CD19/CD22 Chimeric Antigen Receptor T Cell Therapy for Treating Pediatric Patients with Recurrent or Refractory Acute Lymphoblastic Leukemia

Status: active

This phase I trial tests the safety, side effects, and best dose of CD19/CD22 chimeric antigen receptor (CAR) T cells in treating pediatric patients with acute lymphoblastic leukemia (ALL) that has come back after a period of improvement (recurrent) or has not responded to previous treatment (refractory). CD19-CD22-CAR T cells are a type of cancer immunotherapy. CAR T cell therapy combines two of the body’s basic disease fighters: antibodies and T cells. For this type of therapy, cells from the blood are collected and then changed so they can identify an antigen, which is a particle present on the surface of a cancer cell. If the CAR T cells ‘see’ the antigen on the cancer cell, they can attack and kill it. This study uses a specific CAR T cell product that ‘sees’ antigens called CD19 and CD22, which are on ALL cells. Chemotherapy drugs, such as cyclophosphamide and fludarabine, 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. The goal of the chemotherapy drugs used in this study is not to treat cancer. They are used to prepare the body for the new CAR T cells and allow them to grow. This study will test whether CD19-CD22-CAR T cells are safe in treating pediatric patients with relapsed or refractory ALL, and whether they are active against leukemia cells.

Inclusion Criteria

COLLECTION AND MANUFACTURING ELIGIBILITY: A previously collected, autologous leukapheresis product may be used for T cell production
COLLECTION AND MANUFACTURING ELIGIBILITY: Age =< 21 years old
COLLECTION AND MANUFACTURING ELIGIBILITY: Relapsed/refractory CD19- and/or CD22-positive acute leukemia defined as: * CD19 and/or CD22-positivity confirmed within 2 months and after receipt of any CD19 or CD22-directed therapy ** Second or greater relapse ** Any relapse after allogeneic hematopoietic cell transplantation (HCT) ** Refractory disease (primary or in relapse) despite therapy designed to induce remission
COLLECTION AND MANUFACTURING ELIGIBILITY: Estimated life expectancy of > 12 weeks
COLLECTION AND MANUFACTURING ELIGIBILITY: Karnofsky or Lansky (age-dependent) performance score ≥ 50
COLLECTION AND MANUFACTURING ELIGIBILITY: For females of childbearing age: * Not lactating with intent to breastfeed * Not pregnant with negative serum or urine pregnancy test within 7 days prior to enrollment
TREATMENT ELIGIBILITY: Age =< 21 years old
TREATMENT ELIGIBILITY: Detectable CD19- and/or CD22-positive leukemic disease in the bone marrow
TREATMENT ELIGIBILITY: Karnofsky or Lansky (age-dependent) performance score ≥ 50
TREATMENT ELIGIBILITY: Left ventricular ejection fraction > 40%, or shortening fraction ≥ 25%
TREATMENT ELIGIBILITY: Electrocardiogram (EKG) without evidence of clinically significant arrhythmia
TREATMENT ELIGIBILITY: Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 50 mL/min/1.73 m^2 (GFR ≥ 40 mL/min/1.73m^2 if < 2 years of age)
TREATMENT ELIGIBILITY: Forced vital capacity (FVC) ≥ 50% of predicted value; or pulse oximetry ≥ 92% on room air
TREATMENT ELIGIBILITY: Total bilirubin ≤ 3 times the upper limit of normal for age, except in subjects with Gilbert’s syndrome
TREATMENT ELIGIBILITY: Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 5 times the upper limit of normal for age
TREATMENT ELIGIBILITY: Has recovered from all National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade III-IV, non-hematologic acute toxicities from prior therapy
TREATMENT ELIGIBILITY: Prior to planned CAR T cell infusion, patients with a history of prior allogeneic HCT must be at least 3 months from HCT, have no evidence of acute graft-versus-host disease (GVHD), and have not received a donor lymphocyte infusion (DLI) within the 28 days prior to planned infusion
TREATMENT ELIGIBILITY: For females of childbearing age: * Not lactating with intent to breastfeed * Not pregnant with negative serum or urine pregnancy test within 7 days prior to enrollment * If sexually active, agreement to use birth control until 3 months after T cell infusion. Male partners should use a condom

Exclusion Criteria

COLLECTION AND MANUFACTURING ELIGIBILITY: Known primary immunodeficiency
COLLECTION AND MANUFACTURING ELIGIBILITY: Known HIV positivity
COLLECTION AND MANUFACTURING ELIGIBILITY: Known contraindication to receiving protocol defined lymphodepleting chemotherapy regimen
COLLECTION AND MANUFACTURING ELIGIBILITY: History of hypersensitivity reaction to murine-containing products
TREATMENT ELIGIBILITY: Estimated life expectancy of > 8 weeks
TREATMENT ELIGIBILITY: Known primary immunodeficiency
TREATMENT ELIGIBILITY: Known HIV positivity
TREATMENT ELIGIBILITY: Known contraindication to receiving protocol defined lymphodepleting chemotherapy regimen
TREATMENT ELIGIBILITY: History of hypersensitivity reactions to murine protein-containing products
TREATMENT ELIGIBILITY: Severe, uncontrolled bacterial, viral or fungal infection
TREATMENT ELIGIBILITY: Active central nervous system (CNS)-3 disease
TREATMENT ELIGIBILITY: Evidence of active, uncontrolled neurologic disease

PRIMARY OBJECTIVE:

I. To determine the safety profile and propose the recommended phase 2 dose (RP2D) of autologous CD19-CD22-CAR T cells in patients ≤ 21 years of age with recurrent/refractory CD19- and/or CD22-positive leukemia.

SECONDARY OBJECTIVE:

I. To evaluate the anti-leukemic activity of CD19-CD22-CAR T cells.

EXPLORATORY OBJECTIVES:

I. To assess the immunophenotype, expansion, and persistence of CD19-CD22-CAR T cells.

II. To analyze the functional state of CD19-CD22-CAR T cells pre- and post-infusion.

III. To characterize cytokine profiles after treatment with CD19-CD22-CAR T cells.

IV. To estimate relapse rates and investigate mechanisms of resistance or response to, or relapse after, CD19-CD22-CAR T cell therapy.

V. To assess the pharmacokinetics of lymphodepleting chemotherapy (fludarabine and cyclophosphamide) and study the relationship between these pharmacokinetics and immune cells, clinical efficacy and toxicity after

treatment with CD19-CD22-CAR T cell therapy.

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

Patients undergo pheresis to obtain peripheral blood mononuclear cells (PBMCs) for T cell product manufacturing. Patients then undergo lymphodepleting chemotherapy with fludarabine intravenously (IV) on days -5, -4, -3 and -2, cyclophosphamide on days -5 and -4, and CD19-CD22-CAR T cells IV over 30 minutes on day 0 or +1. Patients also undergo bone marrow and cerebrospinal fluid (CSF) sample collection during screening and on study and blood sample collection throughout the study. Additionally, patients may undergo bone marrow and CSF during follow-up.

After completion of study treatment, patients are followed on study for 1 year, with additional long-term follow-up for up to a total of 15 years.

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CD19/CD22 Chimeric Antigen Receptor T Cell Therapy for Treating Pediatric Patients with Recurrent or Refractory Acute Lymphoblastic Leukemia

Inclusion Criteria

Exclusion Criteria

United States

Tennessee

Memphis

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CD19/CD22 Chimeric Antigen Receptor T Cell Therapy for Treating Pediatric Patients with Recurrent or Refractory Acute Lymphoblastic Leukemia

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