Administration of Donor T Cells With the Caspase-9 Suicide Gene
DOTTI
Administration of Haploidentical Donor T Cells Transduced With the Inducible Caspase-9 Suicide Gene
2 other identifiers
interventional
15
1 country
2
Brief Summary
Patients will be receiving a stem cell transplant as treatment for their disease. As part of the stem cell transplant, patients will be given very strong doses of chemotherapy, which will kill all their existing stem cells. 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. 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. In this study, investigators are trying to see whether 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, culture them in the laboratory, and then introduce the "suicide gene" which makes the cells sensitive to a specific drug called AP1903. If the specially modified T cells begin to cause GvHD, the investigators can kill the cells by administering AP1903 to the patient. We have had encouraging results in a previous study regarding the effective elimination of T cells causing GvHD, while sparing a sufficient number of T cells 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 gene into T cells, we insert it using a virus called a retrovirus that has been made for this study. The 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. The major purpose of this study is to find 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 whether these special T cells can help the patient's immune system recover faster after the transplant than they would have otherwise.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at below P25 for phase_1
Started Nov 2011
Longer than P75 for phase_1
2 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
Study Start
First participant enrolled
November 1, 2011
CompletedFirst Submitted
Initial submission to the registry
December 15, 2011
CompletedFirst Posted
Study publicly available on registry
December 16, 2011
CompletedPrimary Completion
Last participant's last visit for primary outcome
May 1, 2029
ExpectedStudy Completion
Last participant's last visit for all outcomes
May 1, 2029
July 11, 2025
July 1, 2025
17.5 years
December 15, 2011
July 8, 2025
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
Clinical and immunological effects of AP1903 administration.
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).
14 days
Secondary Outcomes (3)
T cell dose that produces a greater than 25% risk of Grade II or greater GvHD.
42 days
Immune reconstitution and relative contribution of iCaspase9-modified T cells post-infusion.
Up to 15 years
Overall and disease-free survival.
100 days and 1 year
Study Arms (1)
iCaspase9-transduced T cells
EXPERIMENTALThe 5 dose levels are: 1. 1 x 10\^4 T cells/kg 2. 1 x 10\^5 T cells/kg 3. 5 x 10\^5 T cells/kg 4. 1 x 10\^6 T cells/kg 5. 5 x 10\^6 T cells/kg AP1903 will be administered if there is development of Grade 1 or greater GvHD.
Interventions
Patients will receive the T cells between 30 and 90 days following transplantation. The T cells will be infused through a catheter line.
AP1903 will be administered if there is development of Grade 1 or greater GvHD. Dose: 0.4 mg/kg by IV over 2 hours. Up to 3 additional doses may be administered if the GvHD does not respond or gets worse.
Eligibility Criteria
You may qualify if:
- Lack of a 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)
- Engrafted with an absolute neutrophil count (ANC) \> 500 cells/µL
- Greater than or equal to 50% donor chimerism in either peripheral blood or bone marrow, or relapse of their original disease
- Life expectancy \> 30 days
- Lansky/Karnofsky score greater than or equal to 60
- +5 more criteria
You may not qualify if:
- GvHD
- Severe intercurrent infection
- Pregnancy\*
- Other investigational drugs in the prior 30 days
- Pregnancy test only required for at-risk individuals, defined as female patients of childbearing potential who have received a reduced-intensity conditioning regimen.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (2)
Texas Children's Hospital
Houston, Texas, 77030, United States
The Methodist Hospital
Houston, Texas, 77030, United States
Related Publications (1)
Zhou X, Dotti G, Krance RA, Martinez CA, Naik S, Kamble RT, Durett AG, Dakhova O, Savoldo B, Di Stasi A, Spencer DM, Lin YF, Liu H, Grilley BJ, Gee AP, Rooney CM, Heslop HE, Brenner MK. Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation. Blood. 2015 Jun 25;125(26):4103-13. doi: 10.1182/blood-2015-02-628354. Epub 2015 May 14.
PMID: 25977584DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Malcolm K Brenner, MB, PhD
Baylor College of Medicine
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NA
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SINGLE GROUP
- Sponsor Type
- OTHER
- Responsible Party
- PRINCIPAL INVESTIGATOR
- PI Title
- Director/Professor, Center for Cell and Gene Therapy
Study Record Dates
First Submitted
December 15, 2011
First Posted
December 16, 2011
Study Start
November 1, 2011
Primary Completion (Estimated)
May 1, 2029
Study Completion (Estimated)
May 1, 2029
Last Updated
July 11, 2025
Record last verified: 2025-07
Data Sharing
- IPD Sharing
- Will not share