Study of T Cells Targeting B-Cell Maturation Antigen for Previously Treated Multiple Myeloma
Condition: Myeloma, Plasma-Cell; Myeloma-Multiple
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

      - T cells are white blood cells that fight several cancers. One cancer therapy involves
      removing a persons' T cells, changing them in a lab, and then returning them to the person.
      Researchers want to see if this helps people with multiple myeloma.

      Objective:

      - To test the safety of giving anti-B-Cell Maturation Antigen T cells to people with multiple
      myeloma.

      Eligibility:

      - Adults ages 18-70 with multiple myeloma that has not responded to standard therapies.

      Design:

        -  Participants may be screened with:

        -  Medical history

        -  Physical exam

        -  Blood and urine tests

        -  Heart tests

        -  Bone marrow sample

        -  Multiple scans and X-rays

        -  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 visit the clinic 1, 2, 3, 4, 6, and 12 months after the infusion, then
           every 6 months. A bone marrow sample will be taken at the 2-month visit.

        -  Participants blood will be collected for several years. Participants will have an annual
           physical at National Institutes of Health (NIH) for 5 years after the infusion. Then for
           10 years they will answer health questionnaires.
    

Detailed description: 
      BACKGROUND:

        -  Multiple myeloma (MM) is a malignancy of plasma cells.

        -  MM is nearly always incurable.

        -  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 CAR-expressing T
           cells have anti-malignancy activity in humans.

        -  B-cell maturation antigen (BCMA) is a protein expressed by normal plasma cells and the
           malignant plasma cells of multiple myeloma.

        -  BCMA is not expressed by normal cells except for plasma cells and some mature B cells.

        -  We have constructed an anti-BCMA CAR that can specifically recognize BCMA-expressing
           target cells in vitro and eradicate BCMA-expressing tumors in mice.

        -  Anti-BCMA-CAR-expressing T cells have not been previously tested in humans.

        -  We hypothesize that anti-BCMA-CAR-expressing T cells will specifically eliminate

      BCMA-expressing MM cells in patients

      -Possible toxicities include cytokine-associated toxicities such as fever, hypotension, and
      neurological toxicities. Elimination of normal plasma cells and unknown toxicities are also
      possible.

      OBJECTIVES:

      Primary

      -Determine the safety and feasibility of administering T cells expressing an anti- BCMA CAR
      to patients with MM.

      Secondary

        -  Evaluate the in vivo persistence of anti-BCMA CAR T cells

        -  Assess for evidence of anti-myeloma activity by anti-BCMA CAR T cells

      ELIGIBILITY

        -  Patients must have measurable MM defined as a serum M-protein greater than or equal to
           0.4 g/dL or a urine M-protein greater than or equal to 200 mg/24 hours or an involved
           serum free light chain (FLC) level greater than or equal to 10 mg/dL (provided FLC ratio
           is abnormal) or a biopsy-proven plasmacytoma.

        -  Patients must have previously received at least 3 different treatment regimens for MM.

        -  Patients must have a normal creatinine and a normal cardiac ejection fraction.

        -  An Eastern Cooperative Oncology Group (ECOG) performance status of 0 -2 is required.

        -  Patients on any anticoagulant medications except aspirin are not eligible.

        -  No active infections are allowed.

        -  Absolute neutrophil count greater than or equal to 1000/ L, platelet count greater than
           or equal to 45,000/ L, hemoglobin greater than or equal to 8g/dL

        -  Alanine aminotransferase (ALT) and aspartate transaminase (AST) less than or equal to
           2.5-fold higher than the upper limit of normal

        -  At least 14 days must elapse between the time of any prior systemic treatment (including
           corticosteroids) and the required leukapheresis.

        -  At least 14 days must elapse between the time of any prior systemic treatment (including
           corticosteroids) and initiation of protocol treatment.

        -  Bone marrow plasma cells must be 30% or less of total bone marrow cells 30 days or less
           prior to the start of protocol treatment.

        -  The patient's MM will need to be assessed for BCMA expression by flow cytometry or
           immunohistochemistry performed at the National Institutes of Health (NIH). If unstained,
           paraffinembedded bone marrow or plasmacytoma sections are available from prior biopsies,
           these can be used to determine BCMA expression by immunohistochemistry; otherwise
           patients will need to come to the NIH for a bone marrow biopsy or other biopsy of a
           plasmacytoma to determine BCMA expression. The sample for BCMA expression can come from
           a biopsy obtained at any time before enrollment.

      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- BCMA
           CAR

        -  Patients will receive a lymphocyte-depleting chemotherapy conditioning regimen with the
           intent of enhancing the activity of the infused anti-BCMA-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-
           BCMA-CAR-expressing T cells.

        -  The initial dose level of this dose-escalation trial will be 0.3x10^6 CAR+ T cells/kg of
           recipient bodyweight.

        -  The cell dose administered will be escalated until a maximum tolerated dose is
           determined for patients in which less than 50% of total bone marrow cells are plasma
           cells.

      With Amendment C, all patients with 50% or greater bone marrow plasma cells will receive
      3x10(6) anti-BCMA CAR T cells/kg.

        -  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, 4, 6, 9, and 12 months after
           the CAR T-cell infusion.

        -  Repeat treatments are possible for patients with residual MM and no greater than grade 2
           toxicity with an initial treatment.

        -  Re-enrollment will be allowed for a small number of subjects.
    

Intervention name(s): Cyclophosphamide; Fludarabine; Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells
Intervention type(s): Drug; Drug; Biological
Intervention description(s): 300 mg/m^2 intravenous (IV) over 30 minutes on days -5, -4, and -3; 30 mg/m^2 intravenous (IV) over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3; 0.3x10^6- 15.0x10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0
Other intervention name(s): Cytoxan; Fludara
Intervention MeSH terms: Cyclophosphamide; Fludarabine
Intervention model: Sequential Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Immunotherapy; Anti-BCMA-CAR; Gene Therapy; Adoptive T Cell Therapy; Plasma Cell Malignancy