Administration of Donor T Cells With the Caspase-9 Suicide Gene (DOTTI)
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Purpose
Patients will be receiving a stem cell transplant as treatment for their disease. As part of the stem cell transplant, the patients will be given very strong doses of chemotherapy, after which the stem cells would be killed.
A close relative of the patient will be identified, whose stem cells are not a perfect match for the patient's, but can be used. This type of transplant is called allogeneic, meaning that the cells are from a donor. With this type of donor who is not a perfect match, there is typically an increased risk of developing GVHD and a longer delay in the recovery of the immune system. Seventy to ninety percent of the people who receive unchanged marrow or stem cells from this type of donor will develop severe GvHD.
GvHD is a serious and sometimes fatal side effect of stem cell transplant. GvHD occurs when the new donor cells (graft) recognize that the body tissues of the patient (host) are different from those of the donor. When this happens, cells in the graft may attack the host organs, primarily the skin, liver and intestines causing severe rashes, diarrhea, liver disease, and even death. GvHD is caused by a type of immune cell in the graft called T cells.
While this stem cell selection procedure will reduce the risk of GVHD, it will also result in slower recovery of the patients immune system. As the immune system is responsible for fighting infections in your body, a longer recovery time after a transplant means that the patient may be at increased risk for infections which can become life threatening. In some patients the immune system can also fight leukemia cells and reduce the risk of relapse.
In this study investigators are trying to see if they can make special T cells in the laboratory that can be given to the patient to help their immune system recover faster. As a safety measure, we want to "program" the T cells so that if, after they have been given to the patient, they start to cause GVHD, we can destroy them ("suicide gene").
Investigators will obtain T cells from a donor, and culture them in the laboratory, introduce the gene, called "suicide gene" in order to make it possible to kill them when a specific drug called AP1903 is administered, in order to eliminate the cells cause of GVHD. We have had encouraging results in a previous study regarding the effective elimination of cells cause of GVHD in vitro, whereas being able to spare a sufficient number of cells able to fight infection and potentially cancer.
More specifically T cells made to carry a gene called iCasp9 can be killed when they encounter the drug AP1903. To get the iCasp9 into the T cells, we insert it using a virus called a retrovirus that has been made for this study. The drug (AP1903) that will be used to "activate" the iCasp9 is an experimental drug that has been tested in a study in normal donors with no bad side effects. We hope we can use this drug to kill the T cells. Other drugs that kill or damage T cells have helped GvHD in many studies, but with a more profound reduction of immune-defense. However, if the patient develops significant GvHD they will also receive standard therapy for this complication, in addition to the experimental drug.
The major purpose of this study is to find out a safe and effective dose of "iCasp9" T cells that can be given to patients who receive an allogeneic stem cell transplant. Another important purpose of this study is to find out if these special T cells can help the patient's immune system recover faster after the transplant than they would have otherwise.
| Condition | Intervention | Phase |
|---|---|---|
|
Acute Lymphoblastic Leukemia Myelodysplastic Syndrome Acute Myeloid Leukemia Chronic Myelogenous Leukemia Non Hodgkin Lymphoma Hemophagocytic Lymphohistiocytosis Familial Hemophagocytic Lymphohistiocytosis Hemophagocytic Syndrome Epstein Barr Virus Infection X-linked Lymphoproliferative Disease |
Biological: Allodepleted T Cells Transduced with iCaspase9 Suicide Gene Drug: AP1903 |
Phase 1 |
| Study Type: | Interventional |
| Study Design: | Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | Administration of Haploidentical Donor T Cells Transduced With the Inducible Caspase-9 Suicide Gene |
- Clinical and Immunological effects of AP1903 administration [ Time Frame: 15 years ] [ Designated as safety issue: No ]To evaluate the clinical and immunological effects of AP1903 administration, a dimerizer drug used to activate an iCaspase9 suicide gene mechanism, to subjects who have received escalating doses of T lymphocytes expressing the iCaspase9 gene and developed acute graft-versus-host-disease (GvHD).
- T cell dose that produces a greater than 25% risk of grade II or greater GvHD [ Time Frame: 42 days ] [ Designated as safety issue: Yes ]To discover the number of T cells/kg (up to 5x10^6/kg) that produce a greater than 25% risk of inducing Grade II or greater acute GvHD in these subjects.
- Change in the immune system from baseline to post infusion of iCaspase9 modified T cells (and dimerizer drug) [ Time Frame: up to 15 years ] [ Designated as safety issue: No ]To measure the subsequent immune reconstitution of recipients of iCaspase9 modified T cells (and dimerizer drug) and assess the relative contribution from endogenous T cell recovery and infused gene modified T cells.
- Measure the overall and disease free survival [ Time Frame: 100 days and 1 year ] [ Designated as safety issue: No ]To measure the overall and disease free survival, at 100 days and at 1 year post transplant.
| Estimated Enrollment: | 18 |
| Study Start Date: | November 2011 |
| Estimated Study Completion Date: | July 2030 |
| Estimated Primary Completion Date: | July 2030 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Allodepleted T Cells Transduced with iCaspase9 Suicide Gene
The 5 dose levels are:
|
Biological: Allodepleted T Cells Transduced with iCaspase9 Suicide Gene
Patients will receive the T cells between 30 and 90 days following transplantation. The T cells will be infused through a catheter line.
|
|
Experimental: AP1903
If the patient develops GvHD, AP1903 will be given. If there is mild GvHD that continues, the patient can receive up to 3 additional doses of AP1903, if this drug is helping the GvHD. If the patient has severe GvHD, we will treat them with AP1903 in addition to medicines that are usually used to treat GvHD, like steroids. If the patient has severe GvHD, but has a severe reaction to AP1903 we will treat them with steroids alone. In some cases, though, GvHD does not respond to treatments.
|
Drug: AP1903
AP1903 will be administered if there is development of grade 1 or greater GVHD. Dose: 0.4mg/kg by IV over 2 hours Up to 3 additional doses may be administered if the GVHD does not respond or gets worse |
Detailed Description:
If the patient is doing well after the stem cell transplant and does not have severe GvHD s/he will be eligible to receive the special T cells from Day 30 to 90 after transplant. The specially selected and treated T cells will be given by vein (IV) once.
This is a dose escalation study. This means that at the beginning, patients will be started on the lowest dose (1 of 5 different levels) of T cells. Once that dose schedule proves safe, the next group of patients will be started at a higher dose. This process will continue all 5 dose levels are studied. If the side effects are too severe, the dose will be lowered or the T cell injections will be stopped.
If the patient develops GvHD after being given the specially treated T cells, we will prescribe AP1903, which has been shown to kill cells carrying the iCasp9 gene. This drug will be given as a 2-hour IV infusion.
We will continue to follow the patient weekly in the bone marrow transplant clinic for the first month after the infusion to check for side effects of the treatment and for GvHD. The patient will have the standard tests performed that all patients have after transplant even when not receiving special T cells.
Eligibility| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Inclusion Criteria at Time of Procurement :
- Lack of suitable conventional donor (i.e. 5/6 or 6/6 related or 5/6 or 6/6 unrelated donor) or presence of a rapidly progressive disease not permitting time to identify an unrelated donor
High risk disease in one of the following:
- Myelodysplastic syndrome (MDS) in one of the following categories: RCMD with an IPSS-R of intermediate, poor or very poor, RAEB-1, or RAEB-2
- Acute myeloid leukemia (AML) after first relapse or primary refractory disease
- Chronic myelogenous leukemia (CML) in Chronic Phase 2 or greater, Accelerated Phase or Blast Crisis
- Acute lymphoblastic leukemia (ALL)(after first relapse or primary refractory disease) or High grade Non Hodgkin lymphoma (NHL) (stage III or IV) (after first relapse or primary refractory disease)
- Hemophagocytic lymphohistiocytosis (HLH)
- Familial hemophagocytic lymphohistiocytosis (FLH)
- Viral-associated hemophagocytic syndrome (VAHS)
- T or NK cell lymphoproliferative syndrome
- X-linked lymphoproliferative disease (XLP)
Inclusion Criteria at time of T cell infusion:
- Engrafted with an absolute neutrophils count (ANC) >500 cells/µL.
- Greater or equal than 50% donor chimerism in either peripheral blood or bone marrow, or relapse of their original disease.
- Life expectancy >30 days
- Lansky/Karnofsky score 60 or greater
- Absence of severe renal disease (Creatinine >2X upper limit of normal for age)
- Absence of severe hepatic disease (direct bilirubin >3X upper limit of normal or SGOT >3X upper limit of normal)
- O2 sat >94% on room air
- Patient/Guardian able to give informed consent.
- AP1903 available in the Investigational Pharmacy (required 0.4mg/Kg per dose; vial concentration 5mg/mL, total volume per vial=2 mL).
Exclusion Criteria:
Exclusion Criteria at time of T cell infusion:
- GVHD
- Severe intercurrent infection
- Pregnant*
Other investigational drugs in the prior 30 days.
- Pregnancy test only required for at risk individuals, defined as female patients of childbearing potential who has received a reduced intensity conditioning regimen.
Contacts and Locations| Contact: Malcolm K Brenner, MB, PhD | 832-824-4663 | mkbrenne@txch.org |
| Contact: Yu-Feng Lin | 832-824-4258 | yxlin@txch.org |
| United States, Texas | |
| Texas Children's Hospital | Recruiting |
| Houston, Texas, United States, 77030 | |
| Contact: Malcolm K. Brenner, MB, PhD 832-824-4663 mkbrenne@txch.org | |
| Contact: Yu-Feng Lin 832-824-4258 yxlin@txch.org | |
| The Methodist Hospital | Recruiting |
| Houston, Texas, United States, 77030 | |
| Contact: Malcolm K Brenner, MB, PhD 832-824-4663 mkbrenne@txch.org | |
| Contact: Yu-Feng Lin 832-824-4258 yxlin@txch.org | |
| Principal Investigator: | Malcolm K Brenner, MB, PhD | Baylor College of Medicine |
More Information
No publications provided
| Responsible Party: | Malcolm Brenner, Director/Professor, Center for Cell and Gene Therapy, Baylor College of Medicine |
| ClinicalTrials.gov Identifier: | NCT01494103 History of Changes |
| Other Study ID Numbers: | H-28256-DOTTI, DOTTI |
| Study First Received: | December 15, 2011 |
| Last Updated: | February 5, 2013 |
| Health Authority: | United States: Food and Drug Administration United States: Institutional Review Board |
Keywords provided by Baylor College of Medicine:
|
Acute lymphoblastic leukemia Myelodysplastic syndrome Acute myeloid leukemia Chronic myelogenous leukemia Non Hodgkin lymphoma |
Hemophagocytic lymphohistiocytosis Familial hemophagocytic lymphohistiocytosis Hemophagocytic syndrome Epstein Barr virus infection X-linked lymphoproliferative disease |
Additional relevant MeSH terms:
|
Leukemia Leukemia, Lymphoid Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Myeloid, Acute Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Lymphohistiocytosis, Hemophagocytic Lymphoma Lymphoma, Non-Hodgkin Lymphoproliferative Disorders Myelodysplastic Syndromes Preleukemia Suicide Virus Diseases Epstein-Barr Virus Infections |
Neoplasms by Histologic Type Neoplasms Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Myeloproliferative Disorders Bone Marrow Diseases Hematologic Diseases Histiocytosis, Non-Langerhans-Cell Histiocytosis Precancerous Conditions Self-Injurious Behavior Behavioral Symptoms Herpesviridae Infections DNA Virus Infections |
ClinicalTrials.gov processed this record on May 23, 2013