T Cells Expressing a Novel Fully-Human Anti-BCMA CAR for Treating Multiple Myeloma
Condition: Myeloma-Multiple; Myeloma, Plasma-Cell
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Cyclophosphamide; Fludarabine; Anti-B Cell Maturation Antigen (BCMA) chimeric antigen receptors (CARs) 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) infusion over 30 minutes administered immediately following the cyclophosphamide on day -5, -4, -3; 0.75x10^6 - 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: 35.0
Sex: All
Minimum age: 18 Years
Maximum age: 73 Years
Healthy volunteers: No
Keywords: B-cell Maturation Antigen; Immunotherapy; Chimeric Antigen Receptors; Adoptive T Cell Therapy

Summary:

      Background:

      Multiple myeloma is a cancer of the blood plasma cells. It usually becomes resistant to
      standard treatments. Researchers have developed a procedure called gene therapy. It uses a
      person's own T cells, which are part of the immune system. The cells are changed in a lab and
      then returned to the person. Researchers hope the changed T cells will be better at
      recognizing and killing tumor cells.

      Objective:

      To test the safety of giving changed T cells to people with multiple myeloma.

      Eligibility:

      Adults ages 18-73 who have been diagnosed with multiple myeloma that has not been controlled
      with standard therapies.

      Design:

      Participants will be screened with:

      Medical history

      Physical exam

      Blood tests

      Heart function tests

      Bone marrow sample taken by needle in a hip bone.

      Scan of the chest, abdomen, and pelvis. They may have a brain scan.

      Pregnancy test

      Participants will have apheresis. Blood will be removed through an arm vein. The blood will
      be separated, and T cells removed. The rest of the blood will be returned through a vein in
      the other arm.

      Participants will have a central line placed in a large vein in the arm or chest.

      Participants will get 2 chemotherapy drugs by the central line over 3 days.

      Two days later, participants will get the changed T cells by the central line. They will stay
      in the hospital at least 9 days.

      Participants must stay near the hospital for 2 weeks.

      Participants will have 8 follow-up visits over the next year for blood and urine tests. They
      may have scans.

      Participants blood will be collected regularly over the next several years.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        Multiple Myeloma (MM) criteria:

          -  B Cell Maturation Antigen (BCMA) expression must be detected on malignant plasma cells
             from either bone marrow or a plasmacytoma by flow cytometry or immunohistochemistry.
             If patient has plasmacytomas, one plasmacytoma must be biopsied to demonstrate BCMA
             expression. A specific quantitative level of BCMA expression for eligibility is not
             specified, but patients with multiple myeloma cells that are negative for BCMA by flow
             cytometry and immunohistochemistry on either bone marrow biopsy or plasmacytoma biopsy
             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 BCMA determination comes
             from a sample that was obtained after the patients 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 BCMA staining, otherwise new biopsies
             will need to be performed for determination of BCMA expression.

          -  BCMA 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 anti-BCMA chimeric
             antigen receptors (CARs) T-cell infusion in all patients undergoing a second anti-BCMA
             CAR T-cell infusion.

          -  Bone marrow plasma cells must make up less than 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

          -  Must have prior exposure to an immunomodulatory imide drugs ("IMiD") such as
             lenalidamide and a proteasome inhibitor

          -  Patients must have measurable MM as defined by at least one of the criteria below.

               -  One or more of these abnormalities defines measurable multiple myeloma:

               -  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 2.0 cm in largest dimension

               -  Bone marrow core biopsy with 30% or more plasma cells

        Other inclusion criteria:

          -  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 genders 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 acid (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
             within the past 10 days.

          -  Hemoglobin greater than 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 Gilberts
             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).

          -  Because this protocol requires collection of autologous blood cells by leukapheresis
             in order to prepare anti-BCMA-CAR 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 2 weeks 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 (PBMCs) that have not been genetically engineered must be available.

        EXCLUSION CRITERIA:

          -  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
             child-bearing 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 medical
             illnesses of the cardiovascular, respiratory, endocrine, renal, gastrointestinal,
             genitourinary, neurologic, or immune system, history of myocardial infarction, active
             cardiac arrhythmias including active atrial fibrillation history of any arrhythmias
             other than sinus tachycardia, or atrial fibrillation, currently taking any
             anti-arrythmic or congestive heart failure medications, 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 2 weeks prior to either the required leukapheresis or within 2 weeks
             prior to CAR T-cell infusion (and at any time after the CAR T cell infusion).

          -  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 intra-dural central nervous system masse

          -  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.

          -  Patient must not have received genetically modified cells except on prior National
             Cancer Institute (NCI) gene therapy protocols.