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

Primary Purpose

Leukemia, Acute, Chronic Myelogenous Leukemia (CML), Myelodysplastic Syndrome (MDS)

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Regulatory T-cells
Conventional T-cells
Melphalan
Thiotepa
Fludarabine
Anti-thymocyte globulin, rabbit
CliniMACS CD34 Reagent System
Sponsored by
Everett Meyer
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Leukemia, Acute

Eligibility Criteria

undefined - 60 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Stanford University School of Medicine

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

T-reg Cell Infusion after Allogeneic Stem Cell Transplant

Arm Description

Outcomes

Primary Outcome Measures

Maximum-tolerated Dose (MTD) of Regulatory and Conventional T-cells
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)
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
Assessed as subjects remaining alive 12 months after CD34+ cell infusion (ie, excludes death due to any cause)
Median Overall Survival (OS)
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
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
Serious infections are reported as the number of participants experienced serious infections.

Full Information

First Posted
January 11, 2010
Last Updated
June 1, 2018
Sponsor
Everett Meyer
Collaborators
Doris Duke Charitable Foundation
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1. Study Identification

Unique Protocol Identification Number
NCT01050764
Brief Title
Haploidentical Allogeneic Transplant With Post-transplant Infusion of Regulatory T-cells
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
Study Type
Interventional

2. Study Status

Record Verification Date
June 2018
Overall Recruitment Status
Terminated
Why Stopped
Safety
Study Start Date
June 2009 (undefined)
Primary Completion Date
August 2012 (Actual)
Study Completion Date
June 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Everett Meyer
Collaborators
Doris Duke Charitable Foundation

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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).
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
10 (Actual)

8. Arms, Groups, and Interventions

Arm Title
T-reg Cell Infusion after Allogeneic Stem Cell Transplant
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Regulatory T-cells
Other Intervention Name(s)
T-reg cells
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Conventional T-cells
Other Intervention Name(s)
T-con cells
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Melphalan
Other Intervention Name(s)
L-PAM, L-Sarcolysin, Phenylalanine Mustard
Intervention Description
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)
Intervention Type
Drug
Intervention Name(s)
Thiotepa
Other Intervention Name(s)
thiophosphamide, TESPA, TSPA
Intervention Description
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)
Intervention Type
Device
Intervention Name(s)
Fludarabine
Other Intervention Name(s)
Fludarabine phosphate, Fludarabine 5'-monophosphate, FAMP, Fludara
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Anti-thymocyte globulin, rabbit
Other Intervention Name(s)
Thymoglobulin, rATG
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
CliniMACS CD34 Reagent System
Intervention Description
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.
Primary Outcome Measure Information:
Title
Maximum-tolerated Dose (MTD) of Regulatory and Conventional T-cells
Description
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).
Time Frame
30 days after HSCT infusion
Secondary Outcome Measure Information:
Title
Acute Graft-versus-Host-Disease (aGvHD)
Description
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.
Time Frame
1 year
Title
Overall Survival (OS), 1 Year
Description
Assessed as subjects remaining alive 12 months after CD34+ cell infusion (ie, excludes death due to any cause)
Time Frame
1 year
Title
Median Overall Survival (OS)
Description
Reported as the median overall survival (OS) in months from infusion of the hematopoietic stem cells (HSCT)
Time Frame
25 months
Title
To Measure the Incidence and Severity of Acute and Chronic GvHD
Description
Population of participants that received HSCT and T-reg plus T-con, and developed actue, chronic, or any graft vs host disease (GvHD)
Time Frame
1 year
Title
Serious Infections
Description
Serious infections are reported as the number of participants experienced serious infections.
Time Frame
1 year

10. Eligibility

Sex
All
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Everett H Meyer, MD, PhD
Organizational Affiliation
Stanford University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Stanford University School of Medicine
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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

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