Acute GVHD Suppression Using Costimulation Blockade to Expand Non-malignant Transplant (ASCENT)
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|ClinicalTrials.gov Identifier: NCT03924401|
Recruitment Status : Recruiting
First Posted : April 23, 2019
Last Update Posted : April 6, 2023
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This trial will see if extended abatacept administration (combined with a standard regimen of tacrolimus and mycophenolate mofetil) will prevent acute and chronic graft-versus-host disease (GVHD) in children and adolescents receiving unrelated donor (URD) hematopoietic stem cell transplantation (HSCT), without compromising their engraftment or reconstitution of protective immunity to infection.
The study will enroll 30 pediatric patients with serious non-malignant hematologic diseases (NMHD) undergoing URD HSCT. The trial will include patients with 7/8 donors and those with 8/8 (matched) donors. All participants will receive 8 doses of abatacept. Recruitment is expected to last for about 2 years and participants will be followed for up to 3 years.
|Condition or disease||Intervention/treatment||Phase|
|Graft Versus Host Disease||Drug: Abatacept||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||30 participants|
|Intervention Model:||Single Group Assignment|
|Intervention Model Description:||The trial will include two strata: one for patients with a 7/8 matched donor and one for those with a matched 8/8 donor.|
|Masking:||None (Open Label)|
|Official Title:||Acute GVHD Suppression Using Costimulation Blockade to Expand Non-malignant Transplant (ASCENT)|
|Actual Study Start Date :||August 22, 2019|
|Estimated Primary Completion Date :||March 2025|
|Estimated Study Completion Date :||March 2025|
Experimental: Participants Receiving Abatacept
Pediatric participants who are undergoing URD HSCT for serious NMHD will receive 8 doses of abatacept in addition to conventional GVHD prophylaxis.
All patients will receive 8 doses of abatacept (10 mg/kg intravenously on days -1, +5, +14, +28, +56, +84, +112, and +150) in addition to conventional GVHD prophylaxis.
Other Name: Orencia
- Event-free survival [ Time Frame: Up to 3 years ]Event-free survival is a composite endpoint defined as rejection-free, severe GVHD-free survival. Events for this outcome include death, severe (grade II-IV) acute GVHD up to day 100, moderate to severe chronic GVHD up to 1 year, and/or graft rejection up to 1 year.
- Cytomegalovirus (CMV) Viremia [ Time Frame: Up to Day 180 ]The number of participants experiencing cytomegalovirus (CMV) viremia will be reported. CMV viremia will be defined as the occurrence of a positive polymerase chain reaction (PCR) test prior to Day 180.
- CMV Invasive Disease [ Time Frame: Up to 2 years ]The number of participants experiencing CMV invasive disease will be reported. CMV invasive disease will be defined in accordance with the Blood and Marrow Transplant Clinical Trials Network Manual of Procedures.
- Post-transplant lymphoproliferative disease (PTLD) [ Time Frame: Up to 2 years ]The number of participants experiencing post-transplant lymphoproliferative disease (PTLD) will be reported. PTLD will be defined in accordance with the World Health Organization's (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues.
- Regimen-Related Toxicity [ Time Frame: Day 42 Post-transplant ]The number of participants experiencing regimen-related toxicity (RRT) will be reported. RRT will be scored according to the Bearman scale. Major RRT, defined as grade 4 (causing death) in any organ system or grade 3 for pulmonary, cardiac, renal, oral mucosal, neurologic, or hepatic, will be recorded.
- Neutrophil Recovery [ Time Frame: Up to Day 60 ]The time to neutrophil recover, in days, will be reported. Neutrophil recovery will be defined as the first of 3 consecutive days following the nadir that the absolute neutrophil count is at least 500/microliter of blood.
- Platelet Recovery [ Time Frame: Up to Day 60 ]The time to platelet recover, in days, will be reported. Platelet recovery will be defined as the first day that the platelet count is at least 50,000/microliter of blood, without a transfusion in the preceding 7 days.
- Non-Engraftment [ Time Frame: Day 28 ]The number of participants experiencing non-engraftment will be reported. Non-engraftment will be defined as lack of neutrophil recovery, or neutrophil recovery with lack of myeloid donor chimerism.
- Secondary Graft Failure [ Time Frame: Up to 3 years ]The number of participants experiencing secondary graft failure will be reported. Secondary graft failure will be defined by initial engraftment but subsequent development of an absolute neutrophil count (ANC) < 500/μl for fourteen consecutive days.
- Graft Loss [ Time Frame: Up to 3 years ]The number of participants experiencing graft loss will be reported. Graft loss will be defined by initial engraftment (assessed by neutrophil recovery and donor chimerism) with the subsequent loss of donor myeloid chimerism (regardless whether persistent neutropenia develops).
- Acute GVHD [ Time Frame: Up to 1 year ]The number of participants experiencing acute GVHD (including all grades and stratified by grades) will be reported. Acute GVHD will be assessed according to the Blood and Marrow Transplant Clinical Trials Network Manual of Procedures.
- Chronic GVHD [ Time Frame: Up to 2 years ]The number of participants experiencing chronic GVHD (including overlap syndrome) will be reported. Chronic GVHD will be assessed according to the Blood and Marrow Transplant Clinical Trials Network Manual of Procedures.
- Immune Suppression-Free Survival [ Time Frame: Year 2 ]The number of participants experiencing immune suppression-free survival will be reported. Immune suppression-free survival is measured as participant survival while off all systemic immunosuppressive agents.
- Immune Suppression-Free/Disease-Free Survival [ Time Frame: Year 2 ]The number of participants experiencing immune suppression-free/disease-free survival will be reported. Immune suppression-free/disease-free survival will be defined as rejection-free survival off all systemic immunosuppressive agents.
- Rejection-free survival [ Time Frame: Up to 3 years ]The number of participants experiencing rejection-free survival will be reported. Rejection-free survival will be defined as survival without non-engraftment, secondary graft failure, or graft loss.
- Overall survival [ Time Frame: Up to 3 years ]The number of participants experiencing surviving at the end of the study follow up period will be reported.
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, Learn About Clinical Studies.
|Ages Eligible for Study:||up to 20 Years (Child, Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- Patients with sickle cell disease (stratum 1) must be between the ages of 3-20.99 years and patients with other diseases (stratum 2) between the ages of 0-20.99 years at the time of admission for transplant.
Must have one of the following diseases:
- Glanzmann thrombasthenia
- Chronic granulomatous disease
- Severe congenital neutropenia (with resistance to granulocyte colony-stimulating factor (GCSF) or chronic requirement of GCSF doses ≥10 mcg/kg)
- Leukocyte adhesion deficiency
- Shwachman-Diamond syndrome
- Diamond-Blackfan Anemia (DBA; transfusion dependent, including steroid failure or inability to wean steroids)
- Thalassemia major
- Dyskeratosis congenita
- Chediak Higashi syndrome
- Acquired (immune; non-inherited, non-congenital) SAA
Any genotypic form of SCD with severe disease, defined as one or more of the following criteria:
- Previous clinical stroke, as evidenced by a neurological deficit lasting longer than 24 hours, which is accompanied by radiographic evidence of ischemic brain injury and cerebral vasculopathy.
Asymptomatic cerebrovascular disease, as evidenced by one the following:
- Progressive silent cerebral infarction, as evidenced by serial MRI scans that demonstrate the development of a succession of lesions (at least two temporally discreet lesions, each measuring at least 3 mm in greatest dimension on the most recent scan) or the enlargement of a single lesion, initially measuring at least 3 mm. Lesions must be visible on T2-weighted MRI sequences.
- Cerebral arteriopathy, as evidenced by abnormal TCD testing (confirmed elevated velocities in any single vessel of time-averaged mean of the maximum velocity (TAMMV) > 200 cm/sec for non-imaging TCD) or by significant vasculopathy on magnetic resonance angiograph (MRA; greater than 50% stenosis of > 2 arterial segments or complete occlusion of any single arterial segment).
- Frequent (3 or more per year for preceding 2 years) painful vaso-occlusive episodes (defined as episode lasting 4 hours or more and requiring hospitalization or outpatient treatment with parenteral opioids). If patient is on hydroxyurea and its use has been associated with a decrease in the frequency of episodes, the frequency should be gauged from the 2 years prior to the start of this drug.
- Recurrent (3 or more in lifetime) acute chest syndrome events which have necessitated erythrocyte transfusion therapy.
- Any combination of 3 or more acute chest syndrome episodes and vaso-occlusive pain episodes (defined as above) yearly for 3 years. If patient is on hydroxurea and its use has been associated with a decrease in the frequency of episodes, the frequency should be gauged from the 3 years prior to the start of this drug.
- Other inherited or congenital marrow failure syndromes complicated by SAA
- Other inherited or congenital red blood cell disorders requiring monthly chronic transfusion therapy.
- Congenital platelet disorders requiring frequent platelet transfusions (patient must have received at least 10 transfusions in the last 3 years).
- Other inherited or congenital granulocyte disorders resulting in at least three inpatient hospitalizations in the past three years for infection.
- Must have an unrelated adult donor (marrow or PBSC) who is a 7 or 8/8 match
- All patients and/or their parents or legal guardians must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.
- Must have been evaluated and adequately counseled regarding treatment options by a pediatric hematologist.
- Negative serum pregnancy test for females of childbearing potential only. Pregnancy must be excluded before the start of treatment with study drugs and prevented thereafter by reliable contraceptive methods.
- HLA matched related donor
- Pulmonary dysfunction defined as diffusing capacity of the lungs for carbon monoxide (DLCO; corrected for hemoglobin), forced expiratory volume in one second (FEV1), or forced vital capacity (FVC) < 40% of predicted. In a child unable to perform pulmonary function testing, a chronic need for supplemental oxygen will serve as the exclusionary criterion.
- Renal dysfunction defined as estimated glomerular filtration rate (GFR) of <60 ml/min/1.73m2.
- Severe cardiac dysfunction defined as shortening fraction < 25%.
- Bridging (portal to portal) fibrosis or cirrhosis of the liver
- Clinical stroke within 6 months of anticipated transplant
- Karnofsky or Lansky functional performance score < 50%
- HIV infection
- Uncontrolled viral, bacterial, fungal, or protozoal infection at the time of study enrollment.
- Patient with unspecified chronic toxicity serious enough to detrimentally affect the patient's capacity to tolerate HSCT.
- Patient or patient's guardian(s) unable to understand the nature and risks inherent in the HSCT process.
- History of non-compliance severe enough in the estimation of the treating team to preclude the patient from undergoing unrelated donor transplantation.
- Patient is pregnant or lactating.
- Patient with a 7/8 URD donor and HLA antibody testing (see below) demonstrating an antibody directed against a donor disparate HLA molecule.
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): NCT03924401
|Contact: Ben Watkins, MDfirstname.lastname@example.org|
|Contact: Elizabeth Stenger, MD, MScemail@example.com|
|United States, Alabama|
|Children's of Alabama||Recruiting|
|Birmingham, Alabama, United States, 35233|
|United States, Delaware|
|Nemours/Alfred I. DuPont Hospital for Children||Recruiting|
|Wilmington, Delaware, United States, 19803|
|United States, Georgia|
|Childrens Healthcare of Atlanta||Recruiting|
|Atlanta, Georgia, United States, 30322|
|United States, Illinois|
|Ann & Robert H. Lurie Children's Hospital of Chicago||Recruiting|
|Chicago, Illinois, United States, 60611|
|United States, Massachusetts|
|Dana-Farber Cancer Institute||Recruiting|
|Boston, Massachusetts, United States, 02215|
|United States, Mississippi|
|University of Mississippi Medical Center, Children's Center for Cancer and Blood Disorders||Recruiting|
|Jackson, Mississippi, United States, 39216|
|Contact: Sarah Elizabeth Elkin, NP-C 601-984-2701 firstname.lastname@example.org|
|Principal Investigator: Dereck Davis, MD|
|United States, New Jersey|
|Hackensack Meridian Health||Recruiting|
|Hackensack, New Jersey, United States, 07601|
|United States, New York|
|Oishei Children's Hospital||Recruiting|
|Buffalo, New York, United States, 14203|
|Columbia University Irving Medical Center||Recruiting|
|New York, New York, United States, 10032|
|Contact: Chez Brivett 212-304-7806 email@example.com|
|Principal Investigator: Monica Bhatia, MD|
|Principal Investigator:||John Horan, MD||Emory University|
|Responsible Party:||John Horan, Associate Professor, Emory University|
|Other Study ID Numbers:||
|First Posted:||April 23, 2019 Key Record Dates|
|Last Update Posted:||April 6, 2023|
|Last Verified:||April 2023|
|Individual Participant Data (IPD) Sharing Statement:|
|Plan to Share IPD:||No|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
Non-malignant hematologic diseases
Severe aplastic anemia
Sickle cell disease
Hematopoietic stem cell transplantation
Mismatched unrelated donor
Matched unrelated donor
Graft vs Host Disease
Immune System Diseases
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological
Physiological Effects of Drugs