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

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by Baylor College of Medicine
Sponsor:
Collaborators:
Texas Children's Hospital
The Methodist Hospital System
Center for Cell and Gene Therapy, Baylor College of Medicine
Information provided by (Responsible Party):
Malcolm Brenner, Baylor College of Medicine
ClinicalTrials.gov Identifier:
NCT01494103
First received: December 15, 2011
Last updated: July 24, 2014
Last verified: July 2014
  Purpose

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. Seventy to ninety percent of 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 patient's 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 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 in vitro, whilst 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 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 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.


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: iCaspase9-transduced T cells
Drug: AP1903
Phase 1

Study Type: Interventional
Study Design: 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

Resource links provided by NLM:


Further study details as provided by Baylor College of Medicine:

Primary Outcome Measures:
  • Clinical and immunological effects of AP1903 administration. [ Time Frame: 14 days ] [ 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 5 x 10^6/kg) that produce a greater than 25% risk of inducing Grade II or greater acute GvHD in these subjects.

  • Immune reconstitution and relative contribution of iCaspase9-modified T cells post-infusion. [ 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 of endogenous T cell recovery and infused gene-modified T cells.


Secondary Outcome Measures:
  • 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 of recipients of iCaspase9 T cells 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: 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
Biological: 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.
Drug: 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.


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.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Inclusion Criteria at Time of Procurement:

  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)

Inclusion Criteria at Time of T Cell Infusion:

  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:

Exclusion Criteria at Time of T Cell Infusion:

  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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01494103

Contacts
Contact: Malcolm K Brenner, MB, PhD 832-824-4663 mkbrenne@txch.org
Contact: Yu-Feng Lin 832-824-4258 yxlin@txch.org

Locations
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   
Sponsors and Collaborators
Baylor College of Medicine
Texas Children's Hospital
The Methodist Hospital System
Center for Cell and Gene Therapy, Baylor College of Medicine
Investigators
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: July 24, 2014
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:
Epstein-Barr Virus Infections
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
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 August 28, 2014