Phase I/IIA Study of CART19 Cells for Patients With Chemotherapy Resistant or Refractory CD19+ Leukemia and Lymphoma (Pedi CART-19)

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by Children's Hospital of Philadelphia
Sponsor:
Collaborator:
University of Pennsylvania
Information provided by (Responsible Party):
Stephan Grupp, Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier:
NCT01626495
First received: June 18, 2012
Last updated: June 7, 2014
Last verified: June 2014
  Purpose

This is a study for children who have been previously treated for Leukemia/Lymphoma. In particular, it is a study for people who have a type of Leukemia/Lymphoma that involves B cells (a type of white cell), which contain the cancer. This is a new approach for treatment of Leukemia/Lymphoma that involves B cells (tumor cells). This study will take the subject's white blood cells (T cells) and modify them in order to target the cancer.

The subject's T cells will be modified in one or two different ways that will allow the cells to identify and kill the tumor cells (B cells). Both ways of modifying the cells tells the T cells to go to the B cells (tumor cells) and turn "on" and potentially kill the B cells (tumor cells). The modification is a genetic change to the T cells, or gene transfer, in order to allow the modified T cells to recognize your tumor cells but not other normal cells in the subject's body. These modified cells are called chimeric antigen receptor 19 (CART19) T-cells.

The two types of CART-19 T cells will be given back to subject's through an infusion. In addition to determining the safety of this approach, the purpose of the study is to determine which way of modifying the T cells works better in turning them "on" to fight cancer. This is done by monitoring levels of both types of modified cells in the subject's blood stream, and if possible, in the bone marrow and tumor tissue for four weeks after the infusion. It is expected that one type of modified cell will grow better than the other in the subject's blood. However, it is possible that there will be no difference between the two types of cells.

All subjects who receive CART19 T cells will be enrolled in a Long Term Follow up study to monitor subjects. Subjects will be followed every 6 months for five years following the 1st infusion of the T cells. If the CART19 T cells are no longer found in the blood after five years, then subjects will be contacted yearly for the next 10 years. If the CART19 T cells are found in the blood at five years after the 1st infusion of T cells, then the subjects will continue to be seen once a year until the CART19 T cells are no longer found in the blood for a maximum of 15 years.


Condition Intervention Phase
B Cell Leukemia
B Cell Lymphoma
Biological: CART-19
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: CHP 959 - A Phase I/IIA Study of Redirected Autologous T Cells Engineered to Contain Anti-CD19 Attached to TCRzeta and 4-1BB Signaling Domains in Patients With Chemotherapy Resistant Or Refractory CD19+ Leukemia and Lymphoma

Resource links provided by NLM:


Further study details as provided by Children's Hospital of Philadelphia:

Primary Outcome Measures:
  • Number of Participants with Severe/Adverse Events as a Measure of Safety and Tolerability [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
    Safety of CAR+ T cell infusion and observed side effects


Secondary Outcome Measures:
  • Ability of two different types of CAR+ T cells to expand and persist in the patient [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    The change in the ratio of the vector transduced cells to each other between baseline and week four will be evaluated. Observation and monitoring of patients will continue on a monthly basis until week 24 post dosing

  • Impact of CAR+ T cell infusion on cancer [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    Patients with measurable disease will be assessed for the response of their disease to the CAR+ T cell treatment


Estimated Enrollment: 20
Study Start Date: August 2011
Estimated Study Completion Date: September 2016
Estimated Primary Completion Date: August 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: CART-19 T Cells
The subject's T cells will be modified in one or two different ways that will allow the cells to identify and kill the tumor cells (B cells).
Biological: CART-19

Detailed Description:

At entry subjects will be staged and the suitability of their T cells for CART-19 manufacturing will be determined. Subjects who have adequate T cells will be leukapheresed to obtain large numbers of peripheral blood mononuclear cells (PBMC) for CART-19 manufacturing. The T cells will be purified from the PBMC, transduced with CART-19 lentiviral vector, expanded in vitro and then frozen for future administration. Chemotherapy will then be given. Following tumor burden reassessment, CART-19 cells will be thawed and infused.

Subjects will have blood tests to assess safety, and engraftment and persistence of the CART-19 cells at regular intervals through four weeks after their last infusion of the study. The subsets of circulating T-cells that contain the CART-19:T cell receptor (TCR):type 2 transmembrane glycoprotein (4-1BB) and CART-19:TCR only lentiviral vector will be assessed at various times after infusion and compared to the baseline sample. Following the 6 months of intensive follow-up, subjects will be evaluated quarterly for two years with a medical history, a physical examination, and blood tests. Following this evaluation, subjects will enter a roll-over study for annual follow-up by phone and questionnaire for an additional thirteen years to assess for the diagnosis of long-term health problems, such as development of new malignancy.

Primary objectives:

  1. Determine the safety and feasibility of administration of chimeric antigen receptor T cells transduced with the anti-CD19 lentiviral vector (referred to as "CART-19" cells).
  2. Determine duration of in vivo survival of CART-19 cells. Real Time polymerase chain receptor (RT-PCR) analysis of whole blood will be used to detect and quantify survival of CART-19 TCR:4-1BB and TCR cells over time.

Secondary objectives:

  1. For patients with detectable disease, measure anti-tumor response due to CART-19 cell infusions.
  2. To determine if the 4-1BB transgene is superior to the TCR only transgene as measured by the relative engraftment levels of CART-19 TCR:4-1BB and TCR cells over time.
  3. For patients with stored or accessible tumor cells [such as patients with active chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), etc] determine tumor cell killing by CART-19 cells in vitro.
  4. Determine if cellular or humoral host immunity develops against the murine anti-CD19, and assess correlation with loss of detectable CART-19 (loss of engraftment).
  5. Determine the relative subsets of CART-19 T cells (Tcm, Tem, and Treg)
  Eligibility

Ages Eligible for Study:   1 Year to 24 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Male and female subjects with CD19+ B cell malignancies in patients with no available curative treatment options (such as autologous or allogeneic SCT) who have limited prognosis (several months to <2 year survival) with currently available therapies will be enrolled:

  1. Eligible diseases: CD19+ leukemia or lymphoma

    a. ALL without curative options for therapy, including those not eligible for allogeneic SCT because of: i. age ii. comorbid disease iii. other contraindications to TBI-based conditioning (required for ALL SCT) iv. lack of suitable donor v. prior SCT vi. Declines allo SCT (in CR3) as a therapeutic option after documented discussion about the role of SCT with a BMT physician not part of the study team

    . Patient may be in any complete response, or patient may have active disease but responding or stable after most recent therapy. The intent is not to enroll patients with no degree of disease control, or rapidly increasing disease burden between enrollment and cell infusion.

    b. Diffuse large cell lymphoma or other high-grade NHL, previously identified as CD19+ i. Residual disease after primary therapy and not eligible for autologous SCT. ii. Relapsed after prior autologous SCT. iii. Beyond 1st CR with relapsed or persistent disease and not eligible or appropriate for conventional allogeneic or autologous SCT.

  2. Age 1 to 24 years. Patients ages 22-24 will only be enrolled if they are currently being treated at CHOP or another pediatric facility/oncologist.
  3. Expected survival > 12 weeks
  4. Creatinine < 2.5 mg/dl and less than 2.5x normal for age
  5. ALT <= 5x normal
  6. Bilirubin <2.0 mg/dl
  7. Any relapse after prior SCT will make patient eligible regardless of other prior therapy.
  8. Patients with relapsed disease after prior allogeneic SCT (myeloablative or non-myeloablative) will be eligible if they meet all other inclusion criteria and

    1. Have no active GVHD and require no immunosuppression
    2. Are more than 4 months from transplant (6 months at infusion)
  9. For those patients who require leukapheresis for T cell collection (i.e. no previously collected product exists), adequate venous access for apheresis or eligible for appropriate catheter placement, and no other contraindications for leukapheresis.
  10. Voluntary informed consent is given.

Exclusion Criteria:

  1. Pregnant or lactating women. The safety of this therapy on unborn children is not known. Female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 48 hours before infusion.
  2. Uncontrolled active infection.
  3. Active hepatitis B or hepatitis C infection.
  4. Concurrent use of systemic steroids at the time of cell infusion or cell collection, or a condition, in the treating physician's opinion, that is likely to require steroid therapy during collection or after infusion. Steroids for disease treatment at times other than cell collection or at the time of infusion are permitted. Use of inhaled steroids, or hydrocortisone for physiological replacement in patients with adrenal insufficiency are permitted as well.
  5. Presence of grade 2-4 acute or extensive chronic GVHD.
  6. Under treatment for GVHD.
  7. Previous treatment with any gene therapy products.
  8. Feasibility assessment during screening shows insufficient expansion in response to CD3/CD28 costimulation.
  9. Any uncontrolled active medical disorder that would preclude participation as outlined.
  10. HIV infection.
  11. Patients with active CNS involvement with malignancy (i.e. CNS3 for ALL). Patients with prior CNS disease that has been effectively treated will be eligible. Routine CNS prophylaxis for ALL is permitted.
  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: NCT01626495

Contacts
Contact: Stephan A Grupp, MD, PHD CHOP INFO #: 267-426-0762

Locations
United States, Pennsylvania
CHOP - http://www.chop.edu/service/oncology/pediatric-cancer-research/cart-19-trial.html Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Christine Strait, BS       straitc@email.chop.edu   
Contact: Margie Tartaglione, RN       tartaglione@email.chop.edu   
Principal Investigator: Stephan A Grupp, MD, PHD         
Sponsors and Collaborators
Children's Hospital of Philadelphia
University of Pennsylvania
  More Information

No publications provided

Responsible Party: Stephan Grupp, MD, PHD, Director of Translational Research, Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier: NCT01626495     History of Changes
Other Study ID Numbers: 10-007706 (CHP959)
Study First Received: June 18, 2012
Last Updated: June 7, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, B-Cell
Lymphoma
Lymphoma, B-Cell
Neoplasms by Histologic Type
Neoplasms
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin

ClinicalTrials.gov processed this record on July 26, 2014