treatment (CD19/CD22-CAR T cells, chemotherapy)	Cyclophosphamide	Patients receive fludarabine phosphate IV over 30 minutes on days -4 to -2 and cyclophosphamide IV over 60 minutes on day -2. Patients then receive CD19/CD22-CAR T cells IV over 10-20 minutes on day 0. Patients that benefited from the first dose of CD19/CD22-CAR T cells, had no unacceptable side effects, and have enough cells left over may receive 2 or 3 additional doses of CD19/CD22-CAR T cells.

Primary Outcome Measures

Name	Time	Method
Incidence and severity of dose limiting toxicities (DLTs) following chemotherapy preparative regimen and infusion of CD19/CD22 chimeric antigen receptor (CAR) T cells	Up to 28 days	Will be recorded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 at three dose levels until the maximum tolerated dose (MTD) is determined.
Rate of successful manufacture and expansion of the CD19/CD22 chimeric antigen receptor (CAR) T cells to satisfy the targeted dose level and meet the required release specifications outlined in the Certificate of Analysis (COA)	10-14 days after apheresis or thawing of cryopreserved peripheral blood mononuclear cell	The number of subjects which can successfully manufacture the targeted dose number will be determined for each dose cohort.

Secondary Outcome Measures

Name	Time	Method
The ability to achieve a clinical response after administration of CD19/CD22 chimeric antigen receptor (CAR) T cells	Up to 15 years	Will be assessed by the Response Criteria for Lymphoma and the Response Criteria for Acute Lymphoblastic Leukemia.

Trial Locations

Locations (1)

Lucile Packard Children's Hospital Stanford University; 🇺🇸 Palo Alto, California, United States