Clinical trial NCT01494103: Administration of Donor T Cells With the Caspase-9 Suicide Gene
Official title: Administration of Haploidentical Donor T Cells Transduced With the Inducible Caspase-9 Suicide Gene
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
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
Keywords: 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
Lead sponsor: Baylor College of Medicine
Sponsor class: OTHER
Collaborators: name: The Methodist Hospital Research Institute
name: Center for Cell and Gene Therapy, Baylor College of Medicine
First posted: 2011-12-16
Enrollment: 15
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility 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.

Primary outcomes:
measure: Clinical and immunological effects of AP1903 administration.
timeFrame: 14 days
Secondary outcomes:
measure: T cell dose that produces a greater than 25% risk of Grade II or greater GvHD.
timeFrame: 42 days
measure: Immune reconstitution and relative contribution of iCaspase9-modified T cells post-infusion.
timeFrame: Up to 15 years
measure: Overall and disease-free survival.
timeFrame: 100 days and 1 year
Other outcomes:
Locations:
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Houston
country: United States
facility: The Methodist Hospital
state: Texas
Study officials:
affiliation: Baylor College of Medicine
name: Malcolm K Brenner, MB, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.