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T-cells Expressing an Anti-SLAMF7 CAR for Treating Multiple Myeloma

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ClinicalTrials.gov Identifier: NCT03958656
Recruitment Status : Recruiting
First Posted : May 22, 2019
Last Update Posted : June 27, 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 blood cancer that is usually incurable. T cells are part of the immune system. Researchers think changing a person s T cells to recognize their cancer could help the person s body kill tumor cells. This is a new approach that uses a patient s own cells to target multiple myeloma.

Objective:

To see if giving anti-SLAM7 CAR T cells with a stop switch to people with multiple myeloma is safe andto see if adding a gene to stop T-cell activity can limit toxicity of this therapy.

Eligibility:

People ages 18-73 with multiple myeloma for which prior standard treatment has not worked

Design:

Participants will be screened with:

  • Medical history
  • Physical exam
  • Blood, urine, and heart tests
  • Bone marrow samples: A needle inserted into the participant s bone will remove marrow.
  • Imaging scans: Participants will lie in a machine that takes pictures of the body.

Participants will have apheresis. They will receive a catheter or central line: A plastic tube will be inserted into a chest or arm vein. Blood will be removed and the T cells separated. The rest of the blood will be returned to the participant. The T cells will be manipulated in the lab.

Participants will get chemotherapy through the central line for 3 days.

Participants will receive the manipulated T cells through the central line. They will stay in the hospital at least 9 days.

Participants will have follow-up visits 2 weeks then 1, 2, 3, 4, 6, 9, and 12 months after the infusion. They will then have visits every 6 months for 3 years. Then they will be contacted once per year for 15 years. All visits will include blood tests, and 3 visits will include bone marrow biopsies....


Condition or disease Intervention/treatment Phase
Myeloma-Multiple Myeloma, Plasma-Cell Drug: Cyclophosphamide Drug: Fludarabine Drug: Rimiducid Biological: Anti-SLAMF7 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 an Anti-SLAMF7 CAR for Treating Multiple Myeloma
Actual Study Start Date : June 13, 2019
Estimated Primary Completion Date : May 1, 2023
Estimated Study Completion Date : May 1, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma

Arm Intervention/treatment
Experimental: 1/Conditioning chemotherapy plus CAR T-cells dose escalation
Patients will receive escalating doses (up to 5 planned) of Anti-SLAMF7-CAR+ T cells infused on day 0 + Cyclophosphamide: 300 mg/m^2 IV infusion over 30 minutes on days -5, -4 and -3 + Fludarabine: 30 mg
Drug: Cyclophosphamide
300 mg/m^2 IV over 30 minutes on days -5, -4, and -3

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

Drug: Rimiducid
0.4 mg/kg of Rimiducid IV over 2 hours. (A maximum of 2 doses separated by at least 48 hours) Note: Rimiducid may be administered as needed based on the patient condition at the discretion of the Principal Investigator.

Biological: Anti-SLAMF7 CAR T cells
0.3x10^6- 12.0x10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0

Experimental: 2/Conditioning chemotherapy plus CAR T-cells expansion phase
MTD dose of Anti-SLAMF7- CAR T Cells + Cyclophosphamide: 300 mg/m^2 IV infusion over 30 minutes on days -5, -4 and -3 + Fludarabine: 30mg/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 over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3

Drug: Rimiducid
0.4 mg/kg of Rimiducid IV over 2 hours. (A maximum of 2 doses separated by at least 48 hours) Note: Rimiducid may be administered as needed based on the patient condition at the discretion of the Principal Investigator.

Biological: Anti-SLAMF7 CAR T cells
0.3x10^6- 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 Anti-SLAMF7 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:
  • SLAMF7 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 SLAMF7 expression for eligibility is not specified, but patients with multiple myeloma cells that are negative for SLAMF7 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 SLAMF7 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 SLAMF7 staining, otherwise new biopsies will need to be performed for determination of SLAMF7 expression.
  • SLAMF7 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 CAR-SLAMF7 T-cell infusion in all patients undergoing a second CAR-SLAMF7 T-cell infusion on this clinical trial .
  • Bone marrow plasma cells must make up less than or equal to 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 immunomodulatory drug (IMiD) such as lenolidamide and a proteasome inhibitor
  • Patients must have measurable MM as defined by at least one of the criteria below.

    • 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 1.5 cm in largest dimension
    • Bone marrow core biopsy with 30% or more plasma cells

INCLUSION CRITERIA - OTHER:

  • 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 sexes 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 in the past 14 days.
  • Hemoglobin greater than or equal to 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 or cytopenias).
  • Because this protocol requires collection of autologous blood cells by leukapheresis in order to prepare CAR-SLAMF7 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 14 days 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.
  • Patients receiving prior gene therapy outside of NIH will not be eligible. Patients who previously received CAR T-cell therapy at the NCI will be potentially eligible.

EXCLUSION CRITERIA:

  • Patients who are receiving any other investigational agents.
  • 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 childbearing 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 illnesses of the cardiovascular, respiratory, endocrine, renal, gastrointestinal, genitourinary, neurologic, psychiatric, 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 14 days prior to either the required leukapheresis or within 14 days prior to CAR Tcell infusion (and at any time after the CAR T cell infusion unless approved by the Principal Investigator or an Associate Investigator).
  • 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 currentspinal 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 masses.
  • 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.

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): NCT03958656


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: NCT03958656     History of Changes
Other Study ID Numbers: 190102
19-C-0102
First Posted: May 22, 2019    Key Record Dates
Last Update Posted: June 27, 2019
Last Verified: June 11, 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) ):
Chimeric Antigen Receptors
B-cell Maturation Antigen
Immunotherapy
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
Fludarabine phosphate
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