Description:
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....
Title
- Brief Title: T-cells Expressing an Anti-SLAMF7 CAR for Treating Multiple Myeloma
- Official Title: A Phase I Clinical Trial of T-cells Expressing an Anti-SLAMF7 CAR for Treating Multiple Myeloma
Clinical Trial IDs
- ORG STUDY ID:
190102
- SECONDARY ID:
19-C-0102
- NCT ID:
NCT03958656
Conditions
- Myeloma-Multiple
- Myeloma, Plasma-Cell
Interventions
| Drug | Synonyms | Arms |
|---|
| Cyclophosphamide | | 1/Conditioning chemotherapy plus CAR T-cells dose escalation |
| Fludarabine | | 1/Conditioning chemotherapy plus CAR T-cells dose escalation |
| Rimiducid | | 1/Conditioning chemotherapy plus CAR T-cells dose escalation |
| Anti-SLAMF7 CAR T cells | | 1/Conditioning chemotherapy plus CAR T-cells dose escalation |
Purpose
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....
Detailed Description
Background:
- Multiple myeloma (MM) is a nearly always incurable malignancy of plasma cells.
- T cells can be genetically modified to express chimeric antigen receptors (CARs) that
target malignancy-associated antigens.
- SLAMF7 is highly and uniformly expressed on MM cells but is absent on normal tissues
except for some leukocytes, including a subset of CD8+ T cells, natural killer (NK)
cells, B cells, plasma cells and monocytes.
- We have constructed a novel anti-SLAMF7 CAR that can specifically recognize SLAMF7-
expressing target cells and eradicate SLAMF7-expressing tumors in mice.
- This protocol will test genetic modification of autologous T cells with genes encoding
an inducible caspase 9 (IC9) cell-suicide system plus the anti-SLAMF7 CAR.
- Administration of the dimerizer drug Rimiducid (AP1903) is necessary to activate the IC9
suicide gene and eliminate CAR T cells.
- In this protocol, the suicide gene system will be used to eliminate CAR-expressing T
cells in case of severe toxicities caused by the CAR T cells.
- Possible toxicities include cytokine-associated toxicities such as hypotension, and
neurological toxicities. Elimination of NK cells and normal plasma cells could make
patients more susceptible to infections. Unknown toxicities are also possible.
Objectives:
Primary
- Determine the safety, feasibility of administering T cells expressing an anti-SLAMF7 CAR
plus IC9 cell-suicide system 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 >=0.6 g/dL or a urine
M-protein >=200 mg/24 hours or an involved serum free light chain (FLC) level >=10 mg/dL
(provided FLC ratio is abnormal) or a biopsy-proven plasmacytoma of 1.5 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 drug (IMiD) such as
lenalidomide, and a proteasome inhibitor
- Patients must have a creatinine level of less than or eual to 1.5 mg/dL
- Patients must have a cardiac ejection fraction >= 50%.
- An 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 >= 1000/microL, platelet count >= 55,000/microL, hemoglobin >=
8g/dL
- ALT and AST less thanor 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 and
initiation of protocol treatment. Systemic therapy includes corticosteroids at a dose
equivalent to more than 5 mg of prednisone.
- Bone marrow plasma cells must make up less than or equal to 50% of total bone marrow
cells less than or equal to 24 days prior to the start of protocol treatment.
- The patient s MM will need to be assessed for SLAMF7 expression by flow cytometry or
immunohistochemistry performed at the NIH. The myeloma must express SLAMF7. If
unstained, paraffin-embedded bone marrow or plasmacytoma sections are available from
prior biopsies, these can be used to determine SLAMF7 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 SLAMF7 expression. The sample for
SLAMF7 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, and T cells will be modified to express the
IC9-anti-SLAMF7 CAR construct.
- The chemotherapy conditioning regimen is cyclophosphamide 300 mg/m^2 daily for 3 days
and fludarabine 30 mg/m^2 daily for 3 days. The intent of chemotherapy is to enhance CAR
T-cell activity.
- After the chemotherapy ends, the patients will have two days with no treatments and then
receive an infusion of CAR T cells.
- The initial dose level will be 0.66x10^6 Anti-SLAMF7-CAR + T cells/kg of recipient
bodyweight.
- The cell dose administered will be escalated for up to 4 doses 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 3
years after infusion.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| 1/Conditioning chemotherapy plus CAR T-cells dose escalation | Experimental | Patients will receive escalating doses (up to 4 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/m^22 IV infusion over 30 minutes administered immediately following the cyclophosphamide on days -5, -4, and -3 | - Cyclophosphamide
- Fludarabine
- Rimiducid
- Anti-SLAMF7 CAR T cells
|
| 2/Conditioning chemotherapy plus CAR T-cells expansion phase | Experimental | 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 | - Cyclophosphamide
- Fludarabine
- Rimiducid
- Anti-SLAMF7 CAR T cells
|
Eligibility 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 24 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 lenalidomide 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 0.6 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, 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.
| Maximum Eligible Age: | 73 Years |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Determine the safety of administering T cells expressing Anti-SLAMF7 CAR |
| Time Frame: | 2 weeks-12 months after initial dose |
| Safety Issue: | |
| Description: | List of adverse event frequency |
Details
| Phase: | Phase 1 |
| Primary Purpose: | Interventional |
| Overall Status: | Completed |
| Lead Sponsor: | National Cancer Institute (NCI) |
Trial Keywords
- Chimeric Antigen Receptors
- B-cell Maturation Antigen
- Immunotherapy
- Adoptive T Cell Therapy
Last Updated
April 8, 2021
