Umbilical & Cord Blood (CB) Derived CAR-Engineered NK Cells for B Lymphoid Malignancies
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|ClinicalTrials.gov Identifier: NCT03056339|
Recruitment Status : Recruiting
First Posted : February 17, 2017
Last Update Posted : August 3, 2018
The goal of this clinical research study is to learn if giving genetically changed immune cells, called CAR-NK cells, after chemotherapy will improve the disease in stem cell transplant patients with relapsed (has returned) and/or refractory (has not responded to treatment) B-cell lymphoma or leukemia. Also, researchers want to find the highest tolerable dose of CAR-NK cells to give to patients with relapsed or refractory B-cell lymphoma or leukemia. The safety of this treatment will also be studied.
This is an investigational study. The making of and infusion of genetically changed NK cells and the drug AP1903 (if you receive it, explained below) are not FDA approved or commercially available for use in this type of disease. They are currently being used for research purposes only. The chemotherapy drugs in this study (fludarabine, cyclophosphamide, and mesna) are commercially available and FDA approved.
Up to 36 patients will take part in this study. All will be enrolled at MD Anderson.
|Condition or disease||Intervention/treatment||Phase|
|B-Lymphoid Malignancies Acute Lymphocytic Leukemia Chronic Lymphocytic Leukemia Non-hodgkin Lymphoma||Drug: Fludarabine Drug: Cyclophosphamide Drug: Mesna Biological: iC9/CAR.19/IL15-Transduced CB-NK Cells Drug: AP1903||Phase 1 Phase 2|
Hide Detailed Description
The process of changing the DNA (the genetic material in cells) of NK cells is called "gene transfer." NK cells will be separated out from frozen cord blood using a machine. Researchers then perform a gene transfer to change the NK cells' DNA, and then inject the genetically changed NK cells into the body of the patient receiving the transplant.
NK Cell Dose Levels:
If you choose to participate in this study, you will be assigned to a dose level of CAR-NK cells based on when you joined this study. Up to 3 dose levels of CAR-NK cells will be tested. Up to 12 participants will be enrolled at each dose level until the highest tolerable dose level is found. Each new group will receive a higher dose than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of CAR-NK cells is found. When the highest tolerable dose is found, more participants may be enrolled at that dose level.
Length of Study Participation:
You may be taking part in this study for up to 1 year.
Tests Before Study Drug Administration:
Before you receive study drugs:
- Blood (about 4 tablespoons) will be drawn for research tests and to check for cytokines. Cytokines are proteins that may affect the immune system. This blood will be used as a baseline to study the immune system before starting treatment.
- If your doctor thinks it is needed, you will have a bone marrow aspiration and biopsy to check the status of the disease and for research tests. To collect a bone marrow aspiration/biopsy, an area of the hip is numbed with anesthetic, and a small amount of bone marrow and bone is withdrawn through a large needle.
Within 7 days before you receive study drugs:
- You will have a physical exam.
- Blood (about 4 tablespoons) will be drawn for routine tests. If you can become pregnant, part of the blood will be used for a pregnancy test.
Study Drug Administration:
You will receive fludarabine and cyclophosphamide to help prepare your body for CAR-NK infusion. These drugs may kill some cancer cells, but that is not the main goal for their use. The day you receive the CAR-NK cells is called Day 0. The days before you receive your CAR-NK cells are called minus days. The days after you receive the CAR-NK cells are called plus days.
On Day -6, you will be admitted to the hospital and given fluids by vein to hydrate you.
On Days -5, -4, and -3, you will receive fludarabine by vein over 1 hour and cyclophosphamide by vein over 3 hours. You will also receive mesna by vein over before and after the cyclophosphamide dose to lower the risk of side effects to the bladder caused by cyclophosphamide.
On Days -2 and -1, you will rest.
On Day 0, you will receive the CAR-NK cells as a cell infusion by vein.
If you have graft-versus-host disease (GvHD) or cytokine release syndrome after the CAR-NK cell infusion, you will receive AP1903 by vein and possibly steroids by mouth or by vein.
GvHD occurs when donor cells attack the cells of the person receiving them. Cytokine release syndrome (CRS) occurs when a large amount of proteins are released into the blood. The risks of GvHD and CRS, some of which are serious, are described in greater detail below.
Study Tests After the NK Infusion:
On Day 0, blood (about 4 tablespoons) will be drawn for research tests.
On Day +7, you will have a physical exam.
On Day +3 and then at Weeks 1, 2, 3, 4, 8, 12, and 16, and then at Months 6, 9 and 12:
°Blood (about 5 tablespoons) will be drawn for routine tests, for chimerism tests (to see how well the transplant has taken), and for research tests. Part of the blood at Weeks 4 and 12 will be used to check for HLA antibodies. HLA antibodies may effect how the CAR-NK cells function in your body. Part of the blood on Day +3 and then at Weeks 1, 2, 3, 4, 8, 12, and 16 will be used to check for cytokines. If the doctor thinks it is needed, this will be checked at Months 6, 9, and/or 12.
During Weeks 1, 4, 8, 12, and 16, and at Months 6, 9, and 12:
°If your doctor thinks it is needed, you will have a bone marrow aspiration and biopsy to check the status of the disease and for research tests.
During Weeks 4, 8, 12, and 16, and at Months 6, 9, and 12:
°If your doctor thinks it is needed, you will have a PET/CT scan to check the status of the disease.
If you have a lymph node biopsy while you are on the study, a portion of the tissue may be sent to Dr. Rezvani's lab at MD Anderson to check the status of the disease and to check for CAR-NK cells.
For safety reasons, the U.S. Food and Drug Administration (FDA) requires that patients who receive infusions of cellular products that have been treated with a gene transfer procedure must have long-term follow-up for at least 15 years after receiving the gene transfer.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||36 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Dose Escalation Study Phase I/II of Umbilical Cord Blood-Derived CAR-Engineered NK Cells in Conjunction With Lymphodepleting Chemotherapy in Patients With Relapsed/Refractory B-Lymphoid Malignancies|
|Actual Study Start Date :||June 21, 2017|
|Estimated Primary Completion Date :||June 2022|
|Estimated Study Completion Date :||June 2022|
Experimental: Fludarabine + Cyclophosphamide + CAR-NK Cells
On Days -5, -4, and -3, participants receive Fludarabine and Cyclophosphamide. Participants also receive Mesna before and after the cyclophosphamide dose.
On Day 0, participants receive genetically modified NK cells as a cell infusion.
If participant has graft-versus-host disease (GvHD) or cytokine release syndrome after the NK cell infusion, they receive AP1903 by vein and possibly steroids by mouth or by vein.
30 mg/m2 by vein on Days -5 to -3.
300 mg/m2 by vein on Days -5 to -3.
300 mg/m2 by vein on Days -5 to -3 before and after the cyclophosphamide dose.
Other Name: Mesnex
Biological: iC9/CAR.19/IL15-Transduced CB-NK Cells
Infusion of iC9/CAR.19/IL15-transduced CB-NK cells on Day 0 by vein.
Starting dose: 10E5
Other Name: NK cells
If participant has graft-versus-host disease (GvHD) or cytokine release syndrome after the NK cell infusion, they will receive AP1903 0.4 mg/kg administered as an intravenous infusion.
- Optimal NK Cell Dose Level of Chimeric Antigen Receptors (CAR).CD19-CD28-zeta-2A-iCasp9-IL15-Transduced Cord Blood Natural Killer (CB-NK) Cells in Patients with Relapsed/Refractory CD19+ B Lymphoid Malignancies [ Time Frame: 45 days ]Dose-finding done using the sequentially adaptive phase I-II EffTox trade-off-based design. Toxicity is defined as a grade 3 or 4 GVHD within 45 days of NK cell infusion.
- Toxicity of Chimeric Antigen Receptors (CAR).CD19-CD28-zeta-2A-iCasp9-IL15-Transduced Cord Blood Natural Liller (CB-NK) Cells in Patients with Relapsed/Refractory CD19+ B Lymphoid Malignancies [ Time Frame: 2 weeks after NK cell infusion ]Toxicity defined as cytokine release storm (CRS) within 2 weeks of NK cell infusion requiring transfer to intensive care.
- Efficacy of Chimeric Antigen Receptors (CAR).CD19-CD28-zeta-2A-iCasp9-IL15-Transduced Cord Blood Natural Killer (CB-NK) Cells in Patients with Relapsed/Refractory CD19+ B Lymphoid Malignancies [ Time Frame: 30 days after NK cell infusion ]Efficacy defined as the patient being alive and in remission at day 30 post NK cell infusion.
- Response of Chimeric Antigen Receptors (CAR).CD19-CD28-zeta-2A-iCasp9-IL15-Transduced Cord Blood Natural Killer (CB-NK) Cells in Patients with Relapsed/Refractory CD19+ B Lymphoid Malignancies [ Time Frame: 100 days after NK cell infusion ]Unadjusted distributions of the time-to-event outcomes estimated using the method of Kaplan and Meier and their relationship to prognostic covariates and NK cell dose level evaluated by Bayesian piecewise exponential survival regression.
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): NCT03056339
|Contact: Katy Rezvani, MD, PHDemail@example.com|
|Contact: Bethany Overman, RN,BSN,CPN||713-745-4567|
|United States, Texas|
|University of Texas MD Anderson Cancer Center||Recruiting|
|Houston, Texas, United States, 77030|
|Contact: Clinical Research Operations firstname.lastname@example.org|
|Principal Investigator:||Katy Rezvani, MD, PHD||M.D. Anderson Cancer Center|