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Phase 1 Infused Donor T Regulatory Cells in Steroid Dependent/Refractory Chronic GVHD

Primary Purpose

Graft Versus Host Disease, Allogeneic Hematopoietic Cell Transplant Recipient

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Regulatory T Cells
Sponsored by
Laura Johnston
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Graft Versus Host Disease focused on measuring GVHD, cGVHD

Eligibility Criteria

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

Inclusion Criteria:

  • Steroid dependent/refractory cGVHD defined as:

    • Steroid dependent disease: Persistent cGVHD manifestations requiring a glucocorticoid dose >= prednisone 0.25 mg/kg/day (0.5 mg/kg orally [po] every other day) for at least 12 weeks
    • Steroid refractory disease: Progressive cGVHD manifestations despite treatment with a glucocorticoid dose >= prednisone 0.5 mg/kg/day (1 mg/kg po every other day) for at least 4 weeks
  • Participants must be receiving systemic glucocorticoid therapy for cGVHD; all immunosuppressive therapy may include but not be limited to tacrolimus, sirolimus, CellCept, cyclosporine, and systemic corticosteroid must be at stable doses for 28 days prior to the first cell infusion

  • Chronic GVHD manifestations that can be followed on physical or laboratory exam; these include but are not necessarily limited to:

    • Skin changes
    • Oral mucosa changes
    • Bronchiolitis obliterans
    • Ocular changes
  • Karnofsky performance status >= 60
  • Serum creatinine =< 2 mg/dL
  • Absolute neutrophil count (ANC) > 1 x 10^9/L
  • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 20 x upper limit of normal (ULN) or
  • Total bilirubin =< 10 x ULN
  • Allogeneic hematopoietic cell transplant recipient
  • Transfusion independent
  • Oxygen saturation during exertion is maintained at >= 88% on room air
  • Does not have clinically significant, symptomatic uncontrolled heart disease (e.g., unstable angina, congestive heart failure, or uncontrolled hypertension)
  • DONOR: Age >= 18 to =< 75 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 human leukocyte antigen (HLA) 7/8 or 8/8 matched at the HLA-A, B,C, DRB1
  • DONOR: Serologies for human immunodeficiency virus (HIV) antigen (Ag), HIV 1 and HIV 2 antibody (Ab), human T-lymphotropic virus type I (HTLV 1) and HTLV 2 Ab, hepatitis B surface antigen (sAg) or polymerase chain reaction positive (PCR+), or hepatitis C Ab or PCR+, Syphilis (Treponema) screen and HIV 1 and hepatitis C by nucleic acid testing (NAT) 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 three 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:

  • Original transplant utilized an unrelated donor graft
  • Uncontrolled infections that are not responsive to antimicrobial therapy
  • Progressive malignant disease, including post-transplant lymphoproliferative disease unresponsive to therapy
  • Second malignancy except for skin cancer within the last 5 years
  • Received any investigational agent =< 28 days before Treg infusions
  • Received filgrastim (GCSF) treatment within one month of enrollment
  • Received a donor lymphocyte infusion (DLI) or hematopoietic cell transplantation (HCT) within 3 months of enrollment
  • DONOR: Evidence of active infection or viral hepatitis
  • DONOR: HIV positive
  • DONOR: Pregnant donor

Sites / Locations

  • Stanford University, School of Medicine

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Regulatory T Cells

Arm Description

Cohort 1 at 1x105 Treg cells/kg, Cohort 2 at 5x105 Treg cells/kg and Cohort 3 at 1.5x106 Treg cells/kg with an extension phase at the MTD (or maximum administered dose if the MTD is not reached).

Outcomes

Primary Outcome Measures

The frequency of adverse events related to the donor Treg infusions (e.g., grade III-IV aGVHD by the modified Keystone criteria and grade 3 or higher infusional toxicities graded according to the CTCAE v. 4)
For infusion-related toxicities, recipients will be monitored for 1 hour after the Treg infusion. Additional toxicities which may occur during the first 28 days after the Treg infusions will count towards the assessment of safety and tolerability (DLT assessment) (e.g., development of aGVHD). Acute GVHD will be assessed using the modified Keystone criteria on Days 14, 28, 42, 56, 84 and 180 after the Treg infusion (or if the subject is exhibiting signs of aGVHD in-between study visits). Dose limiting toxicities are defined in Section 8. Only toxicities which occur during the first 28 days after the cell infusion will count towards the assessment of DLTs. A dose of Treg will be considered safe if DLTs occur in only 1/6 or 0/3 members of the cohort during the dose-escalation phase.

Secondary Outcome Measures

Change in absolute blood Treg levels
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.
Improvement in Failure Free Survival (FFS) over cGVHD
FFS is defined as the absence of a third line therapy (treatment failure). Estimated by the Kaplan-Meier product-limit method, with standard confidence limits.
Successful achievement of cGVHD partial response or Complete response by the NIH consensus criteria
Complete Response (CR) - Complete resolution of all reversible manifestations of cGVHD. Irreversible manifestations will be defined as (NIH consensus criteria) are: ocular xerosis, esophageal stricture, and bronchiolitis obliterans. Partial Response (PR) - At least a 25% absolute or 50% relative change (whichever is greater) when comparing start and end measurements in one cGVHD manifestation without worsening in the other manifestations. The results will be summarized in tabular form, with confidence intervals for the trinomial proportions.
The ability to reduce steroid requirements to <0.25 mg/kg-day
Change in >7 points on the Lee cGVHD Symptom scale relates to improvement in quality of life
A one-sample t-test will be used on the change in scale from baseline to months 1, 3, and 6.

Full Information

First Posted
July 15, 2013
Last Updated
September 20, 2021
Sponsor
Laura Johnston
Collaborators
National Institutes of Health (NIH)
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1. Study Identification

Unique Protocol Identification Number
NCT01911039
Brief Title
Phase 1 Infused Donor T Regulatory Cells in Steroid Dependent/Refractory Chronic GVHD
Official Title
A Phase 1 Safety and Tolerability Study of Infused Donor T Regulatory Cells in Steroid Dependent/Refractory Chronic Graft Versus Host Disease
Study Type
Interventional

2. Study Status

Record Verification Date
September 2021
Overall Recruitment Status
Completed
Study Start Date
July 2013 (undefined)
Primary Completion Date
December 31, 2017 (Actual)
Study Completion Date
July 31, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Laura Johnston
Collaborators
National Institutes of Health (NIH)

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
Chronic graft versus host disease (cGVHD) is a common complication of bone marrow or hematopoietic cell transplant from another person (allogeneic transplant). This study will determine if subjects with steroid dependent/refractory cGVHD can tolerate infusion of donor regulatory T cells and whether their cGVHD responds to the infusion.
Detailed Description
PRIMARY OBJECTIVES: Determine the safety and tolerability of donor T regulatory (Treg) cell infusions in subjects with steroid dependent/refractory chronic graft versus host disease. SECONDARY OBJECTIVES: Determine the quantitative blood Treg cell changes following the cell infusions Determine clinical efficacy of donor Treg cells as failure-free survival (FFS) defined by the absence of a new immunosuppressive therapy added, non-relapse mortality, and recurrent malignancy at Day 180 after the first Treg infusion In addition to FFS, the study will measure the change in: cGVHD symptom burden measured by the Lee cGVHD Symptom Scale by increase in >7 points NIH organ-specific cGVHD scale The reduction in daily corticosteroid requirement of prednisone to <=0.25 mg/kg-day at Day 180 after the first Treg infusion

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Graft Versus Host Disease, Allogeneic Hematopoietic Cell Transplant Recipient
Keywords
GVHD, cGVHD

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
Regulatory T Cells
Arm Type
Experimental
Arm Description
Cohort 1 at 1x105 Treg cells/kg, Cohort 2 at 5x105 Treg cells/kg and Cohort 3 at 1.5x106 Treg cells/kg with an extension phase at the MTD (or maximum administered dose if the MTD is not reached).
Intervention Type
Biological
Intervention Name(s)
Regulatory T Cells
Other Intervention Name(s)
donor Treg cell
Primary Outcome Measure Information:
Title
The frequency of adverse events related to the donor Treg infusions (e.g., grade III-IV aGVHD by the modified Keystone criteria and grade 3 or higher infusional toxicities graded according to the CTCAE v. 4)
Description
For infusion-related toxicities, recipients will be monitored for 1 hour after the Treg infusion. Additional toxicities which may occur during the first 28 days after the Treg infusions will count towards the assessment of safety and tolerability (DLT assessment) (e.g., development of aGVHD). Acute GVHD will be assessed using the modified Keystone criteria on Days 14, 28, 42, 56, 84 and 180 after the Treg infusion (or if the subject is exhibiting signs of aGVHD in-between study visits). Dose limiting toxicities are defined in Section 8. Only toxicities which occur during the first 28 days after the cell infusion will count towards the assessment of DLTs. A dose of Treg will be considered safe if DLTs occur in only 1/6 or 0/3 members of the cohort during the dose-escalation phase.
Time Frame
Up to day 180
Secondary Outcome Measure Information:
Title
Change in absolute blood Treg levels
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.
Time Frame
Baseline to day 42
Title
Improvement in Failure Free Survival (FFS) over cGVHD
Description
FFS is defined as the absence of a third line therapy (treatment failure). Estimated by the Kaplan-Meier product-limit method, with standard confidence limits.
Time Frame
At day 180
Title
Successful achievement of cGVHD partial response or Complete response by the NIH consensus criteria
Description
Complete Response (CR) - Complete resolution of all reversible manifestations of cGVHD. Irreversible manifestations will be defined as (NIH consensus criteria) are: ocular xerosis, esophageal stricture, and bronchiolitis obliterans. Partial Response (PR) - At least a 25% absolute or 50% relative change (whichever is greater) when comparing start and end measurements in one cGVHD manifestation without worsening in the other manifestations. The results will be summarized in tabular form, with confidence intervals for the trinomial proportions.
Time Frame
Up to day 180
Title
The ability to reduce steroid requirements to <0.25 mg/kg-day
Time Frame
At day 180
Title
Change in >7 points on the Lee cGVHD Symptom scale relates to improvement in quality of life
Description
A one-sample t-test will be used on the change in scale from baseline to months 1, 3, and 6.
Time Frame
Baseline to day 180

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Steroid dependent/refractory cGVHD defined as: Steroid dependent disease: Persistent cGVHD manifestations requiring a glucocorticoid dose >= prednisone 0.25 mg/kg/day (0.5 mg/kg orally [po] every other day) for at least 12 weeks Steroid refractory disease: Progressive cGVHD manifestations despite treatment with a glucocorticoid dose >= prednisone 0.5 mg/kg/day (1 mg/kg po every other day) for at least 4 weeks Participants must be receiving systemic glucocorticoid therapy for cGVHD; all immunosuppressive therapy may include but not be limited to tacrolimus, sirolimus, CellCept, cyclosporine, and systemic corticosteroid must be at stable doses for 28 days prior to the first cell infusion Chronic GVHD manifestations that can be followed on physical or laboratory exam; these include but are not necessarily limited to: Skin changes Oral mucosa changes Bronchiolitis obliterans Ocular changes Karnofsky performance status >= 60 Serum creatinine =< 2 mg/dL Absolute neutrophil count (ANC) > 1 x 10^9/L Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 20 x upper limit of normal (ULN) or Total bilirubin =< 10 x ULN Allogeneic hematopoietic cell transplant recipient Transfusion independent Oxygen saturation during exertion is maintained at >= 88% on room air Does not have clinically significant, symptomatic uncontrolled heart disease (e.g., unstable angina, congestive heart failure, or uncontrolled hypertension) DONOR: Age >= 18 to =< 75 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 human leukocyte antigen (HLA) 7/8 or 8/8 matched at the HLA-A, B,C, DRB1 DONOR: Serologies for human immunodeficiency virus (HIV) antigen (Ag), HIV 1 and HIV 2 antibody (Ab), human T-lymphotropic virus type I (HTLV 1) and HTLV 2 Ab, hepatitis B surface antigen (sAg) or polymerase chain reaction positive (PCR+), or hepatitis C Ab or PCR+, Syphilis (Treponema) screen and HIV 1 and hepatitis C by nucleic acid testing (NAT) 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 three 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: Original transplant utilized an unrelated donor graft Uncontrolled infections that are not responsive to antimicrobial therapy Progressive malignant disease, including post-transplant lymphoproliferative disease unresponsive to therapy Second malignancy except for skin cancer within the last 5 years Received any investigational agent =< 28 days before Treg infusions Received filgrastim (GCSF) treatment within one month of enrollment Received a donor lymphocyte infusion (DLI) or hematopoietic cell transplantation (HCT) within 3 months of enrollment DONOR: Evidence of active infection or viral hepatitis DONOR: HIV positive DONOR: Pregnant donor
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Laura Johnston
Organizational Affiliation
Stanford University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Stanford University, School of Medicine
City
Palo Alto
State/Province
California
ZIP/Postal Code
94305
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Phase 1 Infused Donor T Regulatory Cells in Steroid Dependent/Refractory Chronic GVHD

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