A Phase I Trial of Regulatory T-cells Plus Low-Dose Interleukin-2 for Steroid-Refractory Chronic Graft-versus-Host-Disease
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 25
- 试验地点
- 2
- 主要终点
- Adverse event profile and the maximum tolerate dose of Treg-enriched infusion plus 8-week low-dose IL-2
研究概览
简要总结
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.
详细描述
After the screening procedures confirm that you are eligible to participate in the research study: If you take part in this research study, you (and your donor) will have the following tests and procedures:
Donor Lymphocytes Collection: Lymphocytes are a type of white blood cell involved with the immune system. Your original marrow/stem cell donor will undergo one white blood cell collection procedures called leukapheresis. Blood from the vein in one arm will be circulated through a special machine to remove the white blood cells, and the rest of the blood will be returned to the donor's other arm. The cells collected from the leukapheresis will be sent to the laboratory where the amount of white blood cells collected will be measured. A sample will be removed for study testing, and the remaining lymphocytes will be set-aside for infusion.
Donor Lymphocyte Processing: Once the lymphocytes are collected from your donor, the CliniMACS System device will enrich (preferentially select) the number of Treg cells. Samples will be taken before and after processing by the CliniMACS System to examine the cells. After completing the necessary safety tests, the Treg-enriched donor lymphocyte cells will be ready for administration.
Donor Cellular Infusion (DCI): The Treg-enriched donor lymphocytes will be infused through an intravenous (I.V.) catheter over approximately 5-10 minutes. Prior to the infusion, you will receive Tylenol and Benadryl to prevent transfusion related reactions. You will be observed for about 1 hour after the infusion. The total anticipated time you will spend in the clinic is approximately 2 hours.
Since the investigators are looking for the highest one-time dose of the anti-inflammatory donor cells that can be administered safely in combination with IL-2 without severe or unmanageable side effects in participants that have cGVHD, not everyone who participates in this research study will receive the same dose of the donor cells. The cell dose you get will depend on the number of participants who have been enrolled in the study before you and how well they have tolerated their cell doses.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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. 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
排除标准
- •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.
研究组 & 干预措施
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).
干预措施: Treg-enriched infusion (Other)
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).
干预措施: Interleukin-2 (Drug)
结局指标
主要结局
Adverse event profile and the maximum tolerate dose of Treg-enriched infusion plus 8-week low-dose IL-2
时间窗: 24 weeks post Treg infusion, with continued follow-up for participants on extended duration IL-2 therapy.
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.
次要结局
- Clinical response of cGVHD as defined by the NIH consensus criteria to Treg-enriched infusion plus 8-week low-dose IL-2(Baseline and 8 weeks post Treg infusion)
- To determine feasibility of Treg-enriched infusion plus 8-week low-dose IL-2(2 Years)
- Expansion of Treg cells in the peripheral blood after a Treg-enriched infusion plus 8-week low-dose IL-2(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)
研究者
John Koreth, MD
Principal Investigator
Dana-Farber Cancer Institute