T-cells Expressing an Anti-SLAMF7 CAR for Treating Multiple Myeloma
Condition: Myeloma-Multiple; Myeloma, Plasma-Cell
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

      Multiple myeloma is a blood cancer that is usually incurable. T cells are part of the immune
      system. Researchers think changing a person's T cells to recognize their cancer could help
      the person's body kill tumor cells. This is a new approach that uses a patient's own cells to
      target multiple myeloma.

      Objective:

      To see if giving anti-Signaling lymphocytic activation molecule F7 (SLAM7) chimeric antigen
      receptor (CAR) T cells with a stop switch to people with multiple myeloma is safe and to see
      if adding a gene to stop T-cell activity can limit toxicity of this therapy.

      Eligibility:

      People ages 18-73 with multiple myeloma for which prior standard treatment has not worked

      Design:

      Participants will be screened with:

        -  Medical history

        -  Physical exam

        -  Blood, urine, and heart tests

        -  Bone marrow samples: A needle inserted into the participant's bone will remove marrow.

        -  Imaging scans: Participants will lie in a machine that takes pictures of the body.

      Participants will have apheresis. They will receive a catheter or central line: A plastic
      tube will be inserted into a chest or arm vein. Blood will be removed and the T cells
      separated. The rest of the blood will be returned to the participant. The T cells will be
      manipulated in the lab.

      Participants will get chemotherapy through the central line for 3 days.

      Participants will receive the manipulated T cells through the central line. They will stay in
      the hospital at least 9 days.

      Participants will have follow-up visits 2 weeks then 1, 2, 3, 4, 6, 9, and 12 months after
      the infusion. They will then have visits every 6 months for 3 years. Then they will be
      contacted once per year for 15 years. All visits will include blood tests, and 3 visits will
      include bone marrow biopsies....
    

Detailed description: 
      Background:

        -  Multiple myeloma (MM) is a nearly always incurable malignancy of plasma cells.

        -  T cells can be genetically modified to express chimeric antigen receptors (CARs) that
           target malignancy-associated antigens.

        -  Signaling lymphocytic activation molecule F7 (SLAM7) is highly and uniformly expressed
           on MM cells but is absent on normal tissues except for some leukocytes, including a
           subset of cluster of differentiation 8 (CD8)+ T cells, natural killer (NK) cells, B
           cells, plasma cells and monocytes.

        -  We have constructed a novel anti-SLAMF7 CAR that can specifically recognize SLAMF7-
           expressing target cells and eradicate SLAMF7-expressing tumors in mice.

        -  This protocol will test genetic modification of autologous T cells with genes encoding
           an inducible caspase 9 (IC9) cell-suicide system plus the anti-SLAMF7 CAR.

        -  Administration of the dimerizer drug Rimiducid (AP1903) is necessary to activate the
           inducible caspase 9 (IC9) suicide gene and eliminate CAR T cells.

        -  In this protocol, the suicide gene system will be used to eliminate CAR-expressing T
           cells in case of severe toxicities caused by the CAR T cells.

        -  Possible toxicities include cytokine-associated toxicities such as hypotension, and
           neurological toxicities. Elimination of NK cells and normal plasma cells could make
           patients more susceptible to infections. Unknown toxicities are also possible.

      Objectives:

      Primary

      - Determine the safety, feasibility of administering T cells expressing an anti-SLAMF7 CAR
      plus IC9 cell-suicide system to patients with MM.

      Eligibility:

        -  Greater than or equal to 18 years of age and less than or equal to age 73.

        -  Patients must have measurable MM defined as a serum M-protein >=0.6 g/dL or a urine
           M-protein >=200 mg/24 hours or an involved serum free light chain (FLC) level >=10 mg/dL
           (provided FLC ratio is abnormal) or a biopsy-proven plasmacytoma of 1.5 cm or more in
           largest dimension, or greater than or equal to 30% bone marrow plasma cells.

        -  Patients must have previously received at least 3 different treatment regimens for MM.

        -  Patients must have prior exposure to an immunomodulatory drug (IMiD) such as
           lenalidomide, and a proteasome inhibitor

        -  Patients must have a creatinine level of less than or equal to 1.5 mg/dL

        -  Patients must have a cardiac ejection fraction >= 50%.

        -  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 >= 1000/microL, platelet count >= 55,000/microL, hemoglobin >=
           8g/dL

        -  Alanine aminotransferase (ALT) and aspartate aminotransferase (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 and
           initiation of protocol treatment. Systemic therapy includes corticosteroids at a dose
           equivalent to more than 5 mg of prednisone.

        -  Bone marrow plasma cells must make up less than or equal to 50% of total bone marrow
           cells less than or equal to 24 days prior to the start of protocol treatment.

        -  The patient's MM will need to be assessed for SLAMF7 expression by flow cytometry or
           immunohistochemistry performed at the National Institutes of Health (NIH). The myeloma
           must express SLAMF7. If unstained, paraffin-embedded bone marrow or plasmacytoma
           sections are available from prior biopsies, these can be used to determine SLAMF7
           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 SLAMF7 expression.
           The sample for SLAMF7 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, and T cells will be modified to express the
           IC9-anti-SLAMF7 CAR construct.

        -  The chemotherapy conditioning regimen is cyclophosphamide 300 mg/m^2 daily for 3 days
           and fludarabine 30 mg/m^2 daily for 3 days. The intent of chemotherapy is to enhance CAR
           T-cell activity.

        -  After the chemotherapy ends, the patients will have two days with no treatments and then
           receive an infusion of CAR T cells.

        -  The initial dose level will be 0.66x10^6 Anti-SLAMF7-CAR + T cells/kg of recipient
           bodyweight.

        -  The cell dose administered will be escalated for up to 4 doses until a maximum tolerated
           dose is determined.

        -  Following the T-cell infusion, there will be a mandatory 9-day minimum 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. Afterwards, follow-up will be every six months up to at least 3
           years after infusion.
    

Intervention name(s): Cyclophosphamide; Fludarabine; Rimiducid; Anti-Signaling lymphocytic activation molecule F7 (SLAMF7) chimeric antigen receptor (CAR) T cells
Intervention type(s): Drug; 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; 0.4 mg/kg of Rimiducid intravenous (IV) over 2 hours. (A maximum of 2 doses separated by at least 48 hours) Note: Rimiducid may be administered as needed based on the patient condition at the discretion of the Principal Investigator.; 0.3x10^6- 12.0x10^6 CAR+ T cells per kg of recipient bodyweight one-time dose on day 0
Other intervention name(s): Cytoxan; Fludara; AP1903
Intervention MeSH terms: Cyclophosphamide; Fludarabine
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Chimeric Antigen Receptors; B-cell Maturation Antigen; Immunotherapy; Adoptive T Cell Therapy