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.
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
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
14
Stanford University, School of Medicine
Palo Alto, California, United States
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.
Time frame: Up to day 180
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.
Time frame: Baseline to day 42
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.
Time frame: At day 180
Successful achievement of cGVHD partial response or Complete response by the NIH consensus criteria
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.
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Time frame: Up to day 180
The ability to reduce steroid requirements to <0.25 mg/kg-day
Time frame: At day 180
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.
Time frame: Baseline to day 180