Lymphodepleting Chemotherapy and Chimeric Antigen Receptor T Cell Therapy for the Treatment of Recurrent or Refractory CD19-positive Leukemia in Pediatric, Adolescent, and Young Adult Patients

Status: approved

This phase II trial studies the side effects and best dose for lymphodepleting chemotherapy given before chimeric antigen receptor (CAR) T cell therapy and to see how well it works in treating pediatric, adolescent, and young adult patients with CD19-positve leukemia that has come back after a period of improvement (recurrent) or that does not respond to treatment (refractory). Lymphodepleting chemotherapy with fludarabine and cyclophosphamide is given before CAR T cell therapy. The chemotherapy drugs help kill cancer cells in the body and help the CAR T cells to grow and work better. CAR T cell therapy combines two of the body’s basic disease fighters: antibodies and T cells. For this type of therapy, peripheral (circulating) immune cells are collected from the blood and then changed so that they can recognize an antigen. This antigen is a particle or 'flag' present on the surface of a cancer cell. If the CAR T cells 'see' the antigen on the cancer cell, they will attack and kill it. This study uses a CAR T cell that 'sees' an antigen called CD19 which is found on CD19-positive leukemia cancer cells. Giving lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by CAR T cell therapy may be safe, tolerable, and/or effective in treating pediatric, adolescent, and young adult patients with recurrent or refractory CD19-positive leukemia.

Inclusion Criteria

AUTOLOGOUS APHERESIS AND MANUFACTURING: CD19+ leukemia with any of the following: * Refractory disease (primary or in relapse) * 2nd or greater relapse * Any relapse after allogeneic hematopoietic cell transplantation * 1st relapse if patient requires an allogeneic hematopoietic cell transplantation (HCT) as part of standard of care relapse therapy, but is found to be ineligible and/or unsuitable for HCT ** Must be confirmed to be CD19+ within 3 months prior to enrollment for treatment ** Relapse may include any measurable level of recurrent detectable disease
AUTOLOGOUS APHERESIS AND MANUFACTURING: Age: ≤ 21 years of age
AUTOLOGOUS APHERESIS AND MANUFACTURING: Karnofsky or Lansky (age-dependent) performance score ≥ 50
AUTOLOGOUS APHERESIS AND MANUFACTURING: Estimated life expectancy of > 12 weeks. Patients with a history of prior allogeneic hematopoietic cell transplantation (HCT) must be clinically recovered from prior HCT therapy, have no evidence of active graft versus host disease (GVHD) and have not received a donor lymphocyte infusion (DLI) within the 28 days prior to apheresis
AUTOLOGOUS APHERESIS AND MANUFACTURING: For females of child bearing age: * Not lactating with intent to breastfeed * Not pregnant with negative serum pregnancy test within 7 days prior to enrollment
TREATMENT: Age: ≤ 21 years of age
TREATMENT: Estimated life expectancy of > 8 weeks
TREATMENT: Detectable disease
TREATMENT: 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 active GVHD * Have not received a donor lymphocyte infusion (DLI) within the 28 days prior to planned infusion
TREATMENT: Adequate cardiac function (with or without use of oral medications) defined as left ventricular ejection fraction > 40%, or shortening fraction ≥ 25%
TREATMENT: Electrocardiogram (EKG) without evidence of clinically significant arrhythmia
TREATMENT: Adequate renal function defined as creatinine clearance or radioisotope glomerular filtration rate (GFR^³) 50 ml/min/1.73m^2 (GFR^³ 40 ml/min/1.73m^2 if < 2 years of age)
TREATMENT: Adequate pulmonary function defined as forced vital capacity (FVC) ≥ 50% of predicted value; or pulse oximetry ≥ 92% on room air if patient is unable to perform pulmonary function testing
TREATMENT: Karnofsky or Lansky (age-dependent) performance score ≥ 50
TREATMENT: Total bilirubin ≤ 3 times the upper limit of normal for age, except in subjects with Gilbert’s syndrome
TREATMENT: Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 5 times the upper limit of normal for age
TREATMENT: Has recovered from all National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTAE) grade III-IV, non-hematologic acute toxicities from prior therapy
TREATMENT: For patients of child bearing age: * Not lactating with intent to breastfeed * Not pregnant with negative serum pregnancy test within 7 days prior to enrollment * If sexually active, agreement to use birth control until 6 months after T cell infusion

Exclusion Criteria

AUTOLOGOUS APHERESIS AND MANUFACTURING: Known primary immunodeficiency
AUTOLOGOUS APHERESIS AND MANUFACTURING: History of HIV infection
AUTOLOGOUS APHERESIS AND MANUFACTURING: Severe intercurrent bacterial, viral or fungal infection
AUTOLOGOUS APHERESIS AND MANUFACTURING: History of hypersensitivity reactions to murine protein-containing products
AUTOLOGOUS APHERESIS AND MANUFACTURING: Known contraindication to receiving protocol defined lymphodepleting chemotherapy regimen
TREATMENT: Active central nervous system (CNS)-3 disease
TREATMENT: Known primary immunodeficiency
TREATMENT: History of HIV infection
TREATMENT: Evidence of active, uncontrolled neurologic disease
TREATMENT: Severe, uncontrolled bacterial, viral or fungal infection
TREATMENT: History of hypersensitivity reactions to murine protein-containing products
TREATMENT: Known contraindication to receiving protocol defined lymphodepleting chemotherapy regimen

PRIMARY OBJECTIVE:

I. To determine the proportion of patients achieving target exposure of fludarabine after treatment with lymphodepleting chemotherapy and autologous anti-CD19 chimeric antigen receptor T-cells SJCAR19 (CD19-CAR T) cell therapy.

SECONDARY OBJECTIVES:

I. To evaluate the toxicity profile after treatment with CD19-CAR T cell therapy.

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

EXPLORATORY OBJECTIVES:

I. To study the expansion, persistence and phenotype of CD19-CAR T cells.

II. To analyze the functional state of transduced and untransduced cells pre- and post-treatment with CAR T cells.

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

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

V. To study the relationships between pharmacokinetics of lymphodepleting chemotherapy (fludarabine and cyclophosphamide) and immune cells, clinical efficacy and toxicity after treatment with CAR T cell therapy.

VI. To explore the association between cyclophosphamide pharmacokinetic parameters and drug-metabolizing enzymes (e.g., CYP2B6*6 status) and drug transporters.

VII. To assess the metabotype of patients treated with CAR T cell therapy, and study relationships between metabotype and chemotherapy pharmacokinetics, immune cells, clinical efficacy and toxicity after treatment with CAR T cell therapy.

VIII. To study electroencephalography (EEG) patterns in patients treated with CAR T cell therapy, and correlate findings with the presence and severity of neurologic signs and symptoms, including immune effector cell associated neurotoxicity syndrome (ICANS), and other treatment-related adverse events.

OUTLINE:

Patients undergo leukapheresis to obtain peripheral blood mononuclear cells (PBMCs) for T cell product manufacturing. Patients then receive fludarabine intravenously (IV) on days -5, -4, -3, and -2, cyclophosphamide IV on days -5 and -4, and CD19-CAR T cells IV on day 0 or +1 in the absence of disease progression or unacceptable toxicity. Patients that remain on-therapy and meet specified criteria may receive additional treatment courses on study. Additionally, patients undergo bone marrow aspiration as well as blood and cerebrospinal fluid (CSF) sample collection throughout the study.

After completion of study treatment, patients are followed up on study for 1 year and then long-term per institutional protocol for 15 years post infusion.

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Lymphodepleting Chemotherapy and Chimeric Antigen Receptor T Cell Therapy for the Treatment of Recurrent or Refractory CD19-positive Leukemia in Pediatric, Adolescent, and Young Adult Patients

Inclusion Criteria

Exclusion Criteria

United States

Tennessee

Memphis

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Lymphodepleting Chemotherapy and Chimeric Antigen Receptor T Cell Therapy for the Treatment of Recurrent or Refractory CD19-positive Leukemia in Pediatric, Adolescent, and Young Adult Patients

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