Phase I Study of B Cell Malignancies Using T Cells Expressing an Anti-CD19 Chimeric Receptor: Assessment of the Impact of Lymphocyte Depletion Prior to T Cell Transfer

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT00924326
First received: June 17, 2009
Last updated: July 22, 2014
Last verified: June 2014
  Purpose

Background:

  • CD19 is an antigen (protein) found on the surface of B cells, a type of white blood cell that helps the immune system by making antibodies. Cancerous B cells also express CD19.
  • An experimental cancer treatment under development at the National Institutes of Health involves taking a sample of a patient s blood, using that sample to produce anti-CD19 cells, and then using the created cells to treat the cancer. This kind of treatment is known as gene therapy, and is very closely monitored by various government agencies.

Objectives:

  • To determine the safety and usefulness of anti-CD19 cells created through gene therapy, including the maximum tolerated dose (the highest dose that does not cause unacceptable side effects).
  • To see if anti-CD19 cells given in conjunction with chemotherapy drugs, fludarabine, and cyclophosphamide has any effect on the treatment of the cancer.

Eligibility:

  • Patients greater than or equal to 18 and less than or equal to 68 years of age who have been diagnosed with cancer that involves B cells, in which more than 50 percent of the cancerous cells are CD19-expressing B cells.
  • Women who are pregnant or breastfeeding are not eligible.

Design:

  • Pretreatment period (3 weeks before the start of the treatment):
  • Physical examination and full medical history to determine eligibility.
  • Heart and lung function tests and blood and bone marrow samples, including leukapheresis (blood sampling procedure that removes white blood cells for use in the lab).
  • Insertion of an IV catheter for the treatment.
  • For patients in the chemotherapy group, treatment with fludarabine and cyclophosphamide for 1 week before start of anti-CD19 study.
  • Days 0 4: Infusion with anti-CD19 cells, followed by treatment with chemotherapy (15-minute infusion every 8 hours over 5 days) on an inpatient basis.
  • Evaluations during the treatment and inpatient recovery period:
  • Physical examination, including vital signs and body weight checks.
  • Blood and urine tests.
  • Possibly biopsy sample of lymph node to evaluate the effects of the treatment on the immune system.
  • Blood and biopsy samples may be kept for further research with patient s consent.

Condition Intervention Phase
Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma
Mantle Cell Lymphoma
Follicular Lymphoma
Large Cell Lymphoma
Drug: Fludarabine
Drug: Cyclophosphamide
Biological: Anti-CD19-CAR PBL
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: Assessment of the Safety and Feasibility of Administering T Cells Expressing an Anti-CD19 Chimeric Antigen Receptor to Patients With B-cell Lymphoma or Leukemia

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Determine the safety and feasibility of the administration of anti-CD19-CAR engineered peripheral blood lymphocytes with a nonmyeloablative conditioning regimen in patients with B-cell malignancies. [ Time Frame: approximately 4 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Determine the in vivo survival of the anti-CD19-CAR-transduced T cells. Determine if the treatment regimen cause regression of B-cell malignancies.

Estimated Enrollment: 40
Study Start Date: February 2009
Estimated Study Completion Date: January 2017
Estimated Primary Completion Date: January 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Single Arm
Patients will receive fludarabine and cyclophosphamide chemotherapy (NMA) for lymphocyte-depletion followed by anti-CD19- CAR-transduced T cells
Drug: Fludarabine
On days -5 through -3, Fludarabine 30mg/m2 IV will be infused over 30 minutes.
Drug: Cyclophosphamide
On days -5 through -3, Cyclophosphamide 300mg/m2 IV will be infused over 60 minutes followed by fludarabine.
Biological: Anti-CD19-CAR PBL
On day 0, cells will infused intravenously (IV) on the patient care unit over 20 - 30 minutes (2-4 days after the last dose of fludarabine).

Detailed Description:

BACKGROUND:

  • We have constructed a retroviral vector that encodes an anti-CD19 chimeric antigen receptor (CAR) that recognizes the CD19 antigen. This chimeric receptor also contains the signaling domains of CD28 and CD3-zeta. The retroviral vector can be used to mediate genetic transfer of this CAR to T cells with high efficiency (> 50%) without the need to perform any selection.
  • In co-cultures with CD19-expressing target cells, anti-CD19-CAR-transduced T cells secreted significant amounts of IFN- >= and IL-2. Anti-CD19-CAR-transduced T cells could specifically recognize and kill primary chronic lymphocytic leukemia cells.
  • We have developed a process for cryopreserving the cell product which may lead to the ability for this product to be manufactured at a central location and shipped to other institutions for treatment of a broader patient population

OBJECTIVES:

  • Primary objectives
  • With the approval of amendment S, determine the safety and feasibility of the administration of cryopreserved anti-CD19-CAR engineered peripheral blood lymphocytes with a nonmyeloablative conditioning regimen in patients with B-cell malignancies.
  • Secondary objectives:
  • With the approval of amendment S, determine the in vivo survival of the cryopreserved anti-CD19-CAR-transduced T cells.
  • Determine if the treatment regimen can cause regression of B-cell malignancies.

ELIGIBILITY:

Patients of 18 years of age or older must:

  • have a CD19-expressing B-cell malignancy of any type
  • be a non-responder to, or recurred after one or more standard chemotherapy-containing regimens for their malignancy
  • currently require treatment due to progressive malignancy
  • deemed to be incurable by standard therapy

Patients may not have:

  • a history of allogeneic stem cell transplantation
  • CNS disease

DESIGN:

  • PBMC obtained by leukapheresis (approximately 5 X 109 cells) will be cultured in the presence of anti-CD3 (OKT3) and aldesleukin in order to stimulate T-cell proliferation.
  • Transduction is initiated by exposure of approximately 108 to 5 X 108 cells to retroviral vector supernatant containing the anti-CD19 CAR.
  • With the approval of amendment S, patients will receive fludarabine and cyclophosphamide chemotherapy (NMA) for lymphocyte-depletion, followed by cryopreserved anti-CD19-CAR-transduced T cells.
  • Patients will be followed until disease progression
  • Patients who have responded to treatment and then progress may receive one retreatment
  Eligibility

Ages Eligible for Study:   18 Years to 68 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

    1. Patient must have a CD19-expressing B cell malignancy of any type. Patients with CLL, mantle cell lymphoma, and follicular lymphoma must have measurable disease after at least one standard chemotherapy regimen. All CLL patients must have

      previously received Ibrutinib. Patients with large cell lymphoma must have measurable disease after at least two prior chemotherapy regimens one of which must have contained doxorubicin and rituximab. Patients with ALL must have relapsed or refractory disease after at least one standard chemotherapy.

    2. Confirmation of diagnosis of B cell malignancy and positivity for CD19 confirmed by the Laboratory of Pathology of the NCI. The choice of weather to use flow Cytometry or immunohistochemistry will be determined by what is the most easily available tissue sample in each patient.

      Immunohistochemistry will be used for lymph node biopsies; flow cytometry will be used for peripheral blood, fine needle aspirates and bone marrow samples.

    3. Patients must have indications for treatment for their B cell malignancy at the time of enrollment on this trial.
    4. Greater than or equal to 18 years of age and less than or equal to age 68.
    5. Willing to sign a durable power of attorney.
    6. Able to understand and sign the Informed Consent Document.
    7. Clinical performance status of ECOG 0 or 1.
    8. Life expectancy of greater than three months.
    9. Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for four months after treatment.
    10. Women of child bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus.
    11. Serology:

      • 1. Seronegative for HIV antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune -competence and thus be less responsive to the experimental treatment and more susceptible to its toxicities.).
      • 2. Seronegative for hepatitis B antigen and hepatitis C antibody unless antigen negative. If hepatitis C antibody test is positive, then patients must be tested for the presence of antigen by RT-PCR and be HCV RNA negative.
    12. Hematology:

      • 1. Absolute neutrophil count greater than or equal to 1000/mm(3) without the support of filgrastim.
      • 2. Platelet count greater than or equal to 50,000/mm(3).
      • 3. Hemoglobin greater than 8.0 g/dl.
      • 4. Lymphocyte count less than or equal to 4,000/ mm(3)
    13. Chemistry:

      • 1. Serum ALT/AST less or equal to 5 times the upper limit of normal.
      • 2. Serum creatinine less than or equal to 1.6 mg/dl
      • 3. Total bilirubin less than or equal to 1.5 mg/dl, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl
    14. More than three weeks must have elapsed since any prior systemic therapy at the time the patient receives the preparative regimen, and patients toxicities must have recovered to a grade 1 or less (except for toxicities such as alopecia or vitiligo).
    15. Normal cardiac ejection fraction and no evidence of pericardial effusion as determined by an echocardiogram.

EXCLUSION CRITERIA:

  1. Patients that require urgent therapy due to tumor mass effects such as bowel obstruction or blood vessel compression.
  2. Patients that have active hemolytic anemia.
  3. Patients with detectable cerebrospinal fluid malignant cells or brain metastases or with a history of cerebrospinal fluid malignant cells or brain metastases, or any residual intracranial implants.
  4. Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the preparative chemotherapy treatment on the fetus or infant.
  5. Active systemic infections, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease.
  6. Any form of primary immunodeficiency (such as Severe Combined

    Immunodeficiency Disease).

  7. Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities).
  8. Concurrent Systemic steroid therapy.
  9. History of severe immediate hypersensitivity reaction to any of the agents used in this study.
  10. History of allogeneic stem cell transplantation
  11. Patients with CNS metastases or symptomatic CNS involvement

    (including cranial neuropathies or mass lesions).

  12. CNS-3 disease or traumatic spinal tap with POSITIVE Steinherz/Bleyer algorithm with cerebral spinal fluid involvement with

    malignancy will make any patient not eligible for this protocol.

  13. Patients with cardiac atrial or cardiac ventricular lymphoma involvement.
  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: NCT00924326

Contacts
Contact: Linda Williams, R.N. (866) 820-4505 linda_williams@nih.gov
Contact: Steven A Rosenberg, M.D. (301) 496-4164 sar@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact NCI/Surgery Branch Recruitment Center    866-820-4505    ncisbirc@mail.nih.gov   
Sponsors and Collaborators
Investigators
Principal Investigator: Steven A Rosenberg, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT00924326     History of Changes
Obsolete Identifiers: NCT00862069
Other Study ID Numbers: 090082, 09-C-0082
Study First Received: June 17, 2009
Last Updated: July 22, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
B Cell Malignancies
T Cell Persistence
Safety
Immunotherapy
Leukemia
Chronic Lymphocytic Leukemia
CLL
Lymphoma

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Lymphoma
Lymphoma, Non-Hodgkin
Lymphoma, Follicular
Lymphoma, Mantle-Cell
Neoplasms by Histologic Type
Neoplasms
Leukemia, B-Cell
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Fludarabine phosphate
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites

ClinicalTrials.gov processed this record on August 28, 2014