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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02215967
Recruitment Status : Completed
First Posted : August 13, 2014
Results First Posted : October 8, 2019
Last Update Posted : October 8, 2019
Sponsor:
Information provided by (Responsible Party):
James Kochenderfer, M.D., National Cancer Institute (NCI)

Brief Summary:

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.

Condition or disease Intervention/treatment Phase
Myeloma, Plasma-Cell Myeloma-Multiple Drug: Cyclophosphamide Drug: Fludarabine Biological: Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 30 participants
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Clinical Trial of T-Cells Targeting B-Cell Maturation Antigen for Previously Treated Multiple Myeloma
Actual Study Start Date : August 12, 2014
Actual Primary Completion Date : April 25, 2019
Actual Study Completion Date : August 15, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma
Drug Information available for: Fludarabine

Arm Intervention/treatment
Experimental: Multiple Myeloma
Dose Escalation with 5 dose levels based on the patients actual bodyweight
Drug: Cyclophosphamide
300 mg/m^2 intravenous (IV) over 30 minutes on days -5, -4, and -3
Other Name: Cytoxan

Drug: Fludarabine
30 mg/m^2 intravenous (IV) over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3
Other Name: Fludara

Biological: Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells
0.3x10^6- 15.0x10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0




Primary Outcome Measures :
  1. Number of Participants With Dose Limiting Toxicities [ Time Frame: After the start of treatment and up to 60 days ]
    Dose limiting toxicities are defined as follows: Grade 3 toxicities possibly or probably related to either the anti-BCMA CAR T cells or the fludarabine and cyclophosphamide chemotherapy and lasting more than 7 days. Grade 4 toxicities possibly or probably related to the study interventions.

  2. Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) [ Time Frame: Date treatment consent signed to date off study, approx. 3 mos and 7 days for DL 0.3 x 10^6 CAR + T cells, 4 mos and 4 days for 1.0 x 10^6 CAR + T cells, 9 mos and 13 days for 3.0 x 10^6 CAR + T cells, and 48 mos and 12 days for 9.0 x 10^6 CAR + T cells. ]
    Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.


Secondary Outcome Measures :
  1. Number of Participants With Best Response [ Time Frame: From start of treatment up to 84 weeks ]
    Best response was assessed by the International Myeloma Working Group response criteria. Partial Remission (PR) is 50% or greater reduction of serum M-protein and 90% or greater reduction in 24-h urinary M-protein. Progressive Disease (PD) is increases of greater or equal to 25% from the lowest post-treatment (nadir) value in serum M-component or urine component or percentage of bone marrow plasma cells. Definite development of new bone lesions or new plasmacytoma. Very Good Partial Remission (VGPR) is serum and urine M-protein detectable by immunofixation but not on electrophoresis. Stringent Complete Remission (sCR) is normal free light chain ratio and absence of clonal cells in bone marrow by immunohistochemistry. Complete Remission is negative immunofixation on the serum and urine. Stable Disease (SD) is not meeting criteria for CR, VGPR, PR or PD.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 73 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02215967


Locations
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United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: James N Kochenderfer, M.D. National Cancer Institute (NCI)
  Study Documents (Full-Text)

Documents provided by James Kochenderfer, M.D., National Cancer Institute (NCI):
Informed Consent Form  [PDF] October 16, 2017


Additional Information:
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: James Kochenderfer, M.D., Principal Investigator, National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02215967    
Other Study ID Numbers: 140168
14-C-0168
First Posted: August 13, 2014    Key Record Dates
Results First Posted: October 8, 2019
Last Update Posted: October 8, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by James Kochenderfer, M.D., National Cancer Institute (NCI):
Immunotherapy
Anti-BCMA-CAR
Gene Therapy
Adoptive T Cell Therapy
Plasma Cell Malignancy
Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists