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

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ClinicalTrials.gov Identifier: NCT03602612
Recruitment Status : Recruiting
First Posted : July 27, 2018
Last Update Posted : March 11, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief 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.


Condition or disease Intervention/treatment Phase
Myeloma-Multiple Myeloma, Plasma-Cell Drug: Cyclophosphamide Drug: Fludarabine Biological: Anti-BCMA CAR T cells Phase 1

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 42 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Clinical Trial of T Cells Expressing a Novel Fully-human Anti-BCMA CAR for Treating Multiple Myeloma
Actual Study Start Date : September 14, 2018
Estimated Primary Completion Date : January 1, 2023
Estimated Study Completion Date : January 1, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma

Arm Intervention/treatment
Experimental: 1/Arm 1
Patients will receive escalating doses (up to 5 planned) of CAR+ T cells infused on day 0 + Cyclophosphamide: 300 mg/m2 IV infusion over 30 minutes on days -5, -4 and -3 + Fludarabine: 30 mg /m^2 IV infusion over 30 minutes administered immediately following the cyclophosphamide on days -5, -4, and -3
Drug: Cyclophosphamide
300 mg/m^2 IV over 30 minutes on days -5, -4, and -3

Drug: Fludarabine
30 mg/m^2 IV infusion over 30 minutes administered immediately following the cyclophosphamide on day -5, -4, -3

Biological: Anti-BCMA CAR T cells
0.75x10^6 - 12.0X10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0

Experimental: 2/ Arm 2
MTD dose of CAR T Cells + Cyclophosphamide: 300 mg/m2 IV infusion over 30 minutes on days -5, -4 and -3 + Fludarabine: 30 mg/m^2 IV infusion over 30 minutes administered immediately following the cyclophosphamide on days -5, -4, and -3
Drug: Cyclophosphamide
300 mg/m^2 IV over 30 minutes on days -5, -4, and -3

Drug: Fludarabine
30 mg/m^2 IV infusion over 30 minutes administered immediately following the cyclophosphamide on day -5, -4, -3

Biological: Anti-BCMA CAR T cells
0.75x10^6 - 12.0X10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0




Primary Outcome Measures :
  1. Determine the safety of administering T cells expressing an BCMA CAR [ Time Frame: 2 weeks-12 months after initial dose ]
    List of adverse event frequency



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:

Multiple Myeloma criteria:

  • BCMA expression must be detected on malignant plasma cells from either bone marrow or a plasmacytoma by flow cytometry or immunohistochemistry. 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 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 21 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
    • Bone marrow plasma cells make up 30% or more of total bone marrow 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 without transfusion support within the past 10 days.
  • 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 1.4 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 currently taking anticoagulants
  • 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, history of atrial fibrillation or other arrhythmias other than sinus tachycardia, 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 CNS metastases or 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.
  • 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.

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): NCT03602612


Contacts
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Contact: Brenna Hansen (240) 760-6168 hansenb3@mail.nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: James N Kochenderfer, M.D. National Cancer Institute (NCI)

Additional Information:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03602612     History of Changes
Other Study ID Numbers: 180125
18-C-0125
First Posted: July 27, 2018    Key Record Dates
Last Update Posted: March 11, 2019
Last Verified: March 7, 2019

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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 National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
B-cell Maturation Antigen
Immunotherapy
Chimeric Antigen Receptor
Adoptive T Cell Therapy

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 phosphate
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
Antimetabolites, Antineoplastic
Antimetabolites