Administration of Donor T Cells With the Caspase-9 Suicide Gene

NCT ID: NCT01494103

Last Updated: 2025-07-11

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE1
• Total Enrollment: 15 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-11-30
• Study Completion Date: 2029-05-31

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.

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 "iCasp9" 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 until 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.

Conditions

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

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

iCaspase9-transduced T cells

The 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.

Group Type: EXPERIMENTAL

iCaspase9-transduced T cells

Intervention Type: BIOLOGICAL

Patients will receive the T cells between 30 and 90 days following transplantation. The T cells will be infused through a catheter line.

AP1903

Intervention Type: DRUG

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.

Interventions

iCaspase9-transduced T cells

Patients will receive the T cells between 30 and 90 days following transplantation. The T cells will be infused through a catheter line.

Intervention Type: BIOLOGICAL

AP1903

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.

Intervention Type: DRUG

Other Intervention Names

AP1903 Dimerizer Drug

Eligibility Criteria

Inclusion Criteria

1. 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.

2. 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)

1. Engrafted with an absolute neutrophil count (ANC) > 500 cells/µL

2. Greater than or equal to 50% donor chimerism in either peripheral blood or bone marrow, or relapse of their original disease

3. Life expectancy > 30 days

4. Lansky/Karnofsky score greater than or equal to 60

5. Absence of severe renal disease (creatinine > 2X upper limit of normal for age)

6. Absence of severe hepatic disease (direct bilirubin > 3X upper limit of normal or SGOT > 3X upper limit of normal)

7. Oxygen saturation > 94% on room air

8. Patient/Guardian able to give informed consent

9. AP1903 available in sufficient quantities to allow for treatment of the patient

Exclusion Criteria

1. GvHD

2. Severe intercurrent infection

3. Pregnancy*

4. 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.

• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

The Methodist Hospital Research Institute

OTHER

Sponsor Role: collaborator

Center for Cell and Gene Therapy, Baylor College of Medicine

OTHER

Sponsor Role: collaborator

Baylor College of Medicine

OTHER

Sponsor Role: lead

Responsible Party

Malcolm Brenner

Director/Professor, Center for Cell and Gene Therapy

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Malcolm K Brenner, MB, PhD

Role: PRINCIPAL_INVESTIGATOR

Baylor College of Medicine

Locations

Texas Children's Hospital

Houston, Texas, United States

The Methodist Hospital

Houston, Texas, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 25977584 (View on PubMed)

Other Identifiers

DOTTI

Identifier Type: OTHER

Identifier Source: secondary_id

H-28256-DOTTI

Identifier Type: -

Identifier Source: org_study_id