CTLs Expressing CD19 Chimeric Receptors, CD19 Positive Malignancies Post SCT, MULTIPRAT
|First Received Date ICMJE||February 9, 2009|
|Last Updated Date||August 8, 2012|
|Start Date ICMJE||April 2009|
|Estimated Primary Completion Date||April 2014 (final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Evaluate safety/persistence of escalating doses of allogeneic CMV, EBV and Adenovirus specific CTLs modified to express artificial T-cell receptors targeting CD19 molecule given for prophylaxis, persistence or relapse of high risk B-cell ALL post HSCT [ Time Frame: 6 weeks ] [ Designated as safety issue: Yes ]|
|Original Primary Outcome Measures ICMJE
||Evaluate safety/persistence of escalating doses of allogeneic CMV, EBV and Adenovirus specific CTLs modified to express artificial T-cell receptors targeting CD19 molecule given for prophylaxis, persistence or relapse of high risk B-cell ALL post HSCT [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]|
|Change History||Complete list of historical versions of study NCT00840853 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||CTLs Expressing CD19 Chimeric Receptors, CD19 Positive Malignancies Post SCT, MULTIPRAT|
|Official Title ICMJE||Phase I/II Study of the Administration of Multi-Virus-Specific Cytotoxic T Lymphocytes Expressing CD19 Chimeric Receptors for Prophylaxis or Therapy of Relapse of CD19 Positive Malignancies Post Hematopoietic Stem Cell Transplantation|
Subjects are having a bone marrow or stem cell transplant for either a type of cancer of the blood called Leukemia or a cancer of the lymph nodes called non- Hodgkin's Lymphoma. Although a transplant can cure leukemia or lymphoma, some people will relapse (return of the disease). In those who relapse, current treatment cures only a very small percentage. Although giving patients a dose of donor immune cells (donor lymphocyte infusion or DLI) before relapse can prevent relapse of the leukemia or lymphoma, DLI can also cause a serious complication called graft versus host disease (GVHD). For these reasons, subjects are being asked to volunteer to take part in a gene transfer research study using special immune cells which are specific for these cancer cells.
The body has different ways of fighting infection and disease. This study combines two of those ways, antibodies and T cells. Antibodies are proteins that protect the body from bacterial and other diseases. T cells (CTLs or cytotoxic T cells) are infection-fighting blood cells that can kill cells, including tumor cells. 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.
The antibody used in this study is called anti-CD19. This antibody sticks to leukemia cells because of a substance on the outside of these cells called CD19. For this study, the anti-CD19 antibody has been changed so that instead of floating free in the blood it is now joined to T cells. When an antibody is joined to a T cell in this way it is called a chimeric receptor.
In the laboratory, we have found that T cells that are trained to recognize common viruses can stay in the blood stream for many years. By joining the anti-CD19 antibody to CTLs that recognize viruses, we believe that we will also be able to make a cell that can last a long time in the body, provide protection from viruses and recognize and kill leukemia. The CTLs which we will join the anti-CD19 antibody to attack three viruses (trivirus-specific CTLs), cytomegalovirus (CMV), Epstein-Barr virus (EBV) and adenovirus.
CMV is a virus that rarely causes problems in healthy people but can cause serious infections in patients with suppressed immune systems. It can cause a very serious pneumonia, and can also affect the intestinal tract, liver and eyes. 2/3 of normal people harbor this virus in their body. If the subject or donor are positive for CMV, the subject is at risk of developing CMV disease after transplant.
EBV causes mononucleosis or "mono" (infection with fatigue, high fever, and swollen lymph nodes). It is normally controlled by a healthy immune system but when the immune system is weak after bone marrow transplant it can cause fevers, enlarged lymph nodes and a type of cancer called lymphoma.
Adenovirus is a virus that causes symptoms of a common cold but can cause life-threatening infections in patients with weak immune systems. It usually affects the lungs, but it can also affect the gut, liver, pancreas and eyes.
Studies have shown that trivirus-specific CTLs grown from the stem cell donor can be given safely to transplant recipients and can stop these viruses from causing severe infections. In this study we are going to see if adding the CD19 chimeric receptor to these cells will provide additional benefit for the prevention or treatment of leukemia or lymphoma relapse and if they persist in the body in the long term. These CD19 chimeric receptor trivirus specific T cells are an investigational product not approved by the Food and Drug Administration.
These CTLs will be reinfused in the body either early after the transplant or when tests indicate relapse of the leukemia or lymphoma. By analyzing the blood periodically, we will see if they remain in the body and effectively combat viruses and leukemia.
The purpose of this study is to find the biggest dose of chimeric T cells that is safe to administer, to assess what the side effects are, to see how long the T cells last and to evaluate whether this therapy might help prevent infections and relapse in people with CD19+ leukemia or lymphoma having a stem cell transplant.
The donor gave us blood to make CD19 chimeric receptor trivirus specific T cells in the laboratory. These cells were grown and frozen for the subject. To make these special T cells we grow them with stimulator cells. Stimulator cells are also made from the donor's blood but they are irradiated so that they can no longer grow. Stimulator cells have been infected with viruses so that they carry proteins from 3 viruses (CMV, adenovirus, and EBV). These cells are cultured with the T cells so that they can learn to see and attack cells infected with CMV, EBV and adenovirus.
To get the CD19 antibody to attach to the surface of the T cell, we inserted 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 us find the T cells in the blood after we inject them. Once we make sufficient numbers of T cells we freeze the cells and test them to make sure they kill CD19+ tumors cells and cells infected with CMV, EBV and adenovirus. Once testing is completed the cells will be ready to give to the subject.
Because the subject will have received cells with a new gene in them the subject will be followed for a total of 15 years to see if there are any long term side effects of gene transfer.
When the subjects enroll on this study, they will be assigned a dose of CD19 chimeric receptor trivirus specific T cells.
The subject will be given an injection of cells into the vein through an IV line at the assigned dose. Before the subjects receive the injection, they may be given a dose of diphenhydramine (Benadryl) and acetaminophen (Tylenol). The injection will take about 20 minutes. We will follow the subject in the clinic after the injection for up to 3 hours. The treatment will be given by the Center for Cell and Gene Therapy at Texas Children's Hospital or The Methodist Hospital.
Medical tests before treatment—
Before being treated, the subject will receive a series of standard medical tests:
Physical exam Blood tests to measure blood cells, kidney and liver function.
Medical tests during and after treatment—
The subject will receive standard medical tests when they are getting the infusions and after:
Physical exams Blood tests to measure blood cells, kidney and liver function.
To learn more about the way the CD19 chimeric receptor trivirus specific T cells are working and how long they last in the body, extra blood will be drawn.
This blood may be drawn from a central line if the subject has one. On the day the subject receives the cells, blood will be taken before the cells are given and 3 hours afterwards. Other blood will be drawn one week, 2 weeks, 4 weeks, 6 weeks and 8 weeks after the infusion, then at Months 3, 6, 9 and 12. Then blood will be drawn every 6 months for 4 years, then yearly for a total of 15 years (up to 30 blood collections). If the subject receives the cells at a time when sensitive tests indicate relapse or a high risk of relapse, they will have additional reviews and blood tests to monitor these tests and look for relapse.
The total blood drawn during the participation in this study will not exceed 300 teaspoons. No more than 10 teaspoons or 1/2 teaspoon per 2.2 pounds of body weight (whichever is lesser) will be drawn at each collection. This volume is considered safe, but may be decreased if the subject has a low red blood cell count (anemic).
If the subject has bone marrow studies in the first year after completing treatment on this study, we may ask to have a sample (about 1 teaspoon) of bone marrow to look for CD19 chimeric receptor T cells for research purposes.
Patients will receive supportive care for acute or chronic toxicity, including blood components or antibiotics, and other intervention as appropriate.
For subjects receiving the CTLs for treatment of their disease: If the subject has stable disease (the tumor did not grow) or there is a reduction in the size of the tumor on imaging studies or by blood count after the T-cell infusion, the subject can receive up to six additional doses of the T cells if they wish. After each T-cell infusion, the subject will be monitored as described above.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 1
|Study Design ICMJE||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Intervention ICMJE||Genetic: CD19CAR/virus specific T cells
CD19CAR/virus specific T cells will be thawed and given by intravenous injection from day +30 post transplant. Subjects will receive one of the following dose levels:
Dose Level 1: 1.5 x 10^7/m2 Dose Level 2: 4.5 x 10^7/m2 Dose Level 3: 1.2 x 10^8/m2
If patients with relapse have a partial response or have stable disease they will be eligible to receive up to 6 further doses of CTLs, each of which will consist of the same number as their first injection.
|Study Arm (s)||Experimental: CD19CAR/virus specific T cells
Intervention: Genetic: CD19CAR/virus specific T cells
|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||36|
|Estimated Completion Date||April 2029|
|Estimated Primary Completion Date||April 2014 (final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
Any patient regardless of sex or age with CD19+ B-ALL undergoing allogeneic HSCT (Group A). OR Any patient regardless of sex or age with CD19+ B-CLL or NHL undergoing allogeneic HSCT (Group B). With minimal residual disease (MRD) or relapse post-HSCT (for the phase I dose escalation) Any patient regardless of sex or age with CD19+ B-ALL undergoing allogeneic HSCT (Group A). OR Any patient regardless of sex or age with CD19+ B-CLL or NHL undergoing allogeneic HSCT (Group B). With minimal residual disease (MRD) or relapse post-HSCT (for the phase I dose escalation) as evidenced by PCR positivity, specific cytogenetic abnormalities, an abnormal population on flow cytometry or increased blasts on bone marrow biopsy or in the peripheral blood.
MRD will be defined as detection in blood or marrow of: 1) Any leukemia specific marker (such as t(9:22) or t(4:11)) documented in the patient's leukemia cells pre transplant on a post transplant evaluation 2) A TCR or immune globulin rearrangement known to be a disease marker for this patient post transplant 3) A leukemia specific phenotype post transplant at a level of > 0.01% 4) Mixed donor chimerism
With no evidence of ALL or CLL/NHL post-HSCT (to be included in the phase II extension). Please note that this population will not be enrolled without FDA review and approval of safety data from Phase I of this protocol.
2) Patients with life expectancy greater than or equal to 6 weeks
3) Patients with a Karnofsky/Lansky score greater than or equal to 50
4) Donor HIV negative
5) Patient or parent/guardian capable of providing informed consent
6) Patients with bilirubin 2x normal or less, AST 3x normal or less, creatinine less than or equal to 2x normal for age and Hgb greater than 8.0
7) Pulse oximetry of greater than 90% on room air
8) Sexually active patients must be willing to utilize one of the more effective birth control methods for 6 months after the CTL infusion. The male partner should use a condom.
9) Available allogeneic CD19CAR transduced tri-virus-specific cytotoxic T lymphocytes with greater than or equal to15% expression of CD19CAR determined by flow-cytometry and greater than 10% killing of one or more viral antigen pulsed targets in a cytotoxicity assay at an effector:target ratio of 20:1.*
10) Patients should have been off other investigational antiviral or antitumor therapy for one month prior to entry in this study.
*Note: Cell dose is based on total cell numbers and not individual antivirus or antileukemic cell numbers.
|Accepts Healthy Volunteers||No|
|Location Countries ICMJE||United States|
|NCT Number ICMJE||NCT00840853|
|Other Study ID Numbers ICMJE||23637-MULTIPRAT, MultiPRAT|
|Has Data Monitoring Committee||Yes|
|Responsible Party||catherine bollard, Baylor College of Medicine|
|Study Sponsor ICMJE||Baylor College of Medicine|
|Information Provided By||Baylor College of Medicine|
|Verification Date||August 2012|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP