Clinical Trials /

T-cells Expressing an Anti-SLAMF7 CAR for Treating Multiple Myeloma

NCT03958656

Description:

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-SLAM7 CAR T cells with a stop switch to people with multiple myeloma is safe andto 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....

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: T-cells Expressing an Anti-SLAMF7 CAR for Treating Multiple Myeloma
  • Official Title: A Phase I Clinical Trial of T Cells Expressing an Anti-SLAMF7 CAR for Treating Multiple Myeloma

Clinical Trial IDs

  • ORG STUDY ID: 190102
  • SECONDARY ID: 19-C-0102
  • NCT ID: NCT03958656

Conditions

  • Myeloma-Multiple
  • Myeloma, Plasma-Cell

Interventions

DrugSynonymsArms
Cyclophosphamide1/Conditioning chemotherapy plus CAR T-cells dose escalation
Fludarabine1/Conditioning chemotherapy plus CAR T-cells dose escalation
Rimiducid1/Conditioning chemotherapy plus CAR T-cells dose escalation
Anti-SLAMF7 CAR T cells1/Conditioning chemotherapy plus CAR T-cells dose escalation

Purpose

Background: Multiple myeloma is a blood cancer that is usually incurable. T cells are part of the immune system. T cells are part of the immune system. Researchers think changing a person s T cells could help the person s body kill tumor cells. Objective: To see if giving anti-SLAM7 CAR T cells to people with multiple myeloma is safe. Eligibility: People ages 18-73 with multiple myeloma for which 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 may have repeat apheresis and T cell infusions if needed. 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.

        -  SLAMF7 is highly and uniformly expressed on MM cells but is absent on normal tissues
           except for some leukocytes, including a subset of 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 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 >=1.0 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 eual to 1.5 mg/dL

        -  Patients must have a cardiac ejection fraction >= 50%.

        -  An 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

        -  ALT and AST less thanor 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 < 21 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 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 5 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.
    

Trial Arms

NameTypeDescriptionInterventions
1/Conditioning chemotherapy plus CAR T-cells dose escalationExperimentalPatients will receive escalating doses (up to 5 planned) of Anti-SLAMF7-CAR+ T cells infused on day 0 + Cyclophosphamide: 300 mg/m^2 IV infusion over 30 minutes on days -5, -4 and -3 + Fludarabine: 30 mg
  • Cyclophosphamide
  • Fludarabine
  • Rimiducid
  • Anti-SLAMF7 CAR T cells
2/Conditioning chemotherapy plus CAR T-cells expansion phaseExperimentalMTD dose of Anti-SLAMF7- CAR T Cells + Cyclophosphamide: 300 mg/m^2 IV infusion over 30 minutes on days -5, -4 and -3 + Fludarabine: 30mg/m^2 IV infusion over 30 minutes administered immediately following the cyclophosphamide on days -5, -4, and -3
  • Cyclophosphamide
  • Fludarabine
  • Rimiducid
  • Anti-SLAMF7 CAR T cells

Eligibility Criteria

        -  INCLUSION CRITERIA - MULTIPLE MYELOMA:

          -  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 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 21 days of the start of protocol
             treatment.

          -  Patients must have received at least 3 different prior treatment regimens for multiple
             myeloma

          -  Must have prior exposure to an immunomodulatory drug (IMiD) such as lenolidamide 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 1.0 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 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 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 PCR test for hepatitis B 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 HCV 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 ALT and 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 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 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, history of atrial fibrillation or other
             arrhythmias other than sinus tachycardia, 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 currentspinal cord compression (without intradural myeloma involvement.

          -  Patients who have a history (or current evidence) of cerebrospinal fluid multiple
             myeloma, or intra-dural 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.
      
Maximum Eligible Age:73 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Determine the safety of administering T cells expressing Anti-SLAMF7 CAR
Time Frame:2 weeks-12 months after initial dose
Safety Issue:
Description:List of adverse event frequency

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Chimeric Antigen Receptors
  • B-cell Maturation Antigen
  • Immunotherapy
  • Adoptive T Cell Therapy

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