Multi-Virus-Specific Cytotoxic T Lymphocytes (CTLs) - 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:	NCT00840853

Purpose

This Phase I/II dose-escalation trial is designed to evaluate the safety and biological efficacy of allogeneic CMV, EBV and Adenovirus (tri-virus) specific cytotoxic T-lymphocytes (CTL) genetically modified to express artificial T-cell receptors (CAR) targeting the CD19 molecule (CD19CAR). Each patient will receive a single dose of CTL after day 30 post HSCT, and will be monitored for toxicity and detection of transduced CTL, as well as disease specific markers, virus specific immunity and B-cell immune reconstitution.

Condition	Intervention	Phase
Acute Lymphoblastic Leukemia	Biological: Genetically modified T cells	Phase I

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Phase I/II Study of the Administration of Multi-Virus-Specific Cyotooxic T Lymphocytes Expressing CD19 Chimeric Receptors for Prophylaxis or Therapy of Relapse of CD19 Positive Malignancies Post Hematopoietic Stem Cell Transplantation

Resource links provided by NLM:

MedlinePlus related topics: Acute Lymphocytic Leukemia Cancer Chronic Lymphocytic Leukemia Leukemia

U.S. FDA Resources

Further study details as provided by Baylor College of Medicine:

Primary Outcome Measures:

Evaluate safety/persistence of escalating doses of allogeneic CMV, EBV and Adenovirus specific CTLs modified to express artificial T-cell receptors targeting CD19 molecule given for prophylaxis, persistence or relapse of high risk B-cell ALL post HSCT [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

To evaluate the effects of gene modified CTL on measurable disease. [ Time Frame: 15 years ] [ Designated as safety issue: Yes ]
To evaluate the impact of the gene modified CTL on virus-specific T-lymphocyte immune reconstitution. [ Time Frame: 15 years ] [ Designated as safety issue: Yes ]
To evaluate the impact of the gene modified CTL on normal CD19+ B-cell immune reconstitution post-HSCT. [ Time Frame: 15 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	18
Study Start Date:	April 2009
Estimated Study Completion Date:	April 2029
Estimated Primary Completion Date:	April 2014 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Dose 1-3 During the dose escalation phase two patients will be entered at each dose level (depending on toxicity). This approach was successfully used in optimizing our previous multi-virus specific CTL infusion regimen. If there are no toxicities and immunological efficacy is not seen at any dose, then the doses will be further escalated after additional local and federal approval. Based on previous experience with viral specific CTLs, we anticipate seeing NO adverse dose response effects on any end-point. Hence, upon completion of the dose escalation, we will treat 6 additional patients at the lowest safe and immunologically effective cell dose so that we will have sufficient information to estimate an overall response rate and design a subsequent extended Phase II protocol.	Biological: Genetically modified T cells Dose Level 1: 1.5 x 10^7/m^2 Dose Level 2: 4.5 x 10^7/m^2 Dose Level 3: 1.2x10^8/m^2

Arms

Assigned Interventions

Experimental: Dose 1-3

During the dose escalation phase two patients will be entered at each dose level (depending on toxicity). This approach was successfully used in optimizing our previous multi-virus specific CTL infusion regimen. If there are no toxicities and immunological efficacy is not seen at any dose, then the doses will be further escalated after additional local and federal approval. Based on previous experience with viral specific CTLs, we anticipate seeing NO adverse dose response effects on any end-point. Hence, upon completion of the dose escalation, we will treat 6 additional patients at the lowest safe and immunologically effective cell dose so that we will have sufficient information to estimate an overall response rate and design a subsequent extended Phase II protocol.

Biological: Genetically modified T cells

Dose Level 1: 1.5 x 10^7/m^2 Dose Level 2: 4.5 x 10^7/m^2 Dose Level 3: 1.2x10^8/m^2

Detailed Description:

The first phase of the trial is the dose-escalation safety study. Patients will be divided into two groups (A and B) depending on the type of B-cell malignancy they are being treated for. Three dose levels will be evaluated in each group namely, 1.5x10^7 cells/m2, 4.5x10^7 cells/m2 and 1.2x10^8 cells/m2. Dose escalation is guided by the modified continual reassessment method (mCRM) in order to determine the maximum tolerated dose (MTD) of transduced T-cells. Dose-limiting toxicity (DLT) is defined as development of grade III-IV GvHD or NCI grade 3 - 4 non-hematologic toxicity that can be attributed to the treatment. MTD is defined as the dose that causes DLT in at most 20% of eligible cases. Based on our previous trials, we expect a shallow dose-toxicity curve for the doses proposed in this trial. The prior probabilities of toxicity of the three dose levels being evaluated (1.5x10^7 cells/m2, 4.5x10^7 cells/m2 and 1.2x10^8 cells/m2) are estimated to be 1.3%, 3.1% and 25%, respectively. In this trial, mCRM is implemented based on an exponential model with a cohort of size 2. To reduce the probability of treating patients at unacceptable toxic dose levels, we employ modifications to the original CRM. Specifically, there will be more than one subject treated in each cohort, dose escalation is limited to no more than one dose level, and patient enrollment starts at the lowest dose level.

Eligibility

Ages Eligible for Study:	up to 80 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Any patient regardless of sex or age with CD19+ B-ALL undergoing allogeneic HSCT (Group A). OR Any patient regardless of sex or age with CD19+ B-CLL or NHL undergoing allogeneic HSCT (Group B). With minimal residual disease (MRD) or relapse post-HSCT (for the phase I dose escalation) as evidenced by PCR positivity, specific cytogenetic abnormalities, an abnormal population on flow cytometry or increased blasts on bone marrow biopsy or in the peripheral blood.

MRD will be defined as detection in blood or marrow of: 1) Any leukemia specific marker (such as t(9:22) or t(4:11)) documented in the patient's leukemia cells pre transplant on a post transplant evaluation 2) A TCR or immune globulin rearrangement known to be a disease marker for this patient post transplant 3) A leukemia specific phenotype post transplant at a level of greater than 0.01% 4) Mixed donor chimerism

OR

With no evidence of ALL or CLL/NHL post-HSCT (to be included in the phase II extension). Please note that this population will not be enrolled without FDA review and approval of safety data from Phase I of this protocol.

2) Patients with life expectancy greater than or equal to 6 weeks

3) Patients with a Karnofsky/Lansky score greater than or equal to 50

4) Donor HIV negative

5) Patient or parent/guardian capable of providing informed consent

6) Patients with bilirubin 2x normal or less, AST 3x normal or less, creatinine less than or equal to 2x normal for age and Hgb greater than 8.0

7) Pulse oximetry of greater than 90% on room air

8) Sexually active patients must be willing to utilize one of the more effective birth control methods for 6 months after the CTL infusion. The male partner should use a condom.

9) Available allogeneic CD19CAR transduced tri-virus-specific cytotoxic T lymphocytes with 15% expression of CD19CAR determined by flow-cytometry and greater than 10% killing of one or more viral antigen pulsed targets in a cytotoxicity assay at an effector:target ratio of 20:1.*

10) Patients should have been off other investigational antiviral or antitumor therapy for one month prior to entry in this study.

*Note: Cell dose is based on total cell numbers and not individual antivirus or antileukemic cell numbers.

Exclusion Criteria:

Severe intercurrent infection
Evidence of graft versus host disease greater than grade II
Pregnant or lactating
History of hypersensitivity reactions to murine protein-containing products.
Currently taking corticosteroids for therapy of GVHD.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00840853

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
Principal Investigator: Gianpietro Dotti, MD
Principal Investigator: Robert Krance, MD
Sub-Investigator: George Carrum, MD
Sub-Investigator: Malcolm K Brenner, MD
Sub-Investigator: Helen E Heslop, MD
Sub-Investigator: Stephen M Gottschalk, MD
Sub-Investigator: Kathryn S Leung, MD
Sub-Investigator: Gianpietro Dotti, MD
Sub-Investigator: Alana A Kennedy-Nasser, MD
Sub-Investigator: Rammurti T Kamble, MD
Sub-Investigator: Hao Liu
Sub-Investigator: Caridad A Martinez, MD
Sub-Investigator: Kenneth P Micklethwaite
Sub-Investigator: Carlos A Ramos, MD
The Methodist Hospital	Recruiting
Houston, Texas, United States, 77030
Contact: George Carrum, MD 713-441-1450 gcarrum@bcm.tmc.edu
Sub-Investigator: George Carrum, MD
Sub-Investigator: Catherine M Bollard, MD
Sub-Investigator: Helen E Heslop, MD
Sub-Investigator: Malcolm K Brenner, MD
Sub-Investigator: Rammurti T Kamble, MD
Sub-Investigator: Carlos Ramos, 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

More Information

No publications provided

Responsible Party:	Catherine Bollard, MD, Baylor College of Medicine
ClinicalTrials.gov Identifier:	NCT00840853 History of Changes
Other Study ID Numbers:	23637-MULTIPRAT
Study First Received:	February 9, 2009
Last Updated:	August 12, 2011
Health Authority:	United States: Food and Drug Administration

Keywords provided by Baylor College of Medicine:

Acute Lymphoblastic Leukemia
ALL
CD19+
HSCT
Allogeneic Hemopoietic Stem Cell Transplantation

Additional relevant MeSH terms:

Leukemia
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Neoplasms by Histologic Type
Neoplasms

Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases

ClinicalTrials.gov processed this record on February 09, 2012