A Pediatric and Young Adult Trial of Genetically Modified T Cells Directed Against CD19 for Relapsed/Refractory CD19+ Leukemia

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Seattle Children's Hospital
Sponsor:
Information provided by (Responsible Party):
Rebecca Gardner, Seattle Children's Hospital
ClinicalTrials.gov Identifier:
NCT02028455
First received: January 3, 2014
Last updated: May 13, 2014
Last verified: May 2014
  Purpose

Patients with relapsed or refractory leukemia often develop resistance to chemotherapy. For this reason, we are attempting to use T cells obtained directly from the patient, which can be genetically modified to express a chimeric antigen receptor (CAR). The CAR enables the T cell to recognize and kill the leukemic cell through the recognition of CD19, a protein expressed of the surface of the leukemic cell in patients with CD19+ leukemia. This is a phase 1/2 study designed to determine the maximum tolerated dose of the CAR+ T cells as well as to determine the efficacy. The phase 1 cohort is restricted to those patients who have already had an allogeneic hematopoietic cell transplant (HCT). The phase 2 is open to all patients regardless of having a history of HCT.


Condition Intervention Phase
CD19+ Leukemia
Biological: Patient Derived CD19 specific CAR T cells also expressing an EGFRt
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Pediatric and Young Adult Leukemia Adoptive Therapy (PLAT)-02: A Phase 1/2 Feasibility and Safety Study of CD19-CAR T Cell Immunotherapy for CD19+ Leukemia

Resource links provided by NLM:


Further study details as provided by Seattle Children's Hospital:

Primary Outcome Measures:
  • Number of Participants With Adverse Events [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]
    The safety of the T cell infusion will be described and the maximum tolerated dose determined

  • Number of participants with an MRD negative complete remission after T cells infusion [ Time Frame: 63 days ] [ Designated as safety issue: No ]
    The efficacy fo the T cell infusion will be estimated based on the number of participants who have an MRD negative bone marrow aspirate following the T cell infusion

  • Number of Participants who have a Releasable Cell Product Generated [ Time Frame: 28 days ] [ Designated as safety issue: No ]
    The feasibility of manufacturing and releasing T cell products from pediatric and young adult patients who relapse with CD19+ leukemia both before and after allo-HCT will be measured.


Secondary Outcome Measures:
  • Persistence of the CD19 CAR+ T cells [ Time Frame: 63 days ] [ Designated as safety issue: No ]
    Participants will be followed for 63 days to determine if the transferred T cells remain detectable in the blood, bone marrow and CSF

  • Number of participants with recrudescence or development of acute GVHD [ Time Frame: 63 days ] [ Designated as safety issue: Yes ]
  • Number of participants who have T cells ablated with cetuximab [ Time Frame: 3 years ] [ Designated as safety issue: No ]
    The efficacy of cetuximab to ablate the T cells will be measured by loss of detection of T cells and any associated toxicities as well as facilitating B cell recovery.


Estimated Enrollment: 80
Study Start Date: January 2014
Estimated Primary Completion Date: January 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort 1
This cohort will determine the maximum tolerated dose of the Patient Derived CD19 specific CAR T cells also expressing an EGFRt and is restricted to patients with a prior history of allo-HCT
Biological: Patient Derived CD19 specific CAR T cells also expressing an EGFRt
Defined Composition CD4 and CD8 T cells Lentivirally Transduced to Express a Second Generation 4-1BB:zeta CD19 CAR and EGFRt
Experimental: Cohort 2A
This cohort is for patient who have a history of allo-HCT with recurrence of disease post HCT and they will receive the MTD of Patient Derived CD19 specific CAR T cells also expressing an EGFRt determined in cohort 1.
Biological: Patient Derived CD19 specific CAR T cells also expressing an EGFRt
Defined Composition CD4 and CD8 T cells Lentivirally Transduced to Express a Second Generation 4-1BB:zeta CD19 CAR and EGFRt
Experimental: Cohort 2B
This cohort is restricted to patients wtih no prior history of allo-HCT and they will receive the MTD of Patient Derived CD19 specific CAR T cells also expressing an EGFRt determined in cohort 1
Biological: Patient Derived CD19 specific CAR T cells also expressing an EGFRt
Defined Composition CD4 and CD8 T cells Lentivirally Transduced to Express a Second Generation 4-1BB:zeta CD19 CAR and EGFRt

Detailed Description:

Upon meeting the eligibility requirements and enrolling on study, subjects will undergo apheresis to obtain the T cells for the generation of the CD19 CAR+ T cells. In patients with a prior history of allogeneic HCT, the T cells obtained are of donor origin. The T cells are isolated from the apheresis product, the CD4 and CD8 T cells are then selected and grown separately, transduced with a lentivirus to express the CD19 CAR as well as a truncated EGFR that has no signaling capacity (noted EGFRt) and expanded in culture over a three week period. During the process of cell generation, subjects will continue to be cared for by their primary oncologist and may undergo additional treatment directed at the leukemia during this time.

After the CAR+ T cells have been generated, the subject undergoes a disease assessment and determination if lymphodepletion is necessary. A variety of lymphodepletion strategies are acceptable and determined on a case by case basis. At least 48 hours after the completion of lymphodepletion, the subject will receive and infusion of CAR+ T cells at an approximate 1:1 ratio of CD4 to CD8 CAR+ T cells.

Following treatment with the CAR+ T cells, subjects will be followed intensely for 2 months with serial blood testing and re-evaluation of disease status with bone marrow aspirates. After 2 months, the subjects clinical care will be resumed by their primary oncologist, and it is possible that they would receive additional chemotherapy or HCT.

Some subjects will receive cetuximab for ablation of the genetically modified T cells. Criteria to receive cetuximab include acute toxicities that are life threatening, as well as an ongoing remission with continued B cell aplasia.

Upon completion of the study, subjects will be followed bi-annually for 5 years, and then annually for 10 additional years with either a medical history, physical exam and blood tests or a phone call/questionnaire. This follow up will help to determine if the subject develops any long-term health problems related to the CAR+ T cells including a new cancer.

  Eligibility

Ages Eligible for Study:   1 Year to 26 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Must be >/= 10kg
  • Clinical diagnosis CD19+ leukemia that meets one of the following:

    1. CD19+ leukemia recurrence after allo-HCT defined as >/= 0.01% disease
    2. 2nd or greater marrow relapse
    3. 1st marrow relapse at end of 1st month of re-induction with marrow having >/= 0.01% blasts by morphology and /or multiparameter flow
    4. primary refractory as defined as having M2 or M3 marrow after 2 or more separate induction regimens
    5. subject has indication for HCT but has been deemed ineligible
  • Karnofsky or lansky of >/= 50
  • Life Expectancy of > 8 weeks
  • Recovered from acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy

    1. must be at least 7 days since last chemotherapy was administered (this does not include intrathecal chemotherapy or maintenance chemotherapy)
    2. at least 3 half lives of any immunotherapy have passed
  • for post allo-HCT subjects, CD3 chimerism >95% donor within 1 month of enrollment
  • normal serum creatinine based on age/gender
  • total bilirubin </= 3x ULN OR direct bilirubin </= 2mg/dl
  • ALT </= 5X ULN
  • SF of >28% by ECHO or EF >50% by MUGA
  • ALC of >/= 100 cells/ul
  • pulse ox >/= 90% on room air
  • agrees to highly effective contraception during and for 12 months after T cell infusion
  • agrees to 15 years of follow up if they receive T cell infusion
  • can tolerate apheresis

Exclusion Criteria:

  • Has received immunosuppressant GVHD mediation in past 4 weeks
  • Has active GVHD
  • Systemic corticosteroids within 7 days of enrollment
  • For Phase 1, has symptomatic CNS involvement of leukemia
  • has detectable genetically modified cell therapy previously given
  • has received virotherapy
  • Hep C PCR positive
  • HepB surface antigen positive
  • HIV positive
  • requires supplemental oxygen
  • CXR show infectious process
  • active clinically significant CNS dysfunction
  • pregnant or breastfeeding
  • has active malignancy other than CD19+ leukemia
  • has active severe infection defined as positive blood culture wtih 48 hours of enrollment or fever above 38.2C and clinical signs of infection within 48 hours of study enrollment
  • has concurrent medical condition that would prevent patient from undergoing protocol based therapy
  • has primary immunodeficiency or bone marrow failure syndrome
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02028455

Contacts
Contact: Rebecca Gardner, MD 206-987-2106
Contact: Dione Froman 206-884-1214

Locations
United States, Washington
Seattle Children's Hospital Recruiting
Seattle, Washington, United States, 98105
Contact: Rebecca Gardner, MD    206-987-2106      
Principal Investigator: Rebecca Gardner, MD         
Sponsors and Collaborators
Seattle Children's Hospital
  More Information

No publications provided

Responsible Party: Rebecca Gardner, Investigator, Seattle Children's Hospital
ClinicalTrials.gov Identifier: NCT02028455     History of Changes
Other Study ID Numbers: PLAT-02
Study First Received: January 3, 2014
Last Updated: May 13, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Seattle Children's Hospital:
pediatric
young adult
acute lymphoblastic leukemia
CD19
leukemia
Chimeric Antigen Receptor
T cell

Additional relevant MeSH terms:
Leukemia
Neoplasms
Neoplasms by Histologic Type

ClinicalTrials.gov processed this record on October 21, 2014