CAR T-cell Therapy (CD70-CAR) for the Treatment of Hematological Malignancies in Pediatric Patients

Status: active

This phase I trial tests the safety, side effects, and best dose of CD70- chimeric antigen receptor (CAR) T-cells works in treating pediatric patients with acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), B-cell acute lymphoblastic leukemia (B-ALL), T-cell acute lymphoblastic leukemia (T-ALL) or lymphoma that has come back after a period of improvement (relapsed) or that does not respond to treatment (refractory). CAR T-cell therapy is a type of treatment in which T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T-cells are removed from the patient and modified in the laboratory to insert a CAR into the T-cells which allows these cells to find and destroy the cancer by recognizing a particular particle (antigen) that is present on the surface of the cancer cells; this particle is called CD70. Chemotherapy drugs, such as fludarabine 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. Lymphodepleting chemotherapy is not intended to treat cancer. It is meant to help prepare the body to receive CD70-CAR T-cells. Giving CD70-CAR T-cells may be safe, tolerable, and/or effective in treating patients with relapsed/refractory AML, MDS, B-ALL, T-ALL, or lymphoma.

Inclusion Criteria

PROCUREMENT AND T-CELL PRODUCTION: A previously frozen, autologous leukapheresis product can be used for T-cell production
PROCUREMENT AND T-CELL PRODUCTION: Age ≤ 21 years old. The first three patients to be enrolled on study will be 17 years of age or older
PROCUREMENT AND T-CELL PRODUCTION: Relapsed/refractory CD70+ hematological malignancy. All patients must have had either prior exposure (or intolerance) to the relevant agent class for patients with malignancies that are characterized by a mutation targeted by an approved therapy (e.g., FLT3-ITD, IDH1, IDH2 etc.) * Relapsed/refractory CD70+ AML or myelodysplastic syndrome (MDS): ** Relapsed disease: Patients developing recurrent disease after a prior complete remission (CR) ** Refractory disease: Patients with persistent disease despite 3 cycles of induction chemotherapy * Relapsed/refractory CD70+ B-cell ALL: ** Relapsed disease that is CD70 positive and CD19 negative/dim or patients otherwise ineligible for CD19 directed therapies including: *** Patients in 2nd or greater relapse *** Patients with relapse after allogeneic hematopoietic stem cell transplantation (HSCT) * Relapsed/refractory CD70+ T-cell ALL: ** Relapsed /refractory disease that is CD70 positive * Mixed Phenotype Acute Leukemia (MPAL): ** Relapsed/refractory that is CD70 positive * Relapsed/refractory CD70+ lymphoma: ** Relapsed disease that is CD70 positive and CD19 negative/dim or patients otherwise ineligible for CD19 directed therapies including: *** Patients in 2nd or greater relapse *** Patients with relapse after allogeneic HSCT
PROCUREMENT AND T-CELL PRODUCTION: Estimated life expectancy of > 12 weeks
PROCUREMENT AND T-CELL PRODUCTION: Karnofsky or Lansky (age- dependent) performance score ≥ 50
PROCUREMENT AND T-CELL PRODUCTION: 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
PROCUREMENT AND T-CELL PRODUCTION: Patient must have an identified HCT donor
PROCUREMENT AND T-CELL PRODUCTION: 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: Age ≤ 21 years old at the time of manufacturing
TREATMENT: Detectable CD70+ disease
TREATMENT: Estimated life expectancy of > 8 weeks
TREATMENT: Karnofsky or Lansky (age-dependent) performance score ≥ 50
TREATMENT: Patients with a history of prior allogeneic HCT must be clinically recovered from prior HCT therapy, have no evidence of active GVHD and have not received a donor lymphocyte infusion (DLI) within the 28 days prior to planned infusion
TREATMENT: Patient must have an identified HCT donor
TREATMENT: Adequate cardiac function 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) 50 ml/min/1.73m^2 (GFR 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: 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 for Adverse Events (CTAE) grade III-IV, non-hematologic acute toxicities from prior therapy
TREATMENT: For females of child bearing age: * Not lactating with intent to breastfeed * Not pregnant with negative serum or urine pregnancy test within 7 days prior to enrollment
TREATMENT: If sexually active, agreement to use birth control as follows: * Females and males of reproductive potential must use effective contraception during treatment with cyclophosphamide and for up to 1 year after completion of therapy * Male patients with female partners of reproductive potential must use effective contraception during treatment with cyclophosphamide and for 4 months after completion of therapy
TREATMENT: Available autologous transduced T cells that has met Good Manufacturing Practice (GMP) release criteria

Exclusion Criteria

PROCUREMENT AND T-CELL PRODUCTION: Known primary immunodeficiency
PROCUREMENT AND T-CELL PRODUCTION: Known history of HIV positivity
PROCUREMENT AND T-CELL PRODUCTION: Severe intercurrent bacterial, viral, or fungal infection
PROCUREMENT AND T-CELL PRODUCTION: History of hypersensitivity to cornstarch or hydroxyethyl starch
PROCUREMENT AND T-CELL PRODUCTION: Patients with acute promyelocytic leukemia (APL)
PROCUREMENT AND T-CELL PRODUCTION: Known contraindication to protocol defined lymphodepleting chemotherapy regimen of fludarabine/cyclophosphamide
TREATMENT: Known primary immunodeficiency
TREATMENT: History of HIV infection
TREATMENT: Clinically significant active infection including fungal infection with ongoing antifungal therapy, viral infection, or uncontrolled viral reactivation of Epstein-Barr Virus (EBV), cytomegalovirus (CMV), adenovirus (Adv), polyomavirus (BKBK-virus), or human herpesvirus-6 (HHV-6)
TREATMENT: Receiving systemic steroids therapy exceeding the equivalent of 0.5 mg/kg/day of methylprednisolone, in the 7 days prior to CD70-CAR T-cell infusion
TREATMENT: Receiving systemic immunosuppressive therapy in the 14 days prior to CD70-CAR T-cell infusion that in the opinion of principal investigator (PI) will interfere with the infused product
TREATMENT: Known contraindication to the protocol defined lymphodepleting chemotherapy regimen of fludarabine/cyclophosphamide

PRIMARY OBJECTIVE:

I. To determine the safety and maximum tolerated dose of intravenous infusions of escalating doses of CD70-CAR T cells in patients (≤ 21 years) with recurrent/refractory CD70+ hematological malignancies after lymphodepleting chemotherapy.

SECONDARY OBJECTIVES:

I. To evaluate the anti-tumor activity of CD70-CAR T cells. For patients with CD70+ hematological malignancies, we will determine the anti-leukemic activity of CD70-CAR T cells in the bone marrow and in the treatment of extramedullary disease. For patients with lymphoma, we will determine the anti-lymphoma activity of CD70-CAR T cells by positron emission tomography (PET)-imaging.

EXPLORATORY OBJECTIVES:

I. To assess the immunophenotype of CD70-CAR T cells and unmodified T cells.

II. To characterize the cytokine profile in the peripheral blood and cerebral spinal fluid (CSF) after treatment with CD70-CAR T cells.

III. For patients with AML or ALL: to characterize leukemic blasts and the tumor micro-environment post CD70-CAR T cells.

OUTLINE: This is a dose-escalation study of CD70-CAR T-cells.

Patients may undergo apheresis prior to treatment and receive lymphodepletion chemotherapy with fludarabine intravenously (IV) on days -4, -3, -2 and cyclophosphamide IV on days -3, and -2. Patients then receive CD70-CAR T-cell IV on day 0 or +1. Patients undergo echocardiography (ECHO) at baseline. Patients also undergo blood sample collection, bone marrow aspirate and biopsy, as well as lumbar puncture (LP) for CSF collection or tissue biopsy throughout the study. Additionally, patients may undergo PET/computed tomography (CT) throughout the study.

Upon completion of study treatment patients are followed up weekly for 4 weeks, at weeks 6 and 8, at months 3, 6, 9, and 12, and then yearly for up to 15 years.

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CAR T-cell Therapy (CD70-CAR) for the Treatment of Hematological Malignancies in Pediatric Patients

Inclusion Criteria

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CAR T-cell Therapy (CD70-CAR) for the Treatment of Hematological Malignancies in Pediatric Patients

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