Trial of Regulatory T-cells Plus Low-Dose Interleukin-2 for Steroid-Refractory Chronic Graft-versus-Host-Disease

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by Dana-Farber Cancer Institute
Sponsor:
Collaborators:
Miltenyi Biotec GmbH
Prometheus Laboratories
Information provided by (Responsible Party):
John Koreth, MD, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier:
NCT01937468
First received: August 30, 2013
Last updated: June 27, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Chronic Graft Versus Host Disease
Chronic GVHD
Complications of Organ Transplant Stem Cells
Other: Treg-enriched infusion
Drug: Interleukin-2
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 I Trial of Regulatory T-cells Plus Low-Dose Interleukin-2 for Steroid-Refractory Chronic Graft-versus-Host-Disease

Resource links provided by NLM:


Further study details as provided by Dana-Farber Cancer Institute:

Primary Outcome Measures:
  • Adverse event profile and the maximum tolerate dose of Treg-enriched infusion plus 8-week low-dose IL-2 [ Time Frame: 24 weeks post Treg infusion, with continued follow-up for participants on extended duration IL-2 therapy. ] [ Designated as safety issue: Yes ]
    Adverse events are considered dose-limiting toxicities by the criteria defined in protocol Section 6.2. If 1 or 0 out of 5 participants in the same dose-level cohort experience a DLT, escalation to the next dose level will take place. If this is dose-level C, then dose C is the MTD. If 2 or more participants out of 5 in the same dose level experience a DLT, then the previous dose-level will be the MTD. If this is dose-level A, accrual will stop.


Secondary Outcome Measures:
  • To determine feasibility of Treg-enriched infusion plus 8-week low-dose IL-2 [ Time Frame: 2 Years ] [ Designated as safety issue: No ]
    In the first 10 products, if 6 or fewer products meet release criteria the system will be considered infeasible and the study will be terminated early.

  • Clinical response of cGVHD as defined by the NIH consensus criteria to Treg-enriched infusion plus 8-week low-dose IL-2 [ Time Frame: Baseline and 8 weeks post Treg infusion ] [ Designated as safety issue: No ]
    The investigators will grade the participants' cGVHD per the NIH guidelines at baseline and after 8 weeks of low-dose IL-2 post Treg infusion. cGVHD response will be assessed according to NIH consensus criteria.

  • Expansion of Treg cells in the peripheral blood after a Treg-enriched infusion plus 8-week low-dose IL-2 [ Time Frame: Baseline, end of weeks 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24 of study paticipation. Also every 8 weeks for participants continuing on extended duration IL-2 therapy ] [ Designated as safety issue: No ]
    Peripheral blood samples will be taken at the various time points for immunological analysis including the measure of quantitative changes in individual immune cell populations, plasma levels of IL-2, and immunosuppressive ability of the expanded Treg cells.


Estimated Enrollment: 25
Study Start Date: November 2013
Estimated Study Completion Date: July 2018
Estimated Primary Completion Date: November 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treg-enriched infusion plus 8-week low-dose Interleukin-2
Treg-enriched Cell Dose: Participants will be targeted to a defined dose of donor Treg-enriched total nucleated cells. Initial enrollment will be at target dose-level A. Subsequent cohorts will be dose escalated/de-escalated per the schema. Interleukin-2: Starting the day of Treg-enriched cell infusion, each participant will receive daily subcutaneous IL-2 for self-administration for 8 weeks, followed by a 4-week hiatus. IL-2 will be administered on an outpatient basis. Expected toxicities and potential risks as well as dose modifications are described in Section 6 (Expected Toxicities and Dosing Delays/Dose Modification).
Other: Treg-enriched infusion
Treg-enriched Cell Dose: Participants will be targeted to a defined dose of donor Treg-enriched total nucleated cells. Initial enrollment will be at target dose-level A. Subsequent cohorts will be dose escalated/de-escalated per the schema
Drug: Interleukin-2
Interleukin-2: Starting the day of Treg-enriched cell infusion, each participant will receive daily subcutaneous IL-2 for self-administration for 8 weeks, followed by a 4-week hiatus. IL-2 will be administered on an outpatient basis. Expected toxicities and potential risks as well as dose modifications are described in Section 6 (Expected Toxicities and Dosing Delays/Dose Modification).
Other Names:
  • Interleukin-2
  • IL-2

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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 eligible.
  • 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

Exclusion Criteria:

  • 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 acceptable)
  • History of thrombotic microangiopathy, hemolytic-uremic syndrome or thrombotic thrombocytopenic purpura
  • New chronic GVHD therapies (e.g. gleevec, extracorporeal photopheresis, rituximab, immunosuppressive medications) in the 4 weeks prior
  • Low-dose IL-2 therapy in the 4 weeks prior
  • Post-transplant exposure to T-cell or alternative 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 Principal Investigator.
  • 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 be discontinued.
  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: NCT01937468

Contacts
Contact: John Koreth, MBBS, DPhil (617) 632-2949 JKORETH@PARTNERS.ORG

Locations
United States, Massachusetts
Brigham and Women's Hospital Recruiting
Boston, Massachusetts, United States, 02215
Contact: John Koreth, DPhil, MBBS    617-632-2949    jkoreth@partners.org   
Principal Investigator: John Koreth, DPhil, MBBS         
Dana-Farber Cancer Insitute Recruiting
Boston, Massachusetts, United States, 02215
Contact: John Koreth, DPhil, MBBS    617-632-2949    jkoreth@partners.org   
Principal Investigator: John Koreth, MD         
Sponsors and Collaborators
Dana-Farber Cancer Institute
Miltenyi Biotec GmbH
Prometheus Laboratories
Investigators
Principal Investigator: John Koreth, MBBS, DPhil Dana-Farber Cancer Institute
  More Information

No publications provided

Responsible Party: John Koreth, MD, Principal Investigator, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT01937468     History of Changes
Other Study ID Numbers: 13-281, R01CA183559-01
Study First Received: August 30, 2013
Last Updated: June 27, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Dana-Farber Cancer Institute:
Chronic GVHD
Chronic graft versus host disease
Allogeneic stem cell transplant

Additional relevant MeSH terms:
Graft vs Host Disease
Immune System Diseases
Interleukin-2
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Central Nervous System Agents

ClinicalTrials.gov processed this record on July 23, 2014