Study of T Cells Targeting B-Cell Maturation Antigen for Previously Treated Multiple Myeloma
Study of T Cells Targeting B-Cell Maturation Antigen for Previously Treated Multiple Myeloma
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.
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.
-  INCLUSION CRITERIA:

 2.1.1.1 Multiple Myeloma criteria

 -  Clear B-cell maturation antigen (BCMA) expression must be detected on greater than 50%
 of malignant plasma cells from either bone marrow or a plasmacytoma by flow cytometry
 or immunohistochemistry. These assays must be performed at the National Institutes of
 Health. It is not required that the specimen used for BCMA determination comes from a
 sample that was obtained after the patient's most recent treatment. BCMA expression
 will need to be documented on the majority of malignant plasma cells at some time
 after the original anti-BCMA chimeric antigen receptor (CAR) T-cell infusion in all
 patients undergoing a second anti-BCMA CAR T-cell infusion. If paraffin embedded
 unstained samples of bone marrow involved with multiple myeloma (MM) or a plasmacytoma
 are available, these can be shipped to the National Institutes of Health (NIH) for
 BCMA staining, otherwise new biopsies will need to be performed for determination of
 BCMA expression.

 -  Bone marrow plasma cells must make up 30% or less of total bone marrow cells based on
 a bone marrow biopsy performed within 30 days of the start of protocol treatment.

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

 -  Patients must have measurable MM as defined by at least one of the criteria below.

 a. One or more of these abnormalities defines measurable disease:

 -  Serum M-protein greater or equal to 1 g/dl (10 g/l).

 -  Urine M-protein greater or equal to 200 mg/24 h.

 -  Serum free light chain (FLC) assay: involved FLC level greater or equal to10
 mg/dl (100 mg/l) provided serum FLC ratio is abnormal.

 -  A biopsy-proven plasmacytoma

 -  Patients must have multiple myeloma that meets the criteria for one of the following
 Disease categories: (1) progressive disease or (2) relapse from Complete Remission
 (CR) as described in the International Uniform Response Criteria for Multiple Myeloma
 and as listed below.

 1. Progressive Disease (which requires 1 or more of the following)(A):

 Increase of greater than or equal to 25% from the lowest response value (nadir)
 in any one or more of these parameters:

 1. Serum M-component (the absolute increase must be greater than or equal to
 0.5 g/dL) (B) and/or

 2. Urine M-component and/or (the absolute increase must be greater than or
 equal to 200 mg/24 h)

 3. Only in patients without measurable serum and urine M-protein levels; the
 difference between involved and uninvolved FLC levels. The absolute increase
 must be > 10 mg/dL.

 4. Bone marrow plasma cell percentage; the absolute percentage must be greater
 than or equal to 10%

 -  Definite development of new bone lesions or soft tissue plasmacytomas or definite
 increase in the size of existing bone lesions or soft tissue plasmacytomas (defined as
 50% or greater increase in the sum of the products of the cross-diameters of target
 lesions)

 -  Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL or 2.65 mmol/L)
 that can be attributed solely to the plasma cell proliferative disorder

 2. Relapse from complete remission (A)

 -  Defined as one or more of the following; must be attributable to myeloma:

 1. Reappearance of serum or urine M-protein by immunofixation or electrophoresis

 2. Development of greater than or equal to 5% plasma cells in the bone marrow

 3. Appearance of any other sign of progression (i.e., new plasmacytoma, lytic bone
 lesion, or hypercalcemia)

 (A)All relapse and progression categories require two consecutive assessments made at any
 time before classification as relapse or disease progression and/or the institution of any
 new therapy.

 (B)For progressive disease, serum M-component increases of greater than or equal to 1 gm/dL
 are sufficient to define progression if starting M-component is greater than or equal to 5
 g/dL.

 2.1.1.2 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 receiving the preparative regimen.

 -  Women of child bearing potential must have a negative pregnancy test because of the
 potentially dangerous effects of the preparative chemotherapy on the fetus.

 -  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.)

 -  Seronegative for hepatitis B antigen, positive hepatitis B tests can be further
 evaluated by confirmatory tests, and if confirmatory tests are negative, the patient
 can be enrolled.

 -  Seronegative for hepatitis C antibody unless antigen negative. If hepatitis C antibody
 test is positive, then patients must be tested for the presence of antigen by Reverse
 transcription polymerase chain reaction (RT-PCR) and be hepatitis C virus (HCV)
 ribonucleic acid (RNA) negative.

 -  Absolute neutrophil count greater than or equal to 1000/mm^3 without the support of
 filgrastim or other growth factors.

 -  Platelet count greater than or equal to 45,000/mm^3 without transfusion support

 -  Hemoglobin greater than 8.0 g/dl.

 -  Less than 5% plasma cells in the peripheral blood leukocytes

 -  Serum alanine transaminase (ALT) and aspartate transaminase (AST) less or equal to 2.5
 times the upper limit of the institutional normal.

 -  Serum creatinine less than or equal to 1.3 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).

 -  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 within 6 weeks of the start of the treatment protocol.

 -  Patients should not take corticosteroids including prednisone, dexamethasone or any
 other corticosteroid for any purpose at doses higher than 5 mg/day of prednisone or
 equivalent dose of another corticosteroid 2 weeks before apheresis and within 2 weeks
 prior to CAR T-cell infusion, and at any time after the CAR T cell infusion.

 2.1.2 EXCLUSION CRITTERIA:

 -  Patients on any anticoagulants except aspirin are not eligible.

 -  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.

 -  Active systemic infections (defined as infections causing fevers or requiring
 antimicrobial treatment), active coagulation disorders or other major uncontrolled
 medical illnesses of the cardiovascular, respiratory, endocrine, renal,
 gastrointestinal, genitourinary 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 are not allowed within 2 weeks prior to
 either the required leukapheresis or the initiation of the conditioning chemotherapy
 regimen.

 -  History of severe immediate hypersensitivity reaction to any of the agents used in
 this study.

 -  History of allogeneic stem cell transplantation

 -  Patients with central nervous system (CNS) metastases or symptomatic CNS involvement
 (including cranial neuropathies or mass lesions and spinal cord compression).

 -  Patients with active autoimmune skin diseases such as psoriasis or other active
 autoimmune diseases such as rheumatoid arthritis.