Trial of Regulatory T-cells Plus Low-Dose Interleukin-2 for Steroid-Refractory Chronic Graft-versus-Host-Disease
Phase: Phase 1
NCT ID: NCT01937468
(View complete trial on ClinicalTrials.gov)
DFCI Protocol ID: 13-281
This research study is a Phase I clinical trial, which tests the safety of an investigational combination of IL-2 plus donor anti-inflammatory Treg cells and also tries to define the appropriate dose of the investigational combination of IL-2 plus donor anti-inflammatory Treg cells to use for further studies. IL-2 is involved with cell signaling and regulation of white blood cells (WBCs). WBCs are part of the immune system. Treg cells are also part of the immune system; they are involved with anti-inflammatory responses. "Investigational" means that the combination of IL-2 and anti-inflammatory Treg cell infusion is being studied. It also means that the FDA (U.S. Food and Drug Administration) has not approved the combination of IL-2 and anti-inflammatory Treg cell infusion for use in people with cGVHD. Chronic GVHD is a medical condition that may occur after you have received your bone marrow, stem cell or cord blood transplant from a donor. The donor's immune system may recognize your body (the host) as foreign and attempt to 'reject' it. This process is known as graft-versus-host disease. Traditional standard therapy to treat cGVHD is prednisone (steroids). Participants on this trial have not responded to steroid therapy. The investigators are looking to assess the safety and optimal dose for the combination of IL-2 plus donor anti-inflammatory Treg cells, that may help control cGVHD by stopping the donor's immune system from 'rejecting' your body.
Dana-Farber Cancer Institute, Brigham and Women's Hospital
John Koreth, MD,
Dana-Farber Cancer Institute
- Participants must meet the following criteria on screening examination to be eligible
to participate in the study:
- Recipient of allogeneic hematopoietic stem cell transplantation
- Participants must have steroid-refractory cGVHD despite use of 2 or more agents.
Steroid-refractory cGVHD is defined as having persistent signs and symptoms of cGVHD
(Appendix D; section 17.4) despite the use of prednisone at ≥ 0.25 mg/kg/day (or 0.5
mg/kg every other day) for at least 4 weeks (or equivalent dosing of alternate
glucocorticoids) without complete resolution of signs and symptoms. Participants with
either extensive chronic GVHD or limited chronic GVHD requiring systemic therapy are
- Stable dose of glucocorticoids for 4 weeks prior to enrollment
- No addition or subtraction of other immunosuppressive medications (e.g.,
calcineurin-inhibitors, sirolimus, mycophenolate-mofetil) for 4 weeks prior to
enrollment. The dose of immunosuppressive medicines may be adjusted based on the
therapeutic range of that drug
- Patient age 18 years old. Because no dosing or adverse event data are currently
available on the use of IL-2 in participants <18 years of age, children are excluded
from this study.
- ECOG performance status 0-2 (Appendix A; section 17.1)
- Participants must have adequate organ function as defined below:
- Hepatic: Adequate hepatic function (total bilirubin <2.0 mg/dl-exception permitted in
participants with Gilbert's Syndrome; AST (SGOT)/ALT (SGPT) ≤2x ULN), unless hepatic
dysfunction is a manifestation of presumed cGVHD. For participants with abnormal
LFTs as the sole manifestation of cGVHD, documented GVHD on liver biopsy will be
required prior to enrollment. Abnormal LFTs in the context of active cGVHD involving
other organ systems may also be permitted if the treating physician documents the
abnormal LFTs as being consistent with hepatic cGVHD, and a liver biopsy will not be
mandated in this situation.
- Pulmonary: FEV1 ≥ 50% or DLCO(Hb) ≥ 40% of predicted, unless pulmonary dysfunction is
deemed to be due to chronic GVHD
- Renal: Serum creatinine less than upper limit of normal institutional limits or
creatinine clearance > 60 mL/min/1.73 m2 for participants with creatinine levels
above institutional normal.
- Adequate bone marrow function indicated by ANC>1000/mm3 and platelets>50,000/mm3
without growth factors or transfusions
- Cardiac: No myocardial infarction within 6 months prior to enrollment or NYHA Class
III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular
arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction
system abnormalities. Prior to study entry, any ECG abnormality at screening must be
documented by the investigator as not medically relevant.
- The effects of IL-2 on the developing human fetus are unknown. For this reason and
because chemotherapeutic agents are known to be teratogenic, women of child-bearing
potential and men must agree to use adequate contraception (hormonal or barrier
method of birth control; abstinence) prior to study entry and for the duration of
study participation. Should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her treating physician immediately.
- Ability to understand and the willingness to sign a written informed consent document
- Participants who exhibit any of the following conditions at screening will not be
eligible for admission into the study.
- Ongoing prednisone requirement >1 mg/kg/day (or equivalent)
- Concurrent use of calcineurin-inhibitor plus sirolimus (either agent alone is
- History of thrombotic microangiopathy, hemolytic-uremic syndrome or thrombotic
- New immunosuppressive medication in the 4 weeks prior
- Extra-corporeal Photopheresis or rituximab therapy in the 4 weeks prior
- Post-transplant exposure to T-cell or IL-2 targeted medication (e.g. ATG,
alemtuzumab, basiliximab, denileukin diftitox) within 100 days prior
- Donor lymphocyte infusion within 100 days prior
- Active malignant relapse
- Active uncontrolled infection
- Inability to comply with IL-2 treatment regimen
- Organ transplant (allograft) recipient
- HIV-positive individuals on combination antiretroviral therapy are ineligible because
of the potential for pharmacokinetic interactions with the agents used after
allogeneic HSCT. In addition, these individuals are at increased risk of lethal
infections. Appropriate studies will be undertaken in participants receiving
combination antiretroviral therapy when indicated.
- Individuals with active uncontrolled hepatitis B or C are ineligible as they are at
high risk of lethal treatment-related hepatotoxicity after HSCT.
- Other investigational drugs within 4 weeks prior to enrollment, unless cleared by the
- Pregnant women are excluded from this study because of the potential for teratogenic
or abortifacient effects. Because there is an unknown but potential risk of adverse
events in nursing infants secondary to treatment of the mother, breastfeeding should