Neoplasms

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Multiple Myeloma

Neoplasms, Plasma Cell

Neoplasms by Histologic Type

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Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

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All Drugs and Chemicals

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Immunomodulating Agents

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Patients will receive escalating doses (up to 4 planned) of Anti-Signaling lymphocytic activation molecule F7 (SLAMF7)-CAR+ T cells infused on day 0 + Cyclophosphamide: 300 mg/m\^2 intravenous (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

Maximum tolerated dose (MTD) dose of Anti-Anti-Signaling lymphocytic activation molecule F7 (SLAMF7)- CAR T Cells + Cyclophosphamide: 300 mg/m\^2 intravenous (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

300 mg/m\^2 intravenous (IV) over 30 minutes on days -5, -4, and -3

30 mg/m\^2 intravenous (IV) over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3

0.4 mg/kg of Rimiducid intravenous (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.

Rimiducid

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

Anti-Signaling lymphocytic activation molecule F7 (SLAMF7) chimeric antigen receptor (CAR) T cells

James N Kochenderfer, M.D.

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-Signaling lymphocytic activation molecule F7 (SLAM7) chimeric antigen receptor (CAR) T cells with a stop switch to people with multiple myeloma is safe and to 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....

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.
* Signaling lymphocytic activation molecule F7 (SLAM7) is highly and uniformly expressed on MM cells but is absent on normal tissues except for some leukocytes, including a subset of cluster of differentiation 8 (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 inducible caspase 9 (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 equal to 1.5 mg/dL
* Patients must have a cardiac ejection fraction \>= 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 \>= 1000/microL, platelet count \>= 55,000/microL, hemoglobin \>= 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 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 National Institutes of Health (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.

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

A Phase I Clinical Trial of T-cells Expressing an Anti-SLAMF7 CAR for Treating Multiple Myeloma

Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). 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.

Response was assessed by the International Uniform Response Criteria for Multiple myeloma 2016 updated version. Complete Remission (CR) is negative immunofixation on the serum and urine, and disappearance of any soft tissue plasmacytomas. Very Good Partial Remission (VGPR) is serum and urine M-protein detectable by immunofixation but not on electrophoresis, or 90% or greater reduction in serum M-protein plus urine M-protein level \<100mg per 24 h. Partial Remission (PR) is 50% or greater reduction of serum M-protein and 90% or greater reduction in 24-h urinary M-protein (or to less than 200mg per 24 h). Progressive Disease (PD) is serum M-component (minimum absolute increase of 0.5g/dL), or urine M-component (minimum absolute increase of 200mg/24h). Stable Disease (SD) is not meeting criteria for CR, VGPR, PR or progressive disease.

Adverse Events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Grade1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening or disabling, and Grade 5 is fatal.

National Cancer Institute (NCI)

Principal Investigator

0.66x10\^6 Anti-Signaling lymphocytic activation molecule F7 (SLAMF7) - Chimeric antigen receptor (CAR) + T cells per kg of recipient bodyweight

LEVEL 1 - 0.66x10^6 Per Kilogram (kg)

2.0x10\^6 Anti-Signaling lymphocytic activation molecule F7 (SLAMF7) - Chimeric antigen receptor (CAR) + T cells per kg of recipient bodyweight

LEVEL 2 - 2.0x10^6 Per kg

6.0x10\^6 Anti-Signaling lymphocytic activation molecule F7 (SLAMF7) - Chimeric antigen receptor (CAR) + T cells per kg of recipient bodyweight

LEVEL 3 - 6.0x10^6 Per kg

12.0x10\^6 Chimeric antigen receptor (CAR) + T cells per kg of recipient bodyweight

LEVEL 4 - 12.0x10^6 Per kg

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Participant 1

Participant 2

Participant 3

Participant 4

Participant 5

Participant 6

Participant 7

Participant 8

Participant 9

Participant 10

Number of Prior Lines of Therapy

3/13 participants not treated in Level 2 (n=1) and Level 5 (n=2) collected baseline data is reported in the table.

Dr. James N. Kochendefer

< Grade 2

Grade 2

Grade 3

Grade 4

Grade 5

3/13 participants enrolled on Level 2 (n=1) and Level 3 (n=2) were not treated,

Number of Participants That Had Any Grade ≤2, and 3, 4 and 5 Adverse Events Following Administration of T Cells Expressing Anti- Signaling Lymphocytic Activation Molecule F7 (SLAMF7) Chimeric Antigen Receptor (CAR)

Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)

Partial Remission at 5 Weeks

Stable Disease at 2 Weeks

Progressive Disease

3/13 participants enrolled on Level 2 (n=1) and Level 3 (n=2) were not treated. No weeks are necessary for PD.

Number of Participants With a Response

Overall Study

Lymphoma

Hodgkin Disease

Lymphatic Diseases

Lymphosarcoma

Hodgkin Lymphoma

Each patient will receive one infusion of CAR modified T cells.

Three dose levels will be evaluated based on safety data from our current study of CD30 CAR T cells. Cohorts of three to six patients will be enrolled at each dose level. Each patient will receive one infusion of CAR modified T cells according to the following dosing schedule:

Dose Level One: 2x10\^7 cells/m2. Dose Level Two: 1x10\^8 cells/m2. Dose Level Three: 2x10\^8 cells/m2.

CAR T Cells

Carlos A Ramos, MD

Vicky Torrano, RN

The subject has a type of lymph gland cancer called Lymphoma.

The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancer. This research study combines two different ways of fighting disease: antibodies and T cells. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including tumor cells or cells that are infected with germs. Both antibodies and T cells have been used to treat patients with cancers; they both have shown promise, but have not been strong enough to cure most patients. Investigators hope that both will work better together.

Investigators have found from previous research that they can put a new gene into T cells that will make them recognize cancer cells and kill them. They now want to test whether these genetically modified T cells given after chemotherapy will be more effective at killing cancer cells.

The gene that will be put into the T cells makes an antibody called anti-CD30. This antibody sticks to lymphoma cells because of a substance on the outside of the cells called CD30. Anti-CD30 antibodies have been used to treat people with lymphoma, but have not been strong enough to cure most patients.

For this study, the anti-CD30 antibody has been changed so that instead of floating free in the blood it is now joined to the T cells. When an antibody is joined to a T cell in this way it is called a chimeric receptor. These CD30 chimeric receptor-activated T cells (CD30.CAR T cells) seem to kill some of the tumor, but they don't last very long and so their chances of fighting the cancer are unknown.

Several studies suggest that the infused T cells need room to be able to multiply and grow to accomplish their functions, and that this may not happen if there are too many other T cells in circulation. Because of that, doctors may use chemotherapy drugs to decrease the level of circulating T cells prior to the CD30.CAR T cells infusion. This is called "lymphodepletion"

CD30.CAR T cells have previously been studied in lymphoma patients.

To prepare the CD30.CAR T cells, research staff will take some blood from the subject. This would be drawn as two separate blood collections.

Alternatively, if the subject's blood counts are low, staff may collect the cells needed to prepare T cells by a pheresis procedure. This procedure will involve placing a needle in both arms, collecting the cells over 3 to 6 hours during which the subject will be required to lie relatively still.

After the T cells have been collected, some of them will be activated stimulating them with antibodies and will then be infected with a retroviral vector (a special virus that can carries a new gene into cells) containing a new gene called anti-CD30 that will make an antibody to lymphoma cells. The trained cells are called CD30.CAR T cells. Then, the cells will be tested to make sure that they kill lymphoma cells that express the CD30 antigen and not normal cells.

The cells generated will be frozen and stored to give back to the subject.

This is a dose escalation study. This means that at the beginning, patients will be started on the lowest doses (1 of 3 different levels) of CD30.CAR T Cells. Once that dose schedule proves safe, the next group of patients will be started at a higher dose. This process will continue until all 3 dose levels are studied. If the side effects are too severe, the dose will be lowered or the T cell infusions will be stopped. The risks of harm and discomfort from the study treatment may bear some relationship to the dose level. The potential for direct benefit, if any, may also vary with the dose level.

Subjects will be given one injection of CD30.CAR T cells. The injection will be on Day 0. The subject may be given a dose of Benadryl and Tylenol before the injection of T cells to minimize any possible allergic reaction. The injection will take 1-10 minutes. The subject will be monitored in the clinic after each injection for up to 3 hours.

At the discretion of the study doctor, if the subject has stable disease (the lymphoma did not grow) or there is a reduction in the size of the lymphoma on imaging studies at week 8 after the T-cell infusion or on subsequent evaluations, then the subject can receive up to six additional doses of the T cells at 8 to 12 weeks intervals. After each T cell injection, the subject will be monitored as described above.

To learn more about the way the CD30.CAR T cells are working and how long they last in the body, extra blood will be drawn. On the day that the subject receives the cells, blood will be taken before the cells are given and several hours afterwards. Other blood will be drawn at 1 week, 2 weeks, 3 weeks (optional), 4 weeks, 6 weeks and 8 weeks, every 3 months for 1 year, every 6 months for 4 years, then yearly for a total of 15 years.

CD30 CAR T Cells, Relapsed CD30 Expressing Lymphoma (RELY-30)

Phase I Study of Relapsed CD30 Expressing Lymphoma Treated With CD30 CAR T Cells (RELY-30)

Each treated patient will be followed for 6 weeks post the T-cell infusion for the evaluation of DLTs.

The investigators will monitor the persistence of these infused cells by measuring the level of the transgene by both phenotypic and molecular analyses.

Although response is not the primary endpoint of this trial, investigators will summarize tumor response by calculating overall response rates along with exact 95% binomial confidence intervals.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
T-cells Expressing an Anti-SLAMF7 CAR for Treating Multiple Myeloma	NCT03958656	Myeloma-Multipl... Myeloma, Plasma...	Cyclophosphamid... Fludarabine Rimiducid Anti-Signaling ...	18 Years - 73 Years	National Institutes of Health Clinical Center (CC)
CD30 CAR T Cells, Relapsed CD30 Expressing Lymphoma (RELY-30)	NCT02917083	Hodgkin's Lymph... Non-Hodgkin Lym...	CAR T Cells	12 Years - 75 Years	Baylor College of Medicine

Spots Global Cancer Trial Database for chimeric antigen receptors