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Haploidentical Allogeneic Transplant With Post-transplant Infusion of Regulatory T-cells

This study has been terminated.
(Safety)
Sponsor:
ClinicalTrials.gov Identifier:
NCT01050764
First Posted: January 15, 2010
Last Update Posted: May 11, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
Doris Duke Charitable Foundation
Information provided by (Responsible Party):
Everett Meyer, Stanford University
  Purpose
Patients with hematologic malignancies will receive myeloablative chemotherapy followed by stem cell rescue with bone marrow or hematopoietic peripheral blood stem cells collected by apheresis from a filgrastim- (G-CSF)-mobilized haploidentical related-donor, ie, hematopoietic peripheral blood stem cell transplant (HSCT).

Condition Intervention Phase
Leukemia, Acute Chronic Myelogenous Leukemia (CML) Myelodysplastic Syndrome (MDS) Non-Hodgkin Lymphoma (NHL) Chronic Lymphocytic Leukemia (CLL) Acute Myelogenous Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Drug: Regulatory T-cells Drug: Conventional T-cells Drug: Melphalan Drug: Thiotepa Device: Fludarabine Drug: Anti-thymocyte globulin, rabbit Drug: CliniMACS CD34 Reagent System Phase 1 Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Feasibility Trial of Post-Transplant Infusion of Allogeneic Regulatory T Cells and Allogeneic Conventional T Cells in Patients With Hematologic Malignancies Undergoing Allogeneic Myeloablative Hematopoietic Cell Transplantation From Haploidentical-Related Donors

Resource links provided by NLM:


Further study details as provided by Everett Meyer, Stanford University:

Primary Outcome Measures:
  • Maximum-tolerated Dose (MTD) of Regulatory and Conventional T-cells [ Time Frame: 30 days after HSCT infusion ]
    The maximum-tolerated dose (MTD) was to be determined based on the safety and feasibility observed for a pre-determined set of cellular dose level combinations of regulatory T-cells (T-reg) and conventional T-cells (T-con).


Secondary Outcome Measures:
  • Acute Graft-versus-Host-Disease (aGvHD) [ Time Frame: 1 year ]
    The primary outcome was incidence of grade 3 or 4 acute graft-vs-host-disease (aGvHD), reported as the number of participants developing grade 3 or 4 aGvHD.

  • Overall Survival (OS), 1 Year [ Time Frame: 1 year ]
    Assessed as subjects remaining alive 12 months after CD34+ cell infusion (ie, excludes death due to any cause)

  • Median Overall Survival (OS) [ Time Frame: 25 months ]
    Reported as the median overall survival (OS) in months from infusion of the hematopoietic stem cells (HSCT)

  • To Measure the Incidence and Severity of Acute and Chronic GvHD [ Time Frame: 1 year ]
    Population of participants that received HSCT and T-reg plus T-con, and developed actue, chronic, or any graft vs host disease (GvHD)

  • Serious Infections [ Time Frame: 1 year ]
    Serious infections are reported as the number of participants experienced serious infections.


Enrollment: 10
Study Start Date: June 2009
Study Completion Date: June 2014
Primary Completion Date: August 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: T-reg Cell Infusion after Allogeneic Stem Cell Transplant Drug: Regulatory T-cells

To ameliorate the impaired immune recovery and address the significant relapse incidence in the haploidentical setting. Cells will be selected by a tandem selection process and infused on day +14. These are the enriched but naturally-occurring regulatory T cells. Possible dose cohorts and levels are:

Cohort 1

  • T-reg: 1 x 10e5/kg
  • T-con: 3 x10e5/kg

Cohort 2

  • T-reg: 3 x 10e5/kg
  • T-con: 1 x 10e6/kg

Cohort 3

  • T-reg: 1 x 10e6/kg
  • T-con: 3 x 10e6/kg

Cohort 4

  • T-reg: 3 x 10e6/kg
  • T-con: 1 x 10e7/kg
Other Name: T-reg cells
Drug: Conventional T-cells
These are conventional (unselected) donor T-cells. Cell dosage of the infusion will be based on the CD3+ cell content and infused on day +16.
Other Name: T-con cells
Drug: Melphalan
Anti-cancer chemotherapy drug administered IV at 140 mg/m² on Day -8 prior to HSCT (a component of the conditioning regiment prior to infusion of cells)
Other Names:
  • L-PAM
  • L-Sarcolysin
  • Phenylalanine Mustard
Drug: Thiotepa
Anti-cancer chemotherapy drug administered IV at 10 mg/kg on Day -7 prior to HSCT (a component of the conditioning regiment prior to infusion of cells)
Other Names:
  • thiophosphamide
  • TESPA
  • TSPA
Device: Fludarabine
Anti-cancer chemotherapy drug administered IV at 160mg/m² on Days -6; -5; -4; and -3 prior to HSCT (a component of the conditioning regiment prior to infusion of cells
Other Names:
  • Fludarabine phosphate
  • Fludarabine 5'-monophosphate
  • FAMP
  • Fludara
Drug: Anti-thymocyte globulin, rabbit
Rabbit-derived antibodies against human T-cells used as transplant rejection prophylaxis. Administered at 6 mg/kg IV on Days -6; -5; -4; and -3 prior to HSCT
Other Names:
  • Thymoglobulin
  • rATG
Drug: CliniMACS CD34 Reagent System
An in vitro medical device system that uses antibodies conjugated to magnetic beads to select and enrich for CD34+ blood stem cells from the allogeneic donor apheresis product prior to HSCT, while removing other cells that can cause GvHD. CD34+ cell dosage will be based on the participant's body weight.

Detailed Description:

This is dose-escalation study intended to evaluate the use of classification determinant 15-positive (CD15+), CD4+, CD127dim, and FoxP3+ regulatory T-cells (T-reg cells) supplemented by conventional T-cells (T-con cells), to enhance the efficacy of allogeneic (CliniMACS CD34+ selected) hematopoietic stem cell transplantation (allo-HSCT), in the setting of leukemia, lymphoma, and myelodysplastic syndrome (MDS). This study investigates amelioration of the impaired immune recovery and address the significant relapse incidence in the haploidentical HSCT setting.

Pre-transplant myeloablative conditioning will be melphalan; thiotepa; fludarabine and rabbit antithymocyte globulin (rATG).

Stem cell rescue will be with CD34+ selected cells. The rescue infusion will be supplemented with infusions of regulatory T-cells (T-reg) and conventional T-cells (T-con) from the same donor collection, on Treatment Days 14 and 16 respectively. CD34+ cell infusion day is Treatment Day 0.

T-reg cells are those cells enriched by immunomagnetic selection of CD25+ cells, and further purified by flow cytometric cell sorting for the CD15+, CD4+, CD127dim, FoxP3+ cell population. These cells are an enriched but naturally-occurring T-cell population.

T-con cells are unseparated/unfractionated cells, ie, as collected by the peripheral blood stem cells apheresis procedure.

Post-transplant follow-up is for 5 years.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   up to 60 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

RECIPIENT

  • Histopathologically-confirmed:
  • Acute leukemia (in first remission with poor risk factors and molecular prognosis)
  • Acute myelogenous leukemia (AML) with -5,-7, t (6;9), tri8, -11
  • Acute lymphoblastic leukemia (ALL) with Ph+ t (9;22), t (4;22), (q34;q11)
  • Acute leukemia with refractory disease or > Complete Remission (CR) 1
  • Chronic myelogenous leukemia (CML) (accelerated, blast or second chronic phase)
  • Myelodysplastic syndrome (in high and high intermediate risk categories)
  • Non-Hodgkin's lymphoma (NHL) with poor risk features and not suitable for autologous transplantation
  • Refractory Chronic lymphocytic leukemia (CLL)
  • At least 21 days from the end of most recent prior therapy to start of the transplant conditioning regimen
  • Must be < 60 years old at time of registration.
  • Karnofsky Performance Status (KPS) > 70%

Must have related donor who is:

  • Genotypically human leukocyte antigen (HLA) -A, B,C and DR beta 1 (DRB1), DQ loci haploidentical to the recipient (but differing for 2 to 3 HLA alleles on the unshared haplotype in the graft-versus-host disease (GvHD) direction)
  • No HLA-matched sibling or matched-unrelated donor is identified.
  • Adequate cardiac and pulmonary function (left ventricular ejection fraction (LVEF) > 45%, diffusing capacity of the lungs for carbon monoxide (DLCO) >50% corrected for hemoglobin)
  • Serum creatinine < 1.5 mg/dL OR Creatinine clearance > 50 mL/min for those above serum creatinine at least 1.5 mg/dL
  • Serum bilirubin < 2.0 mg/dL
  • Alanine transaminase (ALT) < 2x upper normal limit (ULN) (unless secondary to disease)
  • No prior myeloablative therapy or hematopoietic cell transplantation

DONOR:

  • Age ≤ 70 years
  • Weight ≥ 25 kg.
  • Medical history and physical examination confirm good health status as defined by institutional standards
  • Seronegative for HIV Ag within 30 days of apheresis collection for:
  • Hepatitis B surface antigen (sAg) or polymerase chain reaction (PCR) +
  • Hepatitis C ab or PCR+
  • Genotypically haploidentical as determined by HLA typing
  • Female donors (child-bearing potential) must have a negative serum or urine beta-human chorionic gonadotropin (HCG) test within 3 weeks of mobilization
  • Capable of undergoing leukapheresis
  • Has adequate venous access
  • Willing to undergo insertion of a central catheter if leukapheresis via peripheral vein is inadequate
  • Capable of agreeing to second donation of peripheral blood progenitor cell (PBPC) (or a bone marrow harvest) should the patient fail to demonstrate sustained engraftment following the transplant
  • Institutional review board (IRB)-approved consent form signed by donor or legal guardian > 18 years of age

Donor Selection in the priority order:

  • Recipient's biological mother preferred, if available
  • Other available haploidentical donors will be selected based upon the presence of natural killer (NK) alloreactivity between donor and recipient by high-resolution HLA typing of the C locus. An NK-alloreactive donor will be preferentially chosen. Recipients lacking a killer immunoglobulin-like receptor (KIR)-ligand present in the donor along with the corresponding KIR defines "NK alloreactivity".
  • If more than one NK-alloreactive donor is available, preference is to cytomegalovirus (CMV)-seronegative donor

Exclusion Criteria

RECIPIENT:

  • Suitable candidate for autologous transplantation or allogeneic transplantation with an available matched-related or matched-unrelated donor
  • Seropositive for:
  • HIV ab
  • Hepatitis B sAg or PCR+
  • Hepatitis C ab or PCR+
  • History of invasive Aspergillosis
  • Any active, uncontrolled bacterial, viral or fungal infection
  • Uncontrolled central nervous system (CNS) disease involvement
  • Lactating female

DONOR:

  • Evidence of active infection or viral hepatitis
  • Factors of increased risk for complications from leukapheresis or granulocyte-colony stimulating factor (G-CSF) therapy
  • Lactating female
  • HIV-positive
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01050764


Locations
United States, California
Stanford University School of Medicine
Stanford, California, United States, 94305
Sponsors and Collaborators
Everett Meyer
Doris Duke Charitable Foundation
Investigators
Principal Investigator: Everett H Meyer, MD, PhD Stanford University
  More Information

Responsible Party: Everett Meyer, Assistant Professor of Medicine (Blood and Marrow Transplantation), Stanford University
ClinicalTrials.gov Identifier: NCT01050764     History of Changes
Other Study ID Numbers: IRB-15919
BMT204 ( Other Identifier: OnCore )
SU-03312009-2059 ( Other Identifier: Stanford University )
First Submitted: January 11, 2010
First Posted: January 15, 2010
Results First Submitted: February 14, 2017
Results First Posted: May 11, 2017
Last Update Posted: May 11, 2017
Last Verified: April 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Leukemia
Myelodysplastic Syndromes
Preleukemia
Lymphoma, Non-Hodgkin
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Lymphoma
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Myeloproliferative Disorders
Fludarabine
Fludarabine phosphate
Melphalan
Thiotepa
Antineoplastic Agents
Thymoglobulin
Antilymphocyte Serum
Vidarabine