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

Last updated: February 6, 2025
Sponsor: National Cancer Institute (NCI)
Overall Status: Active - Not Recruiting

Phase

1

Condition

Leukemia

Lymphoproliferative Disorders

Bone Neoplasm

Treatment

Cyclophosphamide

Anti-B Cell Maturation Antigen (BCMA) chimeric antigen receptors (CARs) T cells

Fludarabine

Clinical Study ID

NCT03602612
180125
18-C-0125
  • Ages 18-73
  • All Genders

Study 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

  • INCLUSION CRITERIA:

Multiple Myeloma (MM) criteria:

  • B Cell Maturation Antigen (BCMA) expression must be detected on malignant plasmacells from either bone marrow or a plasmacytoma by flow cytometry orimmunohistochemistry. If patient has plasmacytomas, one plasmacytoma must bebiopsied to demonstrate BCMA expression. A specific quantitative level of BCMAexpression for eligibility is not specified, but patients with multiple myelomacells that are negative for BCMA by flow cytometry and immunohistochemistry oneither bone marrow biopsy or plasmacytoma biopsy will not be enrolled. These assaysmust be performed at the National Institutes of Health (NIH). It is not requiredthat the specimen used for BCMA determination comes from a sample that was obtainedafter the patients most recent treatment. If paraffin embedded unstained samples ofbone marrow involved with MM or a plasmacytoma are available, these can be shippedto the NIH for BCMA staining, otherwise new biopsies will need to be performed fordetermination of BCMA expression.

  • BCMA expression will need to be documented on the majority of malignant plasma cellsby flow cytometry at the NIH at some time after the original anti-BCMA chimericantigen receptors (CARs) T-cell infusion in all patients undergoing a secondanti-BCMA CAR T-cell infusion.

  • Bone marrow plasma cells must make up less than 50% of total bone marrow cells basedon 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 formultiple myeloma

  • Must have prior exposure to an immunomodulatory imide drugs ("IMiD") such aslenalidamide 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 10mg/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 ofenrollment on this study and for four months after last day of receiving protocoltreatment.

  • Seronegative for human immunodeficiency virus (HIV) antibody. (The experimentaltreatment being evaluated in this protocol depends on an intact immune system.Patients who are HIV seropositive can have decreased immune-competence and thus areless responsive to the experimental treatment and more susceptible to itstoxicities.)

  • A patient with a negative blood polymerase chain reaction (PCR) test for hepatitis Bdeoxyribonucleic acid (DNA) test can be enrolled. If hepatitis B DNA (PCR) testingis not available, patients with a negative hepatitis B surface antigen and negativehepatitis B core antibody can be enrolled.

  • Patients must be tested for the presence of Hepatitis C antigen by PCR and behepatitis 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 whoare Hepatitis C antibody-negative can be enrolled.

  • Absolute neutrophil count greater than or equal to 1000/mm(3) without the support offilgrastim or other growth factors within the previous 10 days.

  • Platelet count greater than or equal to 55,000/mm(3) without transfusion supportwithin 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 orequal 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 GilbertsSyndrome 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 thepatient starts the cyclophosphamide and fludarabine conditioning regimen, andpatients' toxicities must have recovered to a grade 1 or less (except for toxicitiessuch as alopecia or vitiligo).

  • Because this protocol requires collection of autologous blood cells by leukapheresisin order to prepare anti-BCMA-CAR T cells, systemic anti-myeloma therapy includingsystemic corticosteroid steroid therapy of greater than 5 mg/day of prednisone orequivalent dose of another corticosteroid are not allowed within 2 weeks prior tothe required leukapheresis.

  • Normal cardiac ejection fraction (greater than or equal to 50% by echocardiography)and no evidence of hemodynamically significant pericardial effusion as determined byan echocardiogram.

  • For patients with past participation in gene-therapy, cryopreserved peripheral bloodmononuclear cells (PBMCs) that have not been genetically engineered must beavailable.

Exclusion

EXCLUSION CRITERIA:

  • Patients on any anticoagulants except aspirin.

  • Patients that require urgent therapy due to tumor mass effects or spinal cordcompression.

  • Patients that have active hemolytic anemia.

  • Patients with second malignancies in addition to multiple myeloma are not eligibleif the second malignancy has required treatment within the past 3 years or is not incomplete remission. There are two exceptions to this criterion: successfully treatednon-metastatic basal cell or squamous cell skin carcinoma.

  • Women of child-bearing potential who are pregnant or breastfeeding because of thepotentially dangerous effects of the preparative chemotherapy on the fetus orinfant. Women of child-bearing potential cannot have a positive pregnancy test.Women of child-bearing potential are defined as all women except women who arepost-menopausal or who have had a hysterectomy. Postmenopausal will be defined aswomen 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 uncontrolledmedical illnesses of the cardiovascular, respiratory, endocrine, renal,gastrointestinal, genitourinary, neurologic, or immune system, history of myocardialinfarction, active cardiac arrhythmias including active atrial fibrillation historyof any arrhythmias other than sinus tachycardia, or atrial fibrillation, currentlytaking any anti-arrythmic or congestive heart failure medications, activeobstructive or restrictive pulmonary disease.

  • Any form of primary immunodeficiency (such as Severe Combined ImmunodeficiencyDisease).

  • Systemic corticosteroid steroid therapy of greater than 5 mg/day of prednisone orequivalent dose of another corticosteroid (prednisone, dexamethasone, etc.) is notallowed within 2 weeks prior to either the required leukapheresis or within 2 weeksprior 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 inthis study.

  • Patient unwilling to undergo intensive care unit treatment including mechanicalventilation, cardiopulmonary resuscitation, vasoactive drugs, and hemodialysis.

  • History of allogeneic stem cell transplantation

  • Patients with current spinal cord compression (without intradural myelomainvolvement).

  • Patients who have a history (or current evidence) of cerebrospinal fluid multiplemyeloma, or intra-dural central nervous system masse

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

  • Patients must not have required supplemental oxygen within the past month unless itwas for a resolved infection.

  • Patient must not have received genetically modified cells except on prior NationalCancer Institute (NCI) gene therapy protocols.

Study Design

Total Participants: 35
Treatment Group(s): 3
Primary Treatment: Cyclophosphamide
Phase: 1
Study Start date:
September 14, 2018
Estimated Completion Date:
April 21, 2026

Study 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 B-lymphocyte antigen CD19 (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 immunomodulatory imide drugs (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 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/microliters, platelet count greater than or equal to 55,000/ microliters, hemoglobin greater than or equal to 8g/dL

  • Alanine aminotransferase (ALT) and aspartate aminotransferase (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 patients MM will need to be assessed for BCMA expression by flow cytometry or immunohistochemistry performed at the National Institutes of Health (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/m^2 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.

Connect with a study center

  • National Institutes of Health Clinical Center

    Bethesda, Maryland 20892
    United States

    Site Not Available

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