T Cells Expressing a Novel Fully-Human Anti-BCMA CAR for Treating Multiple Myeloma
T Cells Expressing a Novel Fully-Human Anti-BCMA CAR for Treating Multiple Myeloma
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.

 ...
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
 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 a novel anti-BCMA CAR that can specifically recognize BCMA-
 expressing target cells in vitro and eradicate BCMA-expressing tumors in mice.

 -  This CAR has an antigen-recognition domain made up of a single fully-human heavy chain
 variable region.

 -  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.

 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 greater than or equal to
 1.0 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 of 2.0 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 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 greater than or equal to 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 greater than or equal to 1000/microliters, platelet count
 greater than or equal to 55,000/ microliters, hemoglobin greater than or equal to 8g/dL

 -  ALT and 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.

 -  The patient s MM will need to be assessed for BCMA expression by flow cytometry or
 immunohistochemistry performed at the NIH. The myeloma must express BCMA. If unstained,
 paraffin-embedded 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/m2 daily for 3 days. Fludarabine will be given on the same days as
 the cyclophosphamide.

 -  After the chemotherapy ends, the patients will have two days with no treatments then
 receive an infusion of anti-BCMA- CAR-expressing T cells.

 -  The initial dose level will be 0.75x10^6 CAR+ T cells/kg of recipient bodyweight.

 -  The cell dose administered will be escalated 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 5
 years.
-  INCLUSION CRITERIA:

 Multiple Myeloma criteria:

 -  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 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 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 CAR 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 "IMiD" such as lenolidamide 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 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 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
 within the past 10 days.

 -  Hemoglobin greater than 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).

 -  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 PBMC 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 NCI gene
 therapy protocols.