Safety, Toxicity and MTD of One Intravenous IV Injection of Donor CTLs Specific for CMV and Adenovirus (ACT-CAT)

This study has been completed.
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):
Caridad Martinez, Baylor College of Medicine
ClinicalTrials.gov Identifier:
NCT00880789
First received: April 13, 2009
Last updated: October 13, 2014
Last verified: October 2014

April 13, 2009
October 13, 2014
May 2009
August 2013   (final data collection date for primary outcome measure)
To determine safety, toxicity and MTD of one intravenous injection of donor-derived cytotoxic T lymphocytes (CTLs) specific for CMV and Adenovirus given to patients with or at risk for CMV and adenovirus disease after cord blood transplant [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
Same as current
Complete list of historical versions of study NCT00880789 on ClinicalTrials.gov Archive Site
  • To evaluate the feasibility of generating a sufficient number of umbilical cord blood-derived cytotoxic T lymphocytes (CTLs) specific for CMV and Adenovirus [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • To evaluate the impact of these CTLs on Adenovirus-specific T-lymphocyte immune reconstitution. [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • To evaluate the recovery of virus-specific immunity after CTL infusion and its correlation with viral clearance and/or protection from viral infection/disease. [ Time Frame: 1 year ] [ Designated as safety issue: No ]
Same as current
Not Provided
Not Provided
 
Safety, Toxicity and MTD of One Intravenous IV Injection of Donor CTLs Specific for CMV and Adenovirus
Adoptive Transfer of Cord Blood T Cells To Prevent and Treat CMV and Adenovirus Infections After Transplantation

With this study, we want to see if we can use a kind of white blood cell called T cells to prevent or treat AdV and CMV infection. We will grow these T cells from the cord blood before the patients transplant. These cells have been trained to attack adenovirus/CMV-infected cells and are called Adenoviral/CMV-specific cytotoxic (killer) T-cells or "AdV/CMV-CTL." We would plan to give the patient one dose of AdV/CMV-CTL any time from 30 days after their transplant. We have used T cells made in this way from the blood of donors to prevent infections in patients who are getting a bone marrow or blood stem cell transplant but this will be the first time we make them from cord blood.

We plan to grow T cells from the cord blood in the laboratory in a special way, to see if they can help prevent or treat infections in transplant patients with these viruses. This therapy with specially trained T cells (called CTLs) has had activity against these viruses when the cells are made from donor blood and given to patients receiving bone marrow or blood stem cell transplants. We want to find out if we can use CTLs that we will make from cord blood to prevent or treat viral infections when the patient's immunity is weak after receiving the cord blood transplant. These cells are called "CMV/AdV specific CTLs" because they can attack those two viruses.

The doctor will already have found a cord blood unit that is suitable for the patient's transplant. If the patient agrees to this study we will take 5-10 ml (1-2 teaspoons) from this cord blood unit before the transplant. We will only take as much cord blood as is available in a specially frozen small fraction of the cord blood unit.

We will use this cord blood to grow T cells in the lab. From this blood we will first grow special type of cells called dendritic cells and we will put a specially produced human virus (adenovirus) that carries the CMVpp65 gene into these dendritic cells. The dendritic cells will be irradiated so they cannot grow and then used to stimulate the T cells. This stimulation will train the T cells to kill cells with CMV and adenovirus on their surface.

We will then grow large numbers of these AdV/CMV-specific CTLs by more stimulation with EBV infected B cells (which we will make from the cord blood by infecting them with EBV in the laboratory). We will also put the special virus into these B cells so that they too have AdV/CMV. Again, these B cells will be treated with radiation so they cannot grow. Once we have made enough T cells we will test them to make sure they kill cells infected with Adenovirus and CMV. To make sure that these cells won't attack the patient's own healthy tissues, we test these cells against some of the blood cells that we will grow in the laboratory. These will be used to check to see if the AdV/CMV CTL can attack them. Alternatively, we may take blood from a first degree relative or take a small piece of skin from the patient to grow skin cells, which can also to be used to check if AdV/CMV CTL can attack them. The skin biopsy can be done at the same time as another procedure such as a bone marrow biopsy.

The cord donor's AdV/CMV CTL cells will be thawed and injected into the IV line over a period of up to 10 minutes.Patients may be premedicated with Benadryl and Tylenol. If the patient agrees and if he/she is well enough, one dose of CTL will be given on or after day 30 following transplant. If the patient does not have AdV/CMV infection we will not give antiviral medications to them during this study but we will monitor the patient closely to check for AdV/CMV infection. If the patient does have AdV/CMV infection before CTL infusion they may also be treated with antiviral medications during this study. We will monitor the patients closely for AdV/CMV infection by collecting blood and possibly urine and stool and testing them for AdV/CMV.

Interventional
Phase 1
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Cytomegalovirus Infection
  • Adenovirus Infection
Biological: CMV/AdV specific T cells
CTL Dose Given from Day +30 post SCT (stem cell transplant). For the trial, two patients are allocated in each cohort and are followed for 30 days post IV injection of transduced T-cells for evaluation of DLTs. A maximum 18 patients will be accrued into each group. The final MTD will be the dose with probability closest to the target toxicity rate at these termination points. The trial continues until a minimum of 12 patients have been treated. The trial will stop when the maximum 18 patients have been treated, or when six patients have been treated at the current MTD. We therefore expect to enroll between 12-18 patients into this trial.
Experimental: Dose Level One: 5x10^6/m2
CTL Dose Given from Day +30 post SCT (stem cell transplant). For the trial, two patients are allocated in each cohort and are followed for 30 days post IV injection of transduced T-cells for evaluation of DLTs. A maximum 18 patients will be accrued into each group. The final MTD will be the dose with probability closest to the target toxicity rate at these termination points. The trial continues until a minimum of 12 patients have been treated. The trial will stop when the maximum 18 patients have been treated, or when six patients have been treated at the current MTD. We therefore expect to enroll between 12-18 patients into this trial.
Intervention: Biological: CMV/AdV specific T cells
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
9
June 2014
August 2013   (final data collection date for primary outcome measure)

INCLUSION CRITERIA:

Inclusion criteria at the time of Procurement:

  • Patient with malignant or nonmalignant diseases who are candidates for transplant.
  • Patients must have a single CB unit matched with the patient at 4, 5, or 6/6 HLA class I (serological) and II (molecular) antigens. The unit must be cryopreserved in two fractions, with a minimum of 2.5x10^7 total nucleated cells per kg pre-thaw in the fraction which will be used for the primary transplant. The remaining fraction will be used to generate the CTLs to give at day 30 or beyond as described below.

Inclusion criteria at the time of CTL infusion:

  • Recipients of a single cord blood unit fractionated into 2 fractions (i.e. from a HLA matched or mismatched unrelated donor) transplant at risk for or with CMV/Adenoviral disease or reactivation.
  • Lansky/Karnofsky scores 60 or greater
  • Absolute neutrophil count (ANC) greater than 500/ul.
  • No evidence of GVHD > Grade II at time of enrollment.
  • Life expectancy > 30 days
  • Absence of severe renal disease (Creatinine > x 3 normal for age)
  • Absence of severe hepatic disease. Direct bilirubin must be less than 3 mg/dl and AST less than 5x upper limit of normal
  • Patient must be at least 30 days post transplant to be eligible to receive CTL
  • Written informed consent and/or signed assent line from patient, parent or guardian.
  • Patient not on Fi02 of >60%

EXCLUSION CRITERIA:

Exclusion criteria at the time of Procurement:

  • Pregnant or Lactating
  • Patients with active central nervous system disease
  • Patients with Karnofsky performance status <70%
  • Patients with grade 3 or 4 or primary myelofibrosis
  • Patients with suitable related donors

Exclusion criteria at the time of CTL infusion:

  • Pregnant or lactating
  • Unable to wean steroids to 0.5 mg/kg/day or less prednisone.
  • Patients with other uncontrolled infections (except CMV and/or adenovirus and/or EBVemia in absence of PTLD). For bacterial infections, patients must be receiving definitive therapy and have no signs of progressing infection for 72 hours prior to enrollment. For fungal infections patients must be receiving definitive systemic anti-fungal therapy and have no signs of progressing infection for 1 week prior to enrollment. Progressing infection is defined as hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection.
  • Patients with less than 50% donor chimerism in either peripheral blood or bone marrow or patients with relapse of original disease.
Both
up to 90 Years
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00880789
23668-ACT CAT
Yes
Caridad Martinez, Baylor College of Medicine
Baylor College of Medicine
  • Texas Children's Hospital
  • The Methodist Hospital System
  • Center for Cell and Gene Therapy, Baylor College of Medicine
Principal Investigator: Caridad A. Martinez, MD Baylor College of Medicine/Texas Children's Hospital
Baylor College of Medicine
October 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP