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

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2013 by Stanford University
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Laura Johnston, Stanford University
ClinicalTrials.gov Identifier:
NCT01911039
First received: July 15, 2013
Last updated: July 25, 2013
Last verified: July 2013
  Purpose

Two investigational devices, the CliniMACS cell selection system and the BD influx highspeed cell sorter, will be used together to isolate highly purified regulatory T cells from the donor's cellular product. It is believed that using these devices in combination will produce a cellular product that is highly purified to prevent the infusion of other T cells that may contribute to graft versus host disease.


Condition Intervention Phase
Graft Versus Host Disease
Allogeneic Hematopoietic Cell Transplant Recipient
Biological: Regulatory T Cells
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1 Safety and Tolerability Study of Infused Donor T Regulatory Cells in Steroid Dependent/Refractory Chronic Graft Versus Host Disease

Resource links provided by NLM:


Further study details as provided by Stanford University:

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) [ Time Frame: Up to day 180 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline to day 42 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: At day 180 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Up to day 180 ] [ Designated as safety issue: No ]
    1. 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.
    2. 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 [ Time Frame: At day 180 ] [ Designated as safety issue: No ]
  • Change in >7 points on the Lee cGVHD Symptom scale relates to improvement in quality of life [ Time Frame: Baseline to day 180 ] [ Designated as safety issue: No ]
    A one-sample t-test will be used on the change in scale from baseline to months 1, 3, and 6.


Estimated Enrollment: 20
Study Start Date: July 2013
Estimated Study Completion Date: July 2016
Estimated Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Regulatory T Cells
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).
Biological: Regulatory T Cells
Other Name: donor Treg cell

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:

  1. Determine the quantitative blood Treg cell changes following the cell infusions
  2. 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
  3. In addition to FFS, the study will measure the change in:

    1. cGVHD symptom burden measured by the Lee cGVHD Symptom Scale by increase in >7 points
    2. NIH organ-specific cGVHD scale
    3. The reduction in daily corticosteroid requirement of prednisone to <=0.25 mg/kg-day at Day 180 after the first Treg infusion
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01911039

Contacts
Contact: Joanne M Otani, RN, MSN, PHN 650-721-2372 joanne.otani@stanford.edu

Locations
United States, California
Stanford University Recruiting
Palo Alto, California, United States, 94305
Contact: Joanne Otani, RN, MSN, PHN    650-721-2372    mailto:joanne.otani@stanford.edu   
Principal Investigator: Laura J Johnston, MD         
Sub-Investigator: Sally Arai, MD, PhD         
Sub-Investigator: Ginna Laport, MD         
Sub-Investigator: Robert Lowsky, MD         
Sub-Investigator: Everett Meyer, MD, PhD         
Sub-Investigator: Joanne Otani, RN, MSN, PHN         
Sub-Investigator: Kevin Sheehan, PhD         
Sub-Investigator: Judith Shizuru, MD, PhD         
Sub-Investigator: Wen Kai Weng, MD, PhD         
Sponsors and Collaborators
Laura Johnston
  More Information

No publications provided

Responsible Party: Laura Johnston, Associate Professor, Stanford University
ClinicalTrials.gov Identifier: NCT01911039     History of Changes
Other Study ID Numbers: BMT253, 27285
Study First Received: July 15, 2013
Last Updated: July 25, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Stanford University:
GVHD
cGVHD

Additional relevant MeSH terms:
Graft vs Host Disease
Immune System Diseases

ClinicalTrials.gov processed this record on July 28, 2014