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Autologous T-Lymphocytes Genetically Targeted to the B-Cell Specific Antigen CD19 in Pediatric and Young Adult Patients With Relapsed B-Cell Acute Lymphoblastic Leukemia

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Memorial Sloan-Kettering Cancer Center
Sponsor:
Collaborator:
Dana-Farber Cancer Institute:Dana- Farber/Children's Hospital
Information provided by (Responsible Party):
Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier:
NCT01860937
First received: May 21, 2013
Last updated: May 12, 2014
Last verified: May 2014

May 21, 2013
May 12, 2014
May 2013
May 2016   (final data collection date for primary outcome measure)
safety [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
of gene-modified autologous T cells targeted to CD19 and infused into patients with relapsed/refractory B- ALL. Toxicities that are related to treatment will be graded on a scale of 1 to 5 as described by the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0
safety [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
of gene-modified autologous T cells targeted to CD19 and infused into patients with relapsed or refractory ALL. Toxicities that are related to treatment will be graded on a scale of 1 to 5 as described by the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0
Complete list of historical versions of study NCT01860937 on ClinicalTrials.gov Archive Site
  • assess the persistence of modified T cells [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    Gene-modified T cells will be measured as per Table II from peripheral blood, bone marrow and/or lymph nodes. The percentage of gene-modified T cells T cells will be calculated and summarized at each follow-up time point. The data will be plotted over time to describe the time trend of T cell persistence.
  • the development of B cell aplasia [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    B cell aplasia will be measured as a surrogate marker for 19-28z+ T cell efficacy. Serum levels of normal B cells from peripheral blood and bone marrow aspirates will be monitored by FACS. The mean cell concentrations will be summarized and plotted against time.
  • assess the persistence of modified T cells [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    Gene-modified T cells will be measured as per Table II from peripheral blood, bone marrow and/or lymph nodes. The percentage of gene-modified T cells T cells will be calculated and summarized at each follow-up time point. The data will be plotted over time to describe the time trend of T cell persistence.
  • the development of B cell aplasia [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    B cell aplasia will be measured as a surrogate marker for 19-28z+ T cell efficacy. Serum levels of normal B cells (CD5- CD19+) from peripheral blood and bone marrow aspirates will be monitored by FACS. The mean cell concentrations will be summarized and plotted against time.
Not Provided
Not Provided
 
Autologous T-Lymphocytes Genetically Targeted to the B-Cell Specific Antigen CD19 in Pediatric and Young Adult Patients With Relapsed B-Cell Acute Lymphoblastic Leukemia
A Phase I Trial of Autologous T-Lymphocytes Genetically Targeted to the B-Cell Specific Antigen CD19 in Pediatric and Young Adult Patients With Relapsed B-Cell Acute Lymphoblastic Leukemia

The purpose of this study is to test the safety of giving the patient special cells made from their own blood called "Modified T-cells". The goal is to find a safe dose of modified T-cells for patients whose leukemia has returned to the bone marrow.

This is a phase I multicenter clinical trial for pediatric and young adult patients with relapsed/refractory CD19+ B-ALL. The T cell doses originally proposed in this study were based on doses administered safely in prior autologous T cell adoptive therapy trials65-67, but the dose has been modified based on the toxicities observed in adult patients with morphologic evidence of relapsed B-ALL treated on MSKCC IRB 09-114. Patients will be treated with different doses of T cells depending on the amount of disease at the time of T cell infusion. Patients in Cohort 1 (<5% blasts in the bone marrow) will receive 3 x 10^6 19-28z+ T cells/kg. Patients in Cohort 2 (≥5% blasts in the bone marrow) will receive 1x10^6 19-28z+ T cells/kg.

Interventional
Phase 1
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Relapsed B-Cell Acute Lymphoblastic Leukemia
  • Procedure: leukapheresis or collection of PBMCs
  • Drug: cyclophosphamide
  • Biological: modified T cells
  • Experimental: Cohort 1 (MRD)
    Patients with no morphologic evidence of disease at the time of T cell infusion, (<5% blasts in the bone marrow) as assessed by morphology. Cohort 1 patients will receive conditioning chemotherapy followed by 3x106 19-28z+ T cells/kg. T cells will be infused in a fractionated manner: approximately 1/3 dose on the first day and then the remaining dose on the next day. During formulation of EOP T cells, under or over estimation of CAR modified T-cells may occur. Patients may receive an altered fractionation of the total doses (e.g. ½ on Day 0 and ½ on Day +1) or up to 20% over total cell dose with approval by the participating site PI. In both cohorts, patients will be allowed to receive a 2nd infusion of 19-28z+ T cells if they benefited from the first infusion and did not experience any non-hematologic grade 4 toxicities.
    Interventions:
    • Procedure: leukapheresis or collection of PBMCs
    • Drug: cyclophosphamide
    • Biological: modified T cells
  • Experimental: Cohort 2 (Morphologic Disease)
    Pts with morphologic evidence of disease at the time of T cell infusion, (≥5% blasts in the bone marrow) as assessed by morphology. Pts with increased blasts (5-10% blasts) that are immunophenotypically consistent with recovering marrow from prior re-induction chemo may be treated under Cohort 1 with approval of the participating site PI. Cohort 2 pts will get conditioning chemo followed by 1x106 19-28z+ T cells/kg. T cells will be infused in a fractionated manner: approximately 1/3 dose on the first day & then the remaining dose on the next day. During formulation of EOP T cells, under or over estimation of CAR modified T-cells may occur. Pts may get an altered fractionation of the total doses (e.g. ½ on Day 0 & ½ on Day +1) or up to 20% over total cell dose with approval by the participating site PI. Both cohorts, pts will be allowed to receive a 2nd infusion of 19-28z+ T cells if they benefited from the first infusion & did not experience any non-hematologic grade 4 toxicities.
    Interventions:
    • Procedure: leukapheresis or collection of PBMCs
    • Drug: cyclophosphamide
    • Biological: modified T cells
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
24
May 2016
May 2016   (final data collection date for primary outcome measure)

Inclusion Criteria for Collection Arm of the protocol:

Age < 26 years, whose disease meets one of the following 3 criteria:

  • VHR*
  • Patients in 1st or subsequent marrow relapse (isolated or combined), at the time of relapse, during retrieval therapy, or after achievement of CR.
  • Refractory disease *Definitions of VHR B-ALL include the following:

    • NCI HR-ALL and age ≥ 13 years at diagnosis
    • CNS-3 leukemia at diagnosis
    • Day 29/End of Induction BM MRD > 0.01%
    • Induction failure (M3 BM at Day 29/End of Induction)
    • Hypodiploidy (n< 44 chromosomes and/or a DNA index < 0.81)
    • t(9;22) ALL (Philadelphia Chromosome/Ph+ ALL)
    • t(17;19) ALL
    • MLL gene rearrangement
    • Intrachromosomal amplification of chromosome 21 (iAMP21) Please note patients that only meet the criteria for collection/storage of PBMCs will need to be reconsented prior to infusion of genetically modified T-cells.

Inclusion Criteria for Treatment Arm of this protocol:

  • Patients must have a history of relapsed/refractory CD19+ B-ALL involving the marrow to be eligible for infusion of modified T cells.
  • Please note ≥5% blasts by morphology and/or flow cytometry constitutes a bone marrow relapse on this protocol. Patients must also fulfill one of the following criteria to be eligible for infusion of modified T cells:

    • Second or greater (≥2) relapse
    • Early first marrow relapse (1st CR <18 months)
    • Intermediate/Late first marrow relapse (1st CR >18 months from 1st CR) with poor initial response (≥5% blasts by morphology and/or flow cytometry) following reinduction chemotherapy
    • Refractory Disease
    • Ineligible for HSCT as determined by the treating physician in consultation with the BMT service
    • Patient would not benefit from additional chemotherapy as determined by the treating physician
  • Patients must not receive alternative therapy (e.g. chemotherapy) for up to 8-12 weeks following infusion of modified T cells unless progression of disease is demonstrated
  • KPS or Lansky score ≥ 60
  • Pulmonary function (measured prior to conditioning chemotherapy):

    o > 90% oxygen saturation on room air by pulse oximetry.

  • Renal Function (measured prior to conditioning chemotherapy):

    o Serum creatinine ≤2.0mg/dL for patients over 18 years or ≤2.5 x institutional ULN for age

  • Hepatic Function (measured prior to conditioning chemotherapy):

    • AST ≤ 5 x the institutional ULN. Elevation secondary to leukemic involvement is not an exclusion criterion. Leukemic involvement will be determined by the presence of progressive relapse defined by escalating bone marrow or peripheral blood leukemia blasts within the previous month and the absence of initiation of know hepatotoxic medication (e.g. azoles).
    • Total bilirubin ≤ 2.5 x the institutional ULN

Exclusion Criteria:

  • Karnofsky/Lansky performance status <60.

    • Patients with active of HIV, hepatitis B or hepatitis C infection
    • Patients with any concurrent active malignancies as defined by malignancies requiring any therapy other than expectant observation
    • Patients will be excluded if they have isolated extra-medullary relapse of ALL
    • Females who are pregnant.
    • Patients with active (grade 2-4) acute graft versus host disease (GVHD), chronic GVHD or an overt autoimmune disease (e.g. hemolytic anemia) requiring glucocorticosteroid treatment (>0.5 mg/kg/day prednisone or its equivalent) as treatment.
    • Active central nervous system (CNS) leukemia, as defined by unequivocal morphologic evidence of lymphoblasts in the cerebrospinal fluid (CSF) or symptomatic CNS leukemia (i.e. cranial nerve palsies or other significant neurologic dysfunction) within 28 days of treatment. Prophylactic intrathecal medication is not a reason for exclusion.
Both
up to 26 Years
No
Contact: Kevin Curran, MD 212-639-5836
Contact: Nancy Kernan, MD 212-639-7250
United States
 
NCT01860937
13-052
Not Provided
Memorial Sloan-Kettering Cancer Center
Memorial Sloan-Kettering Cancer Center
Dana-Farber Cancer Institute:Dana- Farber/Children's Hospital
Principal Investigator: Kevin Curran, MD Memorial Sloan-Kettering Cancer Center
Memorial Sloan-Kettering Cancer Center
May 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP