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Donor Regulatory T Cells in Treating Patients With Visceral Acute Graft-versus-Host Disease After Stem Cell Transplant

Primary Purpose

Graft Versus Host Disease

Status
Suspended
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
donor regulatory T lymphocytes
laboratory biomarker analysis
Sponsored by
Everett Meyer
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Graft Versus Host Disease

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Visceral aGVHD defined as: at least stage III/IV acute liver or stage II/III gastrointestinal (GI) GVHD by clinical criteria and/or GI and/or liver biopsy confirmation showing no alternative explanation for symptoms of GVHD
  • Ability to understand and willingness to sign a written informed consent form
  • Must have a 7/8 or 8/8 or haploidentical related donor matched at the human leukocyte antigen (HLA)-A, B, C, DRB1 who was evaluated and provided the donor transplant graft
  • Myeloablative or non-myeloablative allogeneic hematopoietic cell transplantation
  • Karnofsky performance status >= 50
  • DONOR: Age >= 18 to =< 77 years old
  • DONOR: Karnofsky performance status of >= 70% defined by institutional standards
  • DONOR: Must be the same sibling donor from whom the recipient's blood and marrow graft was collected for the original allogeneic transplant that is HLA 7/8 or 8/8 or haploidentical matched at the HLA-A, B, C, and DRB1
  • DONOR: Serologies for human immunodeficiency virus (HIV) antigen (Ag), HIV 1 and HIV 2 antibody (Ab), human T-cell lymphotropic virus (HTLV) 1 and HTLV 2 Ab, hepatitis B surface antigen (sAg) or polymerase chain reaction (PCR)+, or hepatitis C Ab or PCR+, syphilis (Treponema) screen and HIV 1 and hepatitis C by NAT (nucleic acid testing) have been collected prior to apheresis
  • DONOR: Female donors of child-bearing potential must have a negative serum or urine beta-human chorionic gonadotropin (HCG) test within two weeks of apheresis
  • DONOR: Capable of undergoing leukapheresis, have adequate venous access, and be willing to undergo insertion of a central catheter should leukapheresis via peripheral vein be inadequate
  • DONOR: Donor selection will be in compliance with 21 Code of Federal Regulations (CFR) 1271

Exclusion Criteria:

  • Uncontrolled infections not responsive to antimicrobial therapy requiring intensive critical care
  • Progressive malignant disease, including post-transplant lymphoproliferative disease unresponsive to therapy
  • Cytomegalovirus colitis or enteritis as defined by cytomegalovirus (CMV) shell vial or culture positivity from endoscopic biopsy the discretion of the treating physician based upon PCR positivity, clinical presentation and histology
  • Respiratory insufficiency with oxygen requirement > 4 L nasal cannula
  • Multi-organ failure
  • DONOR: Evidence of active infection or viral hepatitis
  • DONOR: HIV positive
  • DONOR: Pregnant donor
  • DONOR: Factors which place the donor at increased risk for complications from leukapheresis

Sites / Locations

  • Stanford University Hospitals and Clinics

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (donor regulatory T lymphocytes)

Arm Description

Patients receive donor regulatory T lymphocytes intravenously (IV) over 5 minutes or less on day 0. Some patients receive a second infusion of frozen donor regulatory T lymphocytes 5-7 days after the initial infusion or 2 additional infusions separated by 5-7 days.

Outcomes

Primary Outcome Measures

Incidence of grade 3 infusion reaction within 24 hours of infusion
Dose-limiting toxicity will be defined as CTCAE Grade 3 or higher cytokine/release syndrome/acute infusion reaction within 24 hours after Treg cell infusion. The rates of defined DLTs will be calculated and the one-sided upper 80%, 90%, and 95% confidence limits calculated.

Secondary Outcome Measures

Incidence of grade 3 or higher non-GVHD infusion-related adverse events
Incidence of grade 3 or higher non-GVHD infusion-related adverse events according to the CTCAE v4 that are not anticipated following HCT will be reported
Grade 4 (life threatening) or 5 (fatal) adverse events
Grade 4 (life threatening) or 5 (fatal) adverse events within after 28 days of Treg infusion that were otherwise unexpected in the immediate post transplant setting will be reported
Grade 4 (life threatening) respiratory distress
Grade 4 (life threatening) respiratory distress within 72 hours of Treg infusion will be reported
Change in blood Treg cell numbers following the infusions
The change in Treg cell counts from baseline to post infusion will be depicted in boxplots of both relative proportion and absolute numbers. Mean log (fold change) and confidence intervals will be calculated. The confidence intervals will be used to test the hypotheses of no change from baseline to post infusion.
Overall survival (OS)
The OS will be estimated by the Kaplan-Meier product-limit method, with standard confidence limits.
Incidence of cGVHD.
Incidence of cGVHD will be reported at Post HCT day +180

Full Information

First Posted
August 14, 2015
Last Updated
August 18, 2021
Sponsor
Everett Meyer
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT02526329
Brief Title
Donor Regulatory T Cells in Treating Patients With Visceral Acute Graft-versus-Host Disease After Stem Cell Transplant
Official Title
A Phase 1 Single Center Safety and Feasibility Study of Primary T Regulatory Cell Therapy to Treat Visceral Acute Graft-versus-Host Disease Following Hematopoietic Cell Transplantation
Study Type
Interventional

2. Study Status

Record Verification Date
August 2021
Overall Recruitment Status
Suspended
Why Stopped
Logistics
Study Start Date
August 6, 2015 (Actual)
Primary Completion Date
November 2022 (Anticipated)
Study Completion Date
June 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Everett Meyer
Collaborators
National Cancer Institute (NCI)

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
This phase I trial studies the side effects and best dose of donor regulatory T cells in treating patients with graft-versus-host disease affecting the liver or gastrointestinal organs (visceral) within 100 days (acute) after undergoing a stem cell transplant. Graft-versus-host disease occurs when donor immune cells infused in a stem cell transplant attack the gut, skin, liver, or other organ systems of the patient. Regulatory T cells are a type of immune cell that may be able to reduce the attack of the donor's immune cells on the patient's normal cells and help treat graft-vs-host disease.
Detailed Description
PRIMARY OBJECTIVES: I. Determine the safety and feasibility of donor T regulatory (Treg) cell infusions in subjects with visceral acute graft-versus-host disease (aGVHD) and incidence of dose limiting toxicities (DLTs) graded according to the Common Terminology Criteria for Adverse Events (CTCAE version 4 [v.4]) with a focus on infusion reactions within 24 hours, respiratory distress within 72 hours of infusion and all-cause mortality within 28 days of infusion. SECONDARY OBJECTIVES: I. Determine the quantitative blood Treg cell changes following the cell infusions. II. Assess dosing requirements and treatment response rates to primary steroid, secondary and tertiary immunosuppressive therapy. III. Post-transplant day +100 and day +180 survival. IV. Post-transplant incidence of chronic graft-versus-host disease (GVHD) at day +180. OUTLINE: This is a dose-escalation study. Patients receive donor regulatory T lymphocytes intravenously (IV) over 5 minutes or less on day 0. Some patients receive a second infusion of frozen donor regulatory T lymphocytes 5-7 days after the initial infusion or 2 additional infusions separated by 5-7 days. After completion of study treatment, patients are followed up weekly until day 28 and then on days 100 and 180.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Graft Versus Host Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
12 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment (donor regulatory T lymphocytes)
Arm Type
Experimental
Arm Description
Patients receive donor regulatory T lymphocytes intravenously (IV) over 5 minutes or less on day 0. Some patients receive a second infusion of frozen donor regulatory T lymphocytes 5-7 days after the initial infusion or 2 additional infusions separated by 5-7 days.
Intervention Type
Biological
Intervention Name(s)
donor regulatory T lymphocytes
Other Intervention Name(s)
donor CD4+CD25+FoxP3+ T cells
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Incidence of grade 3 infusion reaction within 24 hours of infusion
Description
Dose-limiting toxicity will be defined as CTCAE Grade 3 or higher cytokine/release syndrome/acute infusion reaction within 24 hours after Treg cell infusion. The rates of defined DLTs will be calculated and the one-sided upper 80%, 90%, and 95% confidence limits calculated.
Time Frame
24 hours
Secondary Outcome Measure Information:
Title
Incidence of grade 3 or higher non-GVHD infusion-related adverse events
Description
Incidence of grade 3 or higher non-GVHD infusion-related adverse events according to the CTCAE v4 that are not anticipated following HCT will be reported
Time Frame
Up to day 28
Title
Grade 4 (life threatening) or 5 (fatal) adverse events
Description
Grade 4 (life threatening) or 5 (fatal) adverse events within after 28 days of Treg infusion that were otherwise unexpected in the immediate post transplant setting will be reported
Time Frame
28 days
Title
Grade 4 (life threatening) respiratory distress
Description
Grade 4 (life threatening) respiratory distress within 72 hours of Treg infusion will be reported
Time Frame
72 hours
Title
Change in blood Treg cell numbers following the infusions
Description
The change in Treg cell counts from baseline to post infusion will be depicted in boxplots of both relative proportion and absolute numbers. Mean log (fold change) and confidence intervals will be calculated. The confidence intervals will be used to test the hypotheses of no change from baseline to post infusion.
Time Frame
Baseline to up to day 28
Title
Overall survival (OS)
Description
The OS will be estimated by the Kaplan-Meier product-limit method, with standard confidence limits.
Time Frame
Day 100
Title
Incidence of cGVHD.
Description
Incidence of cGVHD will be reported at Post HCT day +180
Time Frame
180 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Visceral aGVHD defined as: at least stage III/IV acute liver or stage II/III gastrointestinal (GI) GVHD by clinical criteria and/or GI and/or liver biopsy confirmation showing no alternative explanation for symptoms of GVHD Ability to understand and willingness to sign a written informed consent form Must have a 7/8 or 8/8 or haploidentical related donor matched at the human leukocyte antigen (HLA)-A, B, C, DRB1 who was evaluated and provided the donor transplant graft Myeloablative or non-myeloablative allogeneic hematopoietic cell transplantation Karnofsky performance status >= 50 DONOR: Age >= 18 to =< 77 years old DONOR: Karnofsky performance status of >= 70% defined by institutional standards DONOR: Must be the same sibling donor from whom the recipient's blood and marrow graft was collected for the original allogeneic transplant that is HLA 7/8 or 8/8 or haploidentical matched at the HLA-A, B, C, and DRB1 DONOR: Serologies for human immunodeficiency virus (HIV) antigen (Ag), HIV 1 and HIV 2 antibody (Ab), human T-cell lymphotropic virus (HTLV) 1 and HTLV 2 Ab, hepatitis B surface antigen (sAg) or polymerase chain reaction (PCR)+, or hepatitis C Ab or PCR+, syphilis (Treponema) screen and HIV 1 and hepatitis C by NAT (nucleic acid testing) have been collected prior to apheresis DONOR: Female donors of child-bearing potential must have a negative serum or urine beta-human chorionic gonadotropin (HCG) test within two weeks of apheresis DONOR: Capable of undergoing leukapheresis, have adequate venous access, and be willing to undergo insertion of a central catheter should leukapheresis via peripheral vein be inadequate DONOR: Donor selection will be in compliance with 21 Code of Federal Regulations (CFR) 1271 Exclusion Criteria: Uncontrolled infections not responsive to antimicrobial therapy requiring intensive critical care Progressive malignant disease, including post-transplant lymphoproliferative disease unresponsive to therapy Cytomegalovirus colitis or enteritis as defined by cytomegalovirus (CMV) shell vial or culture positivity from endoscopic biopsy the discretion of the treating physician based upon PCR positivity, clinical presentation and histology Respiratory insufficiency with oxygen requirement > 4 L nasal cannula Multi-organ failure DONOR: Evidence of active infection or viral hepatitis DONOR: HIV positive DONOR: Pregnant donor DONOR: Factors which place the donor at increased risk for complications from leukapheresis
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Everett Meyer
Organizational Affiliation
Stanford University Hospitals and Clinics
Official's Role
Principal Investigator
Facility Information:
Facility Name
Stanford University Hospitals and Clinics
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Donor Regulatory T Cells in Treating Patients With Visceral Acute Graft-versus-Host Disease After Stem Cell Transplant

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