Ultra-Low Dose IL-2 Therapy as GVHD Prophylaxis in Haploidentical Allogeneic Stem Cell Transplantation
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|ClinicalTrials.gov Identifier: NCT02226861|
Recruitment Status : Active, not recruiting
First Posted : August 27, 2014
Last Update Posted : April 25, 2018
- Stem cell transplantation from a partially matched donor can lead to graft-versus-host disease (GVHD). Researchers want to learn how to improve these transplantations.
- To see if very low doses of Interleukin-2 after a partially matched transplantation prevent GVHD.
- Recipients: age 18 65, with certain bone marrow or lymphatic system diseases and an available family member with partial tissue match.
- Donors: age 18 80.
- Recipients will be screened with medical history, physical exam, and many tests including blood and tissue tying.
- Donors will be screened with medical history, physical exam, blood tests and tissue typing.
- Recipients will stay in the hospital 3 6 weeks.
- All participants will have apheresis. Blood is drawn from one arm, run through a machine that collects white blood cells, then returned into the other arm.
- Recipients will have:
- Intravenous (IV) line placed under the skin and into a neck vein, to stay throughout transplant and recovery. They may also have a catheter inserted for collecting immune cells.
- Bone marrow sample taken by needle. They will have 3 more after transplant.
- Donors will have:
- Filgrastim injected once daily for 5 6 days.
- Stem and immune cells collected by another apheresis.
- Recipients will get:
- Eight 30-minute doses of radiation, sitting at a machine.
- Donor immune cells by IV, 6 days before the transplant day.
- Chemotherapy drugs by IV.
<TAB><TAB>- Donor stem cells by IV on transplant day.
- After transplant, recipients will give self-injections of very low doses of Interleukin-2 once daily for about 12 weeks.
- Before and after transplant, recipients will get medicine to suppress the immune system and antibiotics to prevent infections
- Recipients must stay near NIH for 3 6 months after transplant.
- All recipients and donors will have 3 years of follow-up.
|Condition or disease||Intervention/treatment||Phase|
|Acute Lymphoblastic Leukemia (ALL) Acute Myelogenous Leukemia (AML) Chronic Lymphocytic Leukemia (CLL) Chronic Myelogenous Leukemia (CML) MDS||Device: CliniMACS CD34 selection system Biological: ULD IL-2||Phase 1|
Although allogeneic stem cell transplantation (allo-SCT) is a curative option for many hematologic malignancies, not all have a suitable donor. Haploidentical peripheral blood stem cell transplantation (haplo-SCT) has the advantage of immediate availability, higher stem cell dose, and feasibility of repeated cell collections for generating lymphocyte infusions to treat or prevent relapse or infection. However, haplo-SCT incurs a risk of bidirectional rejection with either severe graft versus host disease (GVHD) or graft rejection by the recipient. Therefore it is important to develop novel strategies to optimize the outcome of haplo-SCT. Designing a haplo-SCT that incorporates the concepts of modulating the immune system and allowing the opportunity for graft manipulation and/or adoptive immunotherapy may improve the treatment outcome. To achieve this, we are first interested in studying the immune modulatory effect of ultra-low dose Interleukin 2 (ULD IL-2) as GVHD prophylaxis.
This is an investigator initiated pilot study to determine the safety and feasibility of ULD IL-2 as GVHD prophylaxis in haploidentical allogeneic stem cell transplantation for patients with hematologic malignancies. Because GVHD has previously been associated with low numbers of circulating CD4+ CD25+FOXP3+ regulatory T cells (T(regs)), research efforts in increasing T(regs) either ex-vivo with adoptive transfer of T(regs) or in vivo using immunomodulatory agents such as IL-2, have shown promise in reducing incidences of GVHD.
The primary objective of this study is to evaluate safety and feasibility. Secondary objectives are to determine the incidences of acute and chronic GVHD, engraftment, overall survival, transplant related mortality, and relapse.
We will adopt the 2 step haplo-SCT method developed by Grosso et. al1 to study our method of GVHD prophylaxis. This 2 step approach, in which the lymphoid and myeloid portions of the graft are given in two separate steps in order to control and optimize T-cell, has already been published as a feasible and safe platform for haplo SCT for patients with hematologic malignancies and has been adopted by the Jefferson University Hospital (PA, USA), where they continue to treat patients under this protocol. As an additional GVHD prophylaxis, we will use sirolimus, an previously established GVHD prophylaxis which may work with ULD IL-2 synergistically to increase T(regs) .
The haploidentical donor will be mobilized by G-CSF and undergo one apheresis to collect lymphocytes and CD34+ stem cell product after Miltenyi CD34+ selection. The products will be cryopreserved until the time of transplantation. Recipients will receive a myeloablative conditioning regimen of fludarabine and total body irradiation (TBI) on days -10 to -6. After the last fraction of TBI, a donor lymphocyte infusion (DLI) product (2 times 10(8) CD3+/kg) will be given. Cyclophosphamide will be given on days -3 and -2, followed by CD 34+ selected donor stem cell product infused on day 0. Sirolimus will be initiated on day -1 until day+60. ULD-IL2 (100,000 IU/m2) will give subcutaneously daily for 12 weeks starting day +1.
This study will evaluate 14 recipients (ages greater than or equal to 18 - less than or equal to 75; planned accrual up to 20 recipient in event of replacement) with hematologic malignancies meeting indication for transplant but who do not have matched related or unrelated donor available. Safety will be monitored continuously with a stopping rule for toxicity based on the treatment-related serious adverse event rate (TRSAE). Safety monitoring will continue until at least 114 days after transplantation, and recipients experiencing adverse events will be monitored until toxicity resolution or stabilization. Stopping rule is defined as nonrelapse mortality and steroid refractory GVHD during the period of safety monitoring for ULD IL-2. Recipients will be followed for up to 3 years to evaluate the incidences of acute and chronic GVHD, engraftment, overall survival, transplant related mortality, and relapse.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||24 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Ultra Low Dose IL-2 Therapy as GVHD Prophylaxis in Haploidentical Allogeneic Stem Cell Transplantation|
|Study Start Date :||August 26, 2014|
|Estimated Primary Completion Date :||June 30, 2018|
|Estimated Study Completion Date :||June 30, 2019|
Subjects will receive CD34-selected stem cells followed by fixed dose ULG IL-2 (100,000 IU/m2) given subcutaneously for 12 weeks+Sirolimus until Day +60
Device: CliniMACS CD34 selection system
Stem cells will be selected with the CliniMACS system before transplant.Biological: ULD IL-2
sterile, white to off-white, preservative-free, lyophilized powder suitable for IV infusion upon reconstitution and dilution
- Safety of ULD IL-2 as GVHD proph [ Time Frame: 4 months ]The primary endpoint to this study is to evaluate the safety of ULD IL-2 as GVHD prophylaxis in haploidentical transplantation.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02226861
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Sawa Ito, M.D.||National Heart, Lung, and Blood Institute (NHLBI)|