Study of T Cells Targeting B-Cell Maturation Antigen for Previously Treated Multiple Myeloma

Condition(s) targeted: Myeloma, Plasma-Cell; Myeloma-Multiple

Intervention: Cyclophosphamide (Drug); Fludarabine (Drug); Anti-BCMA CAR T cells (Biological)

Phase: Phase 1

Status: Recruiting

Sponsored by: National Cancer Institute (NCI)

Official(s) and/or principal investigator(s):
James N Kochenderfer, M.D., Principal Investigator, Affiliation: National Cancer Institute (NCI)

Overall contact:
James N Kochenderfer, M.D., Phone: (301) 594-5340, Email: kochendj@mail.nih.gov

Background:

- T cells are white blood cells that fight several cancers. One cancer therapy involves

removing a person s 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 NIH for 5 years after the infusion. Then for 10 years they will answer health questionnaires.

Official title: A Phase I Clinical Trial of T-Cells Targeting B-Cell Maturation Antigen for Previously Treated Multiple Myeloma

Study design: Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Determine the safety of administering T cells expressing an BCMA CAR

Detailed description: 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 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

1 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 or greater than 30% bone marrow plasma cells.

- 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 ECOG performance status of 0 -2 is required.

- 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

- 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. 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/m2 daily for 3 days

and fludarabine 30 mg/m2 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. 3x106 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 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.

Minimum age: 18 Years. Maximum age: 73 Years. Gender(s): Both.

Criteria:

- INCLUSION CRITERIA:

2. 1.1. 1 Multiple Myeloma criteria

- Clear 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 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 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.

- 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

- Bone marrow plasma cells > 30% of total bone marrow cells

- Patients must have multiple myeloma that meets the criteria for one of the following

Disease categories: (1) progressive disease or (2) relapse from 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 moreof 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 equla 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 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 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 RT-PCR and be HCV RNA negative.

- Absolute neutrophil count greater than or equal to 1000/mm3 without the support of

filgrastim or other growth factors.

- Platelet count greater than or equal to 45,000/mm3 without transfusion support

- 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. 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:

- 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 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.

James N Kochenderfer, M.D., Phone: (301) 594-5340, Email: kochendj@mail.nih.gov

National Institutes of Health Clinical Center, 9000 Rockville Pike, Bethesda, Maryland 20892, United States; Recruiting
For more information at the NIH Clinical Center contact National Cancer Institute Referral Office, Phone: 888-624-1937
Referral Line NCI Experimental Transplantation and Immunology Branch, Phone: (301) 435-5942, Email: nci-transplant@mail.nih.gov

NIH Clinical Center Detailed Web Page

Related publications:

Kochenderfer JN, Rosenberg SA. Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors. Nat Rev Clin Oncol. 2013 May;10(5):267-76. doi: 10.1038/nrclinonc.2013.46. Epub 2013 Apr 2. Review.

Carpenter RO, Evbuomwan MO, Pittaluga S, Rose JJ, Raffeld M, Yang S, Gress RE, Hakim FT, Kochenderfer JN. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin Cancer Res. 2013 Apr 15;19(8):2048-60. doi: 10.1158/1078-0432.CCR-12-2422. Epub 2013 Jan 23.

Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I, Stetler-Stevenson M, Phan GQ, Hughes MS, Sherry RM, Yang JC, Kammula US, Devillier L, Carpenter R, Nathan DA, Morgan RA, Laurencot C, Rosenberg SA. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood. 2012 Mar 22;119(12):2709-20. doi: 10.1182/blood-2011-10-384388. Epub 2011 Dec 8.

Starting date: August 2014
Last updated: June 19, 2015