In Vitro Expanded Allogeneic Epstein-Barr Virus Specific Cytotoxic T-Lymphocytes (EBV-CTLs) Genetically Targeted to the B-Cell Specific Antigen CD19 Positive Residual Or Relapsed Acute Lymphoblastic Leukemia After Allogeneic Hematopoietic Progenitor Cell Transplantation

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by Memorial Sloan-Kettering Cancer Center
Sponsor:
Information provided by (Responsible Party):
Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier:
NCT01430390
First received: September 6, 2011
Last updated: April 30, 2014
Last verified: April 2014
  Purpose

This Phase I dose escalation trial is designed to evaluate the safety and the biologic efficacy of allogeneic EBV specific cytotoxic T -lymphocytes (CTL) genetically modified to express artificial T-cell receptors (CAR) targeting the CD19 molecule (CD19CAR) in patients who have relapsed after allogeneic HSCT. Each patient will receive at least one dose of donor derived, genetically modified CTL and will be monitored for toxicity and detection of transduced CTL as well as disease specific markers.


Condition Intervention Phase
Acute Lymphocytic Leukemia
Biological: Biological/Genetically Modified T cells
Phase 1

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: A Phase I Dose Escalation Trial Using In Vitro Expanded Allogeneic Epstein-Barr Virus Specific Cytotoxic T-Lymphocytes (EBV-CTLs) Genetically Targeted to the B-Cell Specific Antigen CD19 Positive Residual Or Relapsed Acute Lymphoblastic Leukemia After Allogeneic Hematopoietic Progenitor Cell Transplantation

Resource links provided by NLM:


Further study details as provided by Memorial Sloan-Kettering Cancer Center:

Primary Outcome Measures:
  • Evaluate the safety/persistence of escalating doses of allogeneic EBV specific CTL modified to express artificial T cell receptors targeting CD19 molecule given for persistence or relapse of B-Cell ALL post allogeneic HSCT. [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • To assess the effects of the adoptively transferred CD19 specific T-cells on the progression of leukemia. [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • To quantitate the number of chimeric antigen receptor (CAR) positive T-cells in the blood at defined intervals post infusion in order to determine their survival and proliferation in the host. [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • To assess long-term status of treated patients [ Time Frame: 15 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 26
Study Start Date: September 2011
Estimated Study Completion Date: September 2015
Estimated Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Biological/Genetically Modified T cells
During the dose escalation phase three patients will be entered at each dose level (depending on toxicity). If there are no toxicities and immunological efficacy is not seen at any dose, the doses will be further escalated. Upon completion of dose escalation we will treat a maximum of 14 patients at the highest dose.
Biological: Biological/Genetically Modified T cells
Following completion of the chemotherapy, genetically modified T cells will be given intravenously at one of 3 dose levels. After the infusion patients will be monitored clinically and with serial blood and marrow evaluations to assess toxicity, therapeutic effects, and the in-vivo survival of the genetically modified T-cells.

  Eligibility

Ages Eligible for Study:   up to 19 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients treated on this protocol will have been diagnosed with CD19+ leukemia at less than 19 years of age.
  • History of CD19+ leukemia with evidence of bone marrow relapse or persistent MRD following allogenic hematopoietic stem cell transplantation.
  • Persistent minimal residual disease after transplantation must be demonstrated by morphology, karyotype, FSH, flow cytometry or RT-PCR with at least 2 sequential testings separated by at least 1 week.
  • We expect that there will be cases in which a patient will experience a leukemia relapse and will require chemotherapy during the establishment, expansion and modification of EBV-CTLs. The timeline for establishing the EBV-BLCL (3-5 weeks), establishing EBV specific T-cell line (6-8 weeks) and expanding the genetically modified EBV specific T-cell line (1-4 weeks) is considerable. During this time patients may receive chemotherapy at the discretion of their treating physician. If the patient receives chemotherapy they must have recovered from any chemotherapy induced toxicity and meet all eligibility criteria for organ function for this protocol at the time the conditioning therapy is initiated. If the patient has been rendered hypoplastic by the chemotherapy, the patient may proceed to T-cell therapy with conditioning therapy prior to the resurgence of a blastic marrow.
  • The patient's hematopoietic stem cell transplant donor must consent to a leukapheresis or whole blood donations obtained at one or more phlebotomies which, in aggregate, will total approximately 250 ml for adults and no more than 5ml/kg per draw from pediatric donors. Related donors under the age of 18 will donate peripheral blood collected by phlebotomy (including a unit of blood if weight permits) and shall not undergo leukopheresis which is considered above minimal risk to the donor.
  • Unrelated volunteer donors should be between the age if 18 and 60 years as these are the age restrictions for volunteer unrelated donor registries. There is no upper age limit for a related donor. However, the minimum age for a related donor is 7 years as this is the youngest age a person can be considered capable of giving assent to participate in a research study.
  • Organ Function as determined on the day of initiation of lymphodepleting cytoreduction.

    1. KPS or Lansky score > 30
    2. Renal function at the time of treatment: Creatinine ≤2.0mg/dL
    3. Hepatic function at time of treatment: AST ≤ 3.0 x the institutional ULN, total bilirubin ≤ 2.5 x the institutional ULN
    4. Pulmonary function: Oxygen saturation ≥ 90% on room air
  • Patients treated on this protocol will have been diagnosed with CD19+ leukemia at less than 19 years of age.
  • Patients with CNS relapse are eligible. However, if patient receives intrathecal chemotherapy, at least 24 hours must elapse prior to the T-cell infusion.

Exclusion Criteria:

  • 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.
  • Patients with other life-threatening conditions not related to leukemia (e.g. veno-occlusive disease or uncontrolled bacterial, viral or invasive fungal infection) which would confound evaluation of the effects of an infusion of genetically modified T-cells.
  • Females who are pregnant.
  • Patient or guardian is unable to give informed consent or unable to comply with the treatment protocol including appropriate supportive care, follow-up, and research tests.
  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: NCT01430390

Contacts
Contact: Nancy Kernan, MD 212-639-7250
Contact: Renier Brentjens, MD, PhD 212-639-7053

Locations
United States, New York
Memorial Sloan-Kettering Cancer Center 1275 York Avenue Recruiting
New York, New York, United States, 10021
Contact: Nancy Kernan, MD    212-639-7250      
Contact: Renier Brentjens, MD, PhD    212-639-7053      
Principal Investigator: Nancy Kernan, MD         
Sponsors and Collaborators
Memorial Sloan-Kettering Cancer Center
Investigators
Principal Investigator: Nancy Kernan, MD Memorial Sloan-Kettering Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT01430390     History of Changes
Other Study ID Numbers: 11-038
Study First Received: September 6, 2011
Last Updated: April 30, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Memorial Sloan-Kettering Cancer Center:
In Vitro Expanded Allogeneic Epstein-Barr Virus Specific Cytotoxic
T-Lymphocytes (EBV-CTLs)
CD19 specific T-cells
11-038

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases

ClinicalTrials.gov processed this record on July 23, 2014