Clinical Trials /

Phase I/IIA Study of CART19 Cells for Patients With Chemotherapy Resistant or Refractory CD19+ Leukemia and Lymphoma

NCT01626495

Description:

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.

Related Conditions:
  • Chronic Lymphocytic Leukemia
  • Mature B-Cell Lymphoma/Leukemia
Recruiting Status:

Completed

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase I/IIA Study of CART19 Cells for Patients With Chemotherapy Resistant or Refractory CD19+ Leukemia and Lymphoma
  • 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

Clinical Trial IDs

  • ORG STUDY ID: 10-007706, 815870
  • SECONDARY ID: CHP959
  • NCT ID: NCT01626495

Conditions

  • B Cell Leukemia
  • B Cell Lymphoma

Interventions

DrugSynonymsArms
CART-19CART-19 T Cells

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.

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.
      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-CD 19 lentiviral vector (referred to as "CART-19" cells).

        2. Determine duration of in vivio 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 leukema (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)
    

Trial Arms

NameTypeDescriptionInterventions
CART-19 T CellsExperimentalThe subject's thawed 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). The T cells will be infused over 10-15 minutes on days Days 0, and 1. Day 14 is tentative based on response.
  • CART-19

Eligibility Criteria

        Inclusion Criteria:

        Male and female subjects with CD 19+ 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: CD 19+ leukemia or lymphoma

               1. ALL without curative options for therapy, including those not eligible for
                  allogeneic

                  SCT because of:

                    -  age

                    -  co-morbid disease

                    -  other contraindications to TBI-based conditioning (required for ALL SCT)

                    -  lack of suitable donor

                    -  prior SCT

                    -  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. Note: 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.

               2. Follicular lymphoma, previously identified as CD19+

                    -  At least 2 prior combination chemotherapy regimens (not including single
                       agent monoclonal antibody (Rituxan) therapy.

                    -  Stage III-IV disease.

                    -  Less than 1 year between last chemotherapy and progression (i.e. most recent
                       progression free interval <1 year).

                    -  Disease responding or stable after most recent therapy (chemotherapy, MoAb).

               3. CLL

                    -  At least 2 prior chemotherapy regimens (not including single agent
                       monoclonal antibody (Rituxan) therapy.

                    -  Less than 1 year between last chemotherapy and progression (i.e. most recent
                       progression free interval <1 year).

                    -  Not eligible or appropriate for conventional allogeneic SCT

                    -  Disease responding or stable after most recent therapy (chemotherapy, MoAb)

               4. Mantle cell lymphoma

                    -  Beyond 1st CR with relapsed or persistent disease and not eligible or
                       appropriate for conventional allogeneic or autologous SCT

                    -  Disease responding or stable after most recent therapy (chemotherapy, MoAb)

                    -  Relapsed after prior autologous SCT

               5. B-cell prolymphocytic leukemia (PLL) with relapsed or residual disease after at
                  least 1 prior therapy and not eligible for allogeneic SCT.

               6. Diffuse large cell lymphoma or other high-grade NHL, previously identified as
                  CD19+

                    -  Residual disease after primary therapy and not eligible for autologous SCT

                    -  Relapsed after prior autologous SCT

                    -  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

          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

         11. Patients with CNS3 disease will be eligible if CNS disease is responsive to therapy
             (at infusion)

        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. Any uncontrolled active medical disorder that would preclude participation as
             outlined.

          9. HIV infection.

         10. CNS3 disease that is progressive on therapy, or with CNS parenchymal lesions that
             might increase the risk of CNS toxicity
      
Maximum Eligible Age:24 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Subjects With Study Related Adverse Events.
Time Frame:24 weeks
Safety Issue:
Description:Inclusive of any events that are "possibly", "likely", or "definitely" related to study treatment any time from the first day of study treatment until week 24.

Secondary Outcome Measures

Measure:The Number of Subjects With a Successful Product Manufactured
Time Frame:24 weeks
Safety Issue:
Description:
Measure:Number of Subjects With Complete Remission (CR).
Time Frame:4 Weeks
Safety Issue:
Description:Complete remission rate for subjects with Non-CNS3 ALL. National Comprehensive Cancer Network standard response criteria, which define complete remission (CR) as ,5% bone marrow blasts by morphologic determination, with no evidence of extramedullary disease or refractory disease.
Measure:Number of Subjects With Complete Remission With Incomplete Blood Count Recovery (CRi).
Time Frame:4 Weeks
Safety Issue:
Description:Complete remission rate for subjects with Non-CNS3 ALL. National Comprehensive Cancer Network standard response criteria, which define complete remission (CR) as ,5% bone marrow blasts by morphologic determination, with no evidence of extramedullary disease or refractory disease.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:University of Pennsylvania

Trial Keywords

  • Biological: CART19

Last Updated

March 23, 2020