Autologous T-Cells Expressing a Second Generation CAR for Treatment of T-Cell Malignancies Expressing CD5 Antigen (MAGENTA)
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|ClinicalTrials.gov Identifier: NCT03081910|
Recruitment Status : Recruiting
First Posted : March 16, 2017
Last Update Posted : October 5, 2021
|First Submitted Date ICMJE||March 8, 2017|
|First Posted Date ICMJE||March 16, 2017|
|Last Update Posted Date||October 5, 2021|
|Actual Study Start Date ICMJE||November 1, 2017|
|Estimated Primary Completion Date||January 15, 2024 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Dose limiting toxicity (DLT) rate [ Time Frame: 6 weeks post-infusion ]
Defined as the proportion of subjects in each group with DLT evaluated as per the CTCAE 4.0 with the exception of Cytokine Release Syndrome (CRS) and neurological toxicities that are related to T cell infusions.
|Original Primary Outcome Measures ICMJE
||Number of Patients with dose limiting toxicity [ Time Frame: 6 weeks ]
To evaluate the safety of escalating doses of autologous peripheral blood T lymphocytes (ATLs) genetically modified to express chimeric antigen receptors (CAR) targeting the CD5 molecule (CD5.CAR) in combination with lymphodepletion in patients with relapsed/refractory T-cell malignancies.
|Current Secondary Outcome Measures ICMJE
||Overall Response Rate [ Time Frame: 4 weeks pre-infusion and 6 weeks post-infusion ]
Overall response rate is calculated as the proportion of subjects with the best overall response according to a revised response criteria for malignant lymphoma or bone marrow analyses for leukemia. Evaluations of tumor size will be performed within 4 weeks of beginning treatment and 6-8 weeks after T cell infusion (earlier if clinically indicated).
|Original Secondary Outcome Measures ICMJE
||Overall Response Rate [ Time Frame: 6 weeks ]
1.10.1. To measure the anti-tumor effects of CD5.CAR-ATLs in patients with T-cell leukemia or lymphoma.
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||Autologous T-Cells Expressing a Second Generation CAR for Treatment of T-Cell Malignancies Expressing CD5 Antigen|
|Official Title ICMJE||Phase 1 Therapy With Manufactured Autologous T-Cells Expressing a Second Generation Chimeric Antigen Receptor (CAR) for Treatment of T-Cell Malignancies Expressing CD5 Antigen|
Patients eligible for this study have a type of blood cancer called T-cell leukemia or lymphoma (lymph gland cancer).
The body has different ways of fighting infection and disease. No one way seems perfect for fighting cancers. This research study combines two different ways of fighting disease, antibodies and T cells, hoping that they will work together. Antibodies are types of proteins that protect the body from bacterial and other diseases. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells including tumor cells. Both antibodies and T cells have been used to treat patients with cancers; they have shown promise, but have not been strong enough to cure most patients.
T lymphocytes can kill tumor cells but there normally are not enough of them to kill all the tumor cells. Some researchers have taken T cells from a person's blood, grown more of them in the laboratory and then given them back to the person. In some patients who have recently had a bone marrow or stem cell transplant, the number of T cells in their blood may not be enough to grow in the laboratory. In this situation, T cells may be collected from their previous transplant donor, who has a similar tissue type.
The antibody used in this study is called anti-CD5. It first came from mice that have developed immunity to human leukemia. This antibody sticks to T-cell leukemia or lymphoma cells because of a substance on the outside of these cells called CD5. CD5 antibodies have been used to treat people with T-cell leukemia and lymphoma. For this study, anti-CD5 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.
In the laboratory, the investigators have also found that T cells work better if proteins that stimulate T cells are also added, such as one called CD28. Adding the CD28 makes the cells grow better and last longer in the body, thus giving the cells a better chance of killing the leukemia or lymphoma cells.
In this study investigators are going to attach the CD5 chimeric receptor with CD28 added to it to the patient's T cells or the previous bone marrow transplant donor's T cells. The investigators will then test how long the cells last. The decision to use the bone marrow transplant donor's T cells instead of the patient's will be based on 1) whether there is an available and willing donor and 2) the likelihood of the patient's T cells being able to grow in the lab. These CD5 chimeric receptor T cells with CD28 are investigational products not approved by the Food and Drug Administration.
To make the T cells the investigators will take blood from the patient or from the previous bone marrow transplant donor and stimulate it with growth factors to make the T cells grow. To get the CD5 antibody and CD28 to attach to the surface of the T cell, investigators insert the antibody gene into the T cell. This is done with a virus called a retrovirus that has been made for this study and will carry the antibody gene into the T cell. This virus also helps investigators find the T cells in the patient's blood after they are injected. Because the patient will have received cells with a new gene in them the patient will be followed for a total of 15 years to see if there are any long term side effects of gene transfer.
When the patient is enrolled on this study, they will be assigned a dose of CD5 chimeric receptor-T cells Several studies suggest that the infused T cells need room to be able to proliferate (grow) and accomplish their functions and that this may not happen if there are too many other T cells in circulation. Because of that, the patient will receive two chemotherapy medications prior to receiving the CD5 chimeric receptor-T cells.
One medication is called cyclophosphamide and the other fludarabine. The patient will receive 3 daily doses of each drug, ending at least one day before the patient receives the chimeric receptor-T cells. These drugs will decrease the numbers of the patient's own T cells before the CD5 chimeric receptor T cells are infused and also will help decrease the number of other cells that may interfere with the chimeric receptor-T cells working well. Although we do not expect any effect on the patient's tumor with the doses that the patient will receive, these drugs are part of many regimens that are used to treat leukemia or lymphoma.
The patient will be given an injection of cells into the vein through an IV at the assigned dose. The injection will take from 1 to 10 minutes. Before the patient receives the injection, they may be given a dose of Benadryl and Tylenol. The treatment will be given by the Center for Cell and Gene Therapy at Texas Children's Hospital or Houston Methodist Hospital.
The patient will be followed in the clinic after the injection for up to 3 hours, and the patient will have to remain locally for at least 3 weeks after the infusion. If the patient experiences any side effects, they may have to be hospitalized for evaluation and management.
If after a 4-6 week evaluation period after the infusion, the patient has achieved a complete response (measured by bone marrow or radiology scans), the patient's primary oncology doctors may decide the patient should proceed to bone marrow transplant, at which time the patient will be removed from the treatment portion of the study.
Before being treated, the patient will receive a series of standard medical tests:
Physical exam and History; Blood tests to measure blood cells, kidney and liver function; Pregnancy test for female patients who are of child bearing potential; Measurements of the patient's tumor by scans and/or bone marrow studies
The patient will also receive standard medical tests during treatment and after:
Physical exams and History; Blood tests to measure blood cells, kidney and liver function;
Graft versus Host Disease assessments:
Measurements of the patient's tumor by scans and/or bone marrow studies 6-8 weeks after the infusion and then per standard of care.
To learn more about the way the CD5 chimeric receptor-T cells are working and how long they last in the body, extra blood will be drawn. The total amount on any day is about 10 teaspoons (50 mL) or no more than 3 mL per 2.2 pounds body weight in children. This volume is considered safe but may be decreased if the patient is anemic. This blood may be drawn from a central line if the patient has one. Blood will be taken before the chemotherapy drugs, several hours after the T cell infusion, at 1 week, 2 weeks, 3 weeks (optional), 4 weeks, 6 weeks and 8 weeks (optional) after the infusion, at 3 months, 6 months, 9 months, at 1 year, every 6 months for 4 years, then yearly for a total of 15 years. We will also test blood to check for signs of viral infection at the following time points: within 1 to 2 weeks prior to chemotherapy drugs, prior to T cell infusion, then at weeks 1, 2, 3, 4, 6, 8 for all patients, and months 3, 6, 9, 12 for patients who do not proceed to bone marrow transplant. The total blood drawn during participation in this study will not exceed 280 teaspoons.
Once the dose escalation portion of the study is completed, we will expand the trial and treat up to an additional 6 patients (2 cohorts) at the MTD in each group to gather additional safety data and preliminary efficacy data.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Phase 1|
|Study Design ICMJE||Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Study Arms ICMJE||
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE
|Original Estimated Enrollment ICMJE
|Estimated Study Completion Date ICMJE||September 1, 2039|
|Estimated Primary Completion Date||January 15, 2024 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
Procurement Inclusion Criteria
Referred patients will initially be consented for procurement of blood for generation of the transduced ATL. Eligibility criteria at this stage include:
Procurement Exclusion Criteria:
Treatment Inclusion Criteria:
Treatment Exclusion Criteria:
|Ages ICMJE||up to 75 Years (Child, Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT03081910|
|Other Study ID Numbers ICMJE||H-40466, MAGENTA|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||
|IPD Sharing Statement ICMJE||Not Provided|
|Responsible Party||Rayne Rouce, Baylor College of Medicine|
|Study Sponsor ICMJE||Baylor College of Medicine|
|PRS Account||Baylor College of Medicine|
|Verification Date||September 2021|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP