T Cells Expressing a Fully-human AntiCD19 Chimeric Antigen Receptor for Treating B-cell Malignancies
Condition: Lymphoma, B-Cell; Lymphoma, Non-hodgkins
MeSH terms: Lymphoma; Neoplasms; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

      The immune system fights infection and can affect cancer cells. T cells are white blood cells
      that are a major part of the immune system. T cells can destroy tumors. Researchers want to
      try to manipulate the immune system to better recognize and kill tumor cells.

      Objective:

      To test the safety of giving T cells expressing a novel fully-human anti-cluster of
      differentiation 19 (CD19) chimeric antigen receptor (CAR) to people with advanced B-cell
      cancer.

      Eligibility:

      People ages 18-73 with a B-cell cancer that has not been controlled by other therapies.

      Design:

      Participants will be screened with:

      Physical exam

      Blood and urine tests

      Heart tests

      Bone marrow sample taken

      Scans in machines that take pictures

      Participants will have apheresis. Blood is removed through a needle in an arm. T cells are
      removed. The rest of the blood is returned through a needle in the other arm.

      The cells will be changed in a laboratory.

      Participants will get 2 chemotherapy drugs over 3 days.

      Two days later, participants will check into the hospital. They will get an intravenous (IV)
      catheter in an arm or chest vein. They will get the T cells through the IV in 1 infusion.

      After this, participants will stay in the hospital for at least 9 days and stay nearby for 2
      weeks. Then they will have blood tests and see a doctor.

      Participants will have visits 6 visits for 1 year after the infusion. Some may have more
      follow-up visits.

      Participants may samples taken of spinal fluid, bone marrow, and tumors.

      ...
    

Detailed description: 
      Background:

        -  Improved treatments for a variety of treatment-resistant B-cell malignancies including
           Bcell lymphomas and chronic lymphocytic leukemia (CLL), are needed.

        -  A particular need is development of new treatments for chemotherapy-refractory B-cell
           malignancies.

        -  T cells can be genetically modified to express chimeric antigen receptors (CARs) that
           specifically target malignancy-associated antigens.

        -  Autologous T cells genetically modified to express CARs targeting the B-cell antigen
           cluster of differentiation 19 (CD19) have caused complete remissions in a small number
           of patients with leukemia or lymphoma. These results demonstrate that anti-CD19
           CAR-expressing T cells have antimalignancy activity in humans.

        -  The vast majority of B-cell malignancies express CD19.

        -  CD19 is not expressed by normal cells except for B cells.

        -  We have constructed a novel fully-human anti-CD19 CAR that can specifically recognize
           CD19-expressing target cells in vitro and eradicate CD19-expressing tumors in mice.

        -  This fully-human CAR targeting CD19 has not been tested in humans before.

        -  Possible toxicities include cytokine-associated toxicities such as fever, hypotension,
           and neurological toxicities. Elimination of normal B cells is probable, and unknown
           toxicities are also possible.

      Objectives:

      Primary

      -Determine the safety and feasibility of administering T cells expressing a novel fully-human
      anti-CD19 CAR to patients with advanced B-cell malignancies.

      Secondary

        -  Evaluate the in vivo persistence and peak blood levels of anti-CD19 CAR T cells after
           initial and repeated CAR T-cell infusions. CAR T-cell blood levels will be compared
           retrospectively to results with an anti-CD19 CAR containing an antigen-recognition
           moiety derived from a murine antibody.

        -  Assess for evidence of anti-malignancy activity by anti-CD19 CAR T cells

        -  Assess the impact of repeated CAR T-cell infusions on residual malignancy after an
           initial CAR T-cell infusion.

        -  Assess the immunogenicity of the CAR used in this protocol.

      Eligibility:

        -  Patients must have any B-cell lymphoma, or CLL/small lymphocytic lymphoma (SLL). Lower
           grade lymphomas transformed to DLBCL are potentially eligible as is primary mediastinal
           B-cell lymphoma and all other subtypes of Diffuse large B-cell lymphoma (DLBCL).

        -  Patients must have malignancy that is measurable on a computed tomography (CT) scan or
           by flow cytometry of bone marrow or blood.

        -  Patients must have a creatinine of 1.4 mg/dL or less and a normal cardiac ejection
           fraction.

        -  An Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 is required.

        -  No active infections are allowed including any history of hepatitis B or hepatitis C.

        -  Absolute neutrophil count greater than or equal to1000/microliter, platelet count
           greater than or equal to 45,000/microliter, hemoglobin greater than or equal to 8g/dL

        -  Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less or equal
           to 3 times the upper limit of the institutional normal unless liver involvement by
           malignancy is demonstrated.

        -  At least 14 days must elapse between the time of any prior systemic treatment (including
           corticosteroids) and initiation of protocol enrollment.

        -  The patients malignancy will need to be assessed for CD19 expression by flow cytometry
           or immunohistochemistry performed at the National Institutes of Health (NIH). If
           unstained, paraffinembedded bone marrow or lymphoma sections are available from prior
           biopsies, these can be used to determine CD19 expression by immunohistochemistry;
           otherwise, patients will need to come to the NIH for a biopsy to determine CD19
           expression. The sample for CD19 expression can come from a biopsy obtained at any time
           before enrollment.

        -  Patients who have never had an allogeneic hematopoietic stem cell transplant are
           potentially eligible.

      Design:

        -  This is a phase I dose-escalation trial

        -  Patients will undergo leukapheresis

        -  T-cells obtained by leukapheresis will be genetically modified to express an anti-CD19
           CAR

        -  Patients will receive a lymphocyte-depleting chemotherapy conditioning regimen with the
           intent of enhancing the activity of the infused anti-CD19-CAR-expressing T cells.

        -  The chemotherapy conditioning regimen is cyclophosphamide 300 mg/m(2) daily for 3 days
           and fludarabine 30 mg/m(2) daily for 3 days. Fludarabine will be given on the same days
           as the cyclophosphamide.

        -  Two days after the chemotherapy ends, patients will receive an infusion of
           anti-CD19-CAR-expressing T cells.

        -  The initial dose level of this dose-escalation trial will be 0.66x10(6) CAR+ T cells/kg
           of recipient bodyweight.

        -  The cell dose administered will be escalated until a maximum tolerated dose is
           determined.

        -  Following the T-cell infusion, there is a mandatory 9-day inpatient hospitalization to
           monitor for toxicity.

        -  Outpatient follow-up is planned for 2 weeks, and 1, 2, 3, 6, 9, and 12 months after the
           CAR T-cell infusion. Long-term gene-therapy follow-up consisting of yearly visits to a
           doctor near the patient s home for 4 more years and then yearly telephone contact for 10
           additional years will be required.

        -  Repeat treatments consisting of the conditioning chemotherapy followed by a CAR T-cell
           infusion are planned for eligible patients with any best responses except continuing
           complete remission or progressive malignancy.

        -  Re-enrollment will be allowed for a small number of subjects.
    

Intervention name(s): Anti-cluster of differentiation 19 (CD19)-Chimeric Antigen Receptor (CAR) T cells; Cyclophosphamide; Fludarabine
Intervention type(s): Biological; Drug; Drug
Intervention description(s): Dose-escalation trial starting dose: 0.66x10^6 CAR+ T cells/kg(weight based dosing)(up to a maximum dose of 18x10^6 CAR+ T cells/kg) infuse on day 0; 300 mg/m^2 intravenous (IV) infusion over 30 minutes on days -5, -4 and -3; 30 mg/m^2 intravenous (IV) infusion over 30 minutes administered immediately following the cyclophosphamide on days -5, -4,and -3
Other intervention name(s): Cytoxan; Fludara
Intervention MeSH terms: Cyclophosphamide; Fludarabine
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Gene Therapy; Adoptive T Cell Therapy; Allogeneic Stem Cell Transplantation; T-cell infusion; Residual Malignancy