Safety, Toxicity and Maximum Tolerated Dose (MTD) of One Intravenous IV Injection of Donor Cytotoxic T-lymphocytes (CTLs) Specific for Cytomegalovirus (CMV) and Adenovirus - Full Text View

Sponsor:	Baylor College of Medicine
Collaborators:	Texas Children's Hospital The Methodist Hospital System Center for Cell and Gene Therapy, Baylor College of Medicine
Information provided by:	Baylor College of Medicine
ClinicalTrials.gov Identifier:	NCT00880789

Purpose

This trial is design to evaluate the safety, toxicity and maximum tolerated dose (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 infections after cord blood transplantation.

A dose escalation scheme utilizing cohorts of two patients will be used. At each dose level, two patients will be treated and observed for 30 days for toxicity and dose escalation and through to 45 days for GVHD. If one of the initial cohort of two patients experience DLT (Dose LImiting Toxicity), then two additional patients will be treated at this dose level. If two or more of four or six patients experience DLT, then this dose level will be considered unacceptable toxicity and the number of infused CTL will be de-escalated unless we are at the initial dosing levels. If 5x10^6CTL/m2 result in unacceptable toxicity, the study will be closed to accrual.

The maximum tolerated dose of infused CMV/AdV-specific CTL will be that number at which DLT is observed in at most one of six patients and the next higher dose presents unacceptable toxicity, as defined above. If the highest number of CTL safely infused is 2.5x10^7/m^2 per dose, then no MTD exists among these dosing levels. Note: at least six patients must be treated at the 2.5x10^7/m^2 dose level. Additional patients will be treated at dose level 1 in order to assess the secondary objectives of virus-specific immunity from the CTL infusions.

Condition	Intervention	Phase
Cytomegalovirus Infection Adenovirus Infection	Biological: Dose Escalation Comparison	Phase I

Study Type:	Interventional
Study Design:	Treatment, Non-Randomized, Open Label, Dose Comparison, Single Group Assignment, Safety Study
Official Title:	Adoptive Transfer of Cord Blood T Cells To Prevent and Treat CMV and Adenovirus Infections After Transplantation

Resource links provided by NLM:

MedlinePlus related topics: Cytomegalovirus Infections

U.S. FDA Resources

Further study details as provided by Baylor College of Medicine:

Primary Outcome Measures:

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 ]

Secondary Outcome Measures:

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 ]

Estimated Enrollment:	18
Study Start Date:	May 2009
Estimated Study Completion Date:	May 2015
Estimated Primary Completion Date:	May 2014 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Dose Level One: 5x10^6/m2: Experimental 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.	Biological: Dose Escalation Comparison 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.
Dose Level Two: 1.0 x 10^7/m2: Experimental See Dose Level 1.	Biological: Dose Escalation Comparison 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.
Dose Level Three: 1.5 x 10^7/m2: Experimental See Dose Level 1.	Biological: Dose Escalation Comparison 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.
Dose Level Four: 2.5x10^7/m2: Experimental See Dose Level 1.	Biological: Dose Escalation Comparison 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.

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Eligibility

Ages Eligible for Study:	up to 90 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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
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 > 3 mg/dl or AST less than 5x upper limit of normal)
Patient must be at least 30 days but less than 365 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 at the time of Procurement:

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:

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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00880789

Contacts

Contact: Catherine Bollard, MD

832-824-4781

cmbollar@txccc.org

Locations

United States, Texas
Texas Children's Hospital	Recruiting
Houston, Texas, United States, 77030
Contact: Catherine Bollard, MD 832-824-4781 cmbollar@txccc.org
Principal Investigator: Catherine Bollard, MD
Sub-Investigator: George Carrum, MD
Sub-Investigator: Robert A Krance, MD
Sub-Investigator: Malcolm K Brenner, MD
Sub-Investigator: Helen E Heslop, MD
Sub-Investigator: Cliona M Rooney, MD
Sub-Investigator: Stephen M Gottschalk, MD
Sub-Investigator: Kathryn S Leung, MD
Sub-Investigator: Ann M Leen, MD
Sub-Investigator: Jessica A Shafer, MD
Sub-Investigator: Nabil M Ahmed, MD
Sub-Investigator: Alana A Kennedy-Nasser, MD
Sub-Investigator: John A Craddock, MD
Sub-Investigator: Rammurti T Kamble, MD
Sub-Investigator: Caridad A Martinez, MD
Sub-Investigator: Carlos A Ramos, MD
Sub-Investigator: Barbara Savoldo, MD
The Methodist Hospital	Recruiting
Houston, Texas, United States, 77030
Contact: Geroge Carrum, MD 713-441-1450 gcarrum@bcm.tmc.edu
Sub-Investigator: George Carrum, MD
Texas Children's Cancer Center GCRC	Recruiting
Houston, Texas, United States, 77030
Contact: Catherine Bollard, MD 832-824-4781 cmbollar@txccc.org
Principal Investigator: Catherine Bollard, MD

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:

Catherine Bollard, MD

Baylor College of Medicine/Texas Children's Hospital

More Information

No publications provided

Responsible Party:	Baylor College of Medicine/Texas Children's Hospital ( Catherine Bollard, MD )
Study ID Numbers:	23668-ACT CAT
Study First Received:	April 13, 2009
Last Updated:	December 2, 2009
ClinicalTrials.gov Identifier:	NCT00880789 History of Changes
Health Authority:	United States: Food and Drug Administration

Keywords provided by Baylor College of Medicine:

Cord Blood Transplant
cytomegalovirus
CMV
Adenovirus
ADV

Additional relevant MeSH terms:

Virus Diseases
Communicable Diseases
Adenoviridae Infections
Cytomegalovirus Infections

DNA Virus Infections
Infection
Herpesviridae Infections

ClinicalTrials.gov processed this record on February 08, 2010