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

Brief Title

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

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.
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

Clinical and immunological effects of AP1903 administration.

Secondary Outcome

 T cell dose that produces a greater than 25% risk of Grade II or greater GvHD.

Condition

Acute Lymphoblastic Leukemia

Intervention

iCaspase9-transduced T cells

Study Arms / Comparison Groups

 iCaspase9-transduced T cells
Description:  The 5 dose levels are:
1 x 10^4 T cells/kg
1 x 10^5 T cells/kg
5 x 10^5 T cells/kg
1 x 10^6 T cells/kg
5 x 10^6 T cells/kg
AP1903 will be administered if there is development of Grade 1 or greater GvHD.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

15

Start Date

November 2011

Completion Date

May 2029

Primary Completion Date

May 2029

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.
      

Gender

All

Ages

N/A - N/A

Accepts Healthy Volunteers

No

Contacts

Malcolm K Brenner, MB, PhD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01494103

Organization ID

H-28256-DOTTI

Secondary IDs

DOTTI

Responsible Party

Principal Investigator

Study Sponsor

Baylor College of Medicine

Collaborators

 The Methodist Hospital System

Study Sponsor

Malcolm K Brenner, MB, PhD, Principal Investigator, Baylor College of Medicine


Verification Date

September 2020