T-cells Expressing an Anti-SLAMF7 CAR for Treating Multiple Myeloma
Condition: Myeloma-Multiple; Myeloma, Plasma-Cell
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Cyclophosphamide; Fludarabine; Rimiducid; Anti-Signaling lymphocytic activation molecule F7 (SLAMF7) chimeric antigen receptor (CAR) T cells
Intervention description: 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
Intervention MeSH terms: Cyclophosphamide; Fludarabine
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 13.0
Sex: All
Minimum age: 18 Years
Maximum age: 73 Years
Healthy volunteers: No
Keywords: Chimeric Antigen Receptors; B-cell Maturation Antigen; Immunotherapy; Adoptive T Cell Therapy

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....
    

Eligibility criteria:

        -  INCLUSION CRITERIA - MULTIPLE MYELOMA:

          -  Signaling lymphocytic activation molecule F7 (SLAMF7) expression must be detected on
             malignant plasma cells from either bone marrow or a plasmacytoma by flow cytometry or
             immunohistochemistry. A specific quantitative level of SLAMF7 expression for
             eligibility is not specified, but patients with multiple myeloma cells that are
             negative for SLAMF7 by flow cytometry and immunohistochemistry will not be enrolled.
             These assays must be performed at the National Institutes of Health (NIH). It is not
             required that the specimen used for SLAMF7 determination comes from a sample that was
             obtained after the patient's most recent treatment. If paraffin embedded unstained
             samples of bone marrow involved with MM or a plasmacytoma are available, these can be
             shipped to the NIH for SLAMF7 staining, otherwise new biopsies will need to be
             performed for determination of SLAMF7 expression.

          -  SLAMF7 expression will need to be documented on the majority of malignant plasma cells
             by flow cytometry at the NIH at some time after the original chimeric antigen receptor
             (CAR)-SLAMF7 T-cell infusion in all patients undergoing a second CAR-SLAMF7 T-cell
             infusion on this clinical trial.

          -  Bone marrow plasma cells must make up less than or equal to 50% of total bone marrow
             cells based on a bone marrow biopsy performed within 24 days of the start of protocol
             treatment.

          -  Patients must have received at least 3 different prior treatment regimens for multiple
             myeloma (MM)

          -  Must have prior exposure to an immunomodulatory drug (IMiD) such as lenalidomide and a
             proteasome inhibitor

          -  Patients must have measurable MM as defined by at least one of the criteria below.

               -  Serum M-protein greater or equal to 0.6 g/dL.

               -  Urine M-protein greater or equal to 200 mg/24 h.

               -  Serum free light chain (FLC) assay: involved FLC level greater or equal to 10
                  mg/dL (100 mg/L) provided serum FLC ratio is abnormal.

               -  A biopsy-proven plasmacytoma at least 1.5 cm in largest dimension

               -  Bone marrow core biopsy with 30% or more plasma cells

        INCLUSION CRITERIA - OTHER:

          -  Greater than or equal to 18 years of age and less than or equal to age 73.

          -  Able to understand and sign the Informed Consent Document.

          -  Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0-2

          -  Patients of both sexes must be willing to practice birth control from the time of
             enrollment on this study and for four months after last day of receiving protocol
             treatment.

          -  Seronegative for human immunodeficiency virus (HIV) antibody. (The experimental
             treatment being evaluated in this protocol depends on an intact immune system.
             Patients who are HIV seropositive can have decreased immune-competence and thus are
             less responsive to the experimental treatment and more susceptible to its toxicities.)

          -  A patient with a negative blood polymerase chain reaction (PCR) test for hepatitis B
             deoxyribonucleic (DNA) test can be enrolled. If hepatitis B DNA (PCR) testing is not
             available, patients with a negative hepatitis B surface antigen and negative hepatitis
             B core antibody can be enrolled.

          -  Patients must be tested for the presence of Hepatitis C antigen by PCR and be
             hepatitis C virus (HCV) ribonucleic acid (RNA) negative in order to be eligible. Only
             if Hepatitis C PCR testing is not available in a timely manner, patients who are
             Hepatitis C antibody-negative can be enrolled.

          -  Absolute neutrophil count greater than or equal to 1000/mm^3 without the support of
             filgrastim or other growth factors within the previous 10 days.

          -  Platelet count greater than or equal to 55,000/mm^3 without transfusion support in the
             past 14 days.

          -  Hemoglobin greater than or equal to 8.0 g/dL.

          -  Less than 5% plasma cells in the peripheral blood leukocytes

          -  Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less or
             equal to 2.5 times the upper limit of the institutional normal.

          -  Serum creatinine less than or equal to 1.5 mg/dL.

          -  Total bilirubin less than or equal to 2.0 mg/dL, except in patients with Gilbert's
             Syndrome who must have a total bilirubin less than 3.0 mg/dL.

          -  At least 14 days must have elapsed since any prior systemic therapy at the time the
             patient starts the cyclophosphamide and fludarabine conditioning regimen, and patients
             toxicities must have recovered to a grade 1 or less (except for toxicities such as
             alopecia or vitiligo or cytopenias).

          -  Because this protocol requires collection of autologous blood cells by leukapheresis
             in order to prepare CAR-SLAMF7 T cells, systemic anti-myeloma therapy including
             systemic corticosteroid steroid therapy of greater than 5 mg/day of prednisone or
             equivalent dose of another corticosteroid are not allowed within 14 days prior to the
             required leukapheresis.

          -  Normal cardiac ejection fraction (greater than or equal to 50% by echocardiography)
             and no evidence of hemodynamically significant pericardial effusion as determined by
             an echocardiogram.

          -  For patients with past participation in gene-therapy, cryopreserved peripheral blood
             mononuclear cells (PBMC) that have not been genetically engineered must be available.

          -  Patients receiving prior gene therapy outside of NIH will not be eligible. Patients
             who previously received CAR T-cell therapy at the National Cancer Institute (NCI) will
             be potentially eligible.

        EXCLUSION CRITERIA:

          -  Patients who are receiving any other investigational agents.

          -  Patients on any anticoagulants except aspirin

          -  Patients that require urgent therapy due to tumor mass effects or spinal cord
             compression.

          -  Patients that have active hemolytic anemia.

          -  Patients with second malignancies in addition to multiple myeloma are not eligible if
             the second malignancy has required treatment within the past 3 years or is not in
             complete remission. There are two exceptions to this criterion: successfully treated
             non-metastatic basal cell or squamous cell skin carcinoma.

          -  Women of child-bearing potential who are pregnant or breastfeeding because of the
             potentially dangerous effects of the preparative chemotherapy on the fetus or infant.
             Women of child bearing potential cannot have a positive pregnancy test. Women of
             childbearing potential are defined as all women except women who are post-menopausal
             or who have had a hysterectomy. Postmenopausal will be defined as women over the age
             of 55 who have not had a menstrual period in at least 1 year.

          -  Active systemic infections (defined as infections causing fevers or requiring
             anti-microbial treatment), active coagulation disorders or other major uncontrolled
             illnesses of the cardiovascular, respiratory, endocrine, renal, gastrointestinal,
             genitourinary, neurologic, psychiatric, or immune system, history of myocardial
             infarction, active cardiac arrhythmias, active obstructive or restrictive pulmonary
             disease.

          -  Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency
             Disease).

          -  Systemic corticosteroid steroid therapy of greater than 5 mg/day of prednisone or
             equivalent dose of another corticosteroid (prednisone, dexamethasone, etc.) is not
             allowed within 14 days prior to either the required leukapheresis or within 14 days
             prior to CAR Tcell infusion (and at any time after the CAR T-cell infusion unless
             approved by the Principal Investigator or an Associate Investigator).

          -  History of severe immediate hypersensitivity reaction to any of the agents used in
             this study.

          -  Patient unwilling to undergo intensive care unit treatment including mechanical
             ventilation, cardiopulmonary resuscitation, vasoactive drugs, and hemodialysis.

          -  History of allogeneic stem cell transplantation

          -  Patients with current spinal cord compression (without intradural myeloma involvement.

          -  Patients who have a history (or current evidence) of cerebrospinal fluid multiple
             myeloma, or intradural central nervous system masses.

          -  Patients with active autoimmune skin diseases such as psoriasis or other active
             autoimmune diseases such as rheumatoid arthritis.

          -  Patients must not have required supplemental oxygen within the past month unless it
             was for a resolved infection.