Extended vs Short-Term Abatacept Dosing for Graft-versus-Host Disease (ABA3 Trial)
Recruiting in Palo Alto (17 mi)
+13 other locations
Age: Any Age
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Boston Children's Hospital
Prior Safety Data
Breakthrough Therapy
Approved in 4 jurisdictions
Trial Summary
What is the purpose of this trial?This is a multicenter randomized, double blind, Phase 2 trial for patients receiving transplants from 7 of 8 HLA matched donors, in which an extended dosing regimen of abatacept, and a short-term dosing regimen + placebo, when added to standard calcineurin inhibitor + methotrexate-based prophylaxis, will be compared for their ability to improve outcomes in patients with a minimum follow-up of one year post-transplant. All patients will receive 4 doses of abatacept (Days -1, +5, +14, +28). Prior to the fifth dose, patients will be randomly assigned to the 4-dose abatacept arm and receive 4 doses of placebo or 8-dose abatacept arm and receive 4 more doses of abatacept. The primary endpoint of the study will be severe AGVHD-free, severe CGVHD-free, relapse-free survival (SGRFS). The study will end when the last patient has reached 2 years after transplant. Results will first be calculated and the study unblinded when the last patient has reached one year post-transplant.
How is the drug abatacept unique in treating graft-versus-host disease?
Abatacept is unique because it works by blocking T-cell activation, which is a different approach compared to traditional treatments. It has shown promise in reducing the need for steroids and improving outcomes in patients with steroid-refractory chronic graft-versus-host disease.
12345Will I have to stop taking my current medications?
The trial protocol does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.
Is abatacept safe for humans?
Abatacept has been shown to be generally safe in humans, with studies reporting it was well-tolerated and had few serious side effects when used for conditions like graft-versus-host disease. It has been used safely in combination with other medications to prevent and treat this condition.
12456What data supports the effectiveness of the drug abatacept for graft-versus-host disease?
Research shows that abatacept, when used in patients with steroid-refractory chronic graft-versus-host disease, led to a 58% response rate and was well tolerated. It also helped reduce the use of prednisone, a common steroid, by 51.3% in responders, indicating its potential effectiveness in managing this condition.
12456Eligibility Criteria
This trial is for patients at least 2 years old, weighing over 10 kg, with certain hematologic malignancies treatable by HCT and in remission. They need a partially matched unrelated donor and must not have severe psychiatric diseases, active infections, HIV, or inherited predispositions to cancer or transplant morbidities.Inclusion Criteria
I am mostly able to carry out normal activities without assistance.
I am at least 2 years old and weigh more than 10 kg.
My blood cancer is in remission and can be treated with a stem cell transplant.
Exclusion Criteria
My MDS does not have more than 5% blasts.
I am HIV positive.
I have had a stem cell transplant from a donor.
I do not have Chronic Lymphocytic Leukemia, Myeloma, or Primary Myelofibrosis.
My leukemia has minimal residual disease above 0.01%, making me ineligible.
I have not had severe acute or chronic graft-versus-host disease, nor has my condition worsened.
My kidney function is reduced, with a GFR under 50.
I do not have genetic conditions like Fanconi Anemia or Down Syndrome.
My cancer has returned and is active.
My lung function is very low or I need extra oxygen.
I do not have genetic conditions like Li-Fraumeni syndrome or BRCA mutations.
I do not have any ongoing serious infections.
I am currently being treated for active tuberculosis.
Participant Groups
The study compares extended versus short-term dosing of Abatacept added to standard GVHD prophylaxis in patients receiving transplants from mismatched donors. It aims to determine which regimen better prevents severe acute and chronic GVHD without relapse post-transplant.
2Treatment groups
Experimental Treatment
Placebo Group
Group I: Standard GVHD Prophylaxis + Abatacept Extended dosingExperimental Treatment1 Intervention
Standard GVHD prophylaxis of calcineurin inhibitor (cyclosporine or tacrolimus) and methotrexate + 8 doses of Abatacept.
Group II: Standard GVHD Prophylaxis + Abatacept + PlaceboPlacebo Group2 Interventions
Standard GVHD prophylaxis of calcineurin inhibitor (cyclosporine or tacrolimus) and methotrexate + 4 doses of Abatacept (investigational product) + 4 doses of Placebo.
Abatacept is already approved in European Union, United States, Canada, Japan for the following indications:
🇪🇺 Approved in European Union as Orencia for:
- Rheumatoid arthritis
- Polyarticular juvenile idiopathic arthritis
- Psoriatic arthritis
🇺🇸 Approved in United States as Orencia for:
- Rheumatoid arthritis
- Polyarticular juvenile idiopathic arthritis
- Psoriatic arthritis
🇨🇦 Approved in Canada as Orencia for:
- Rheumatoid arthritis
- Polyarticular juvenile idiopathic arthritis
🇯🇵 Approved in Japan as Orencia for:
- Rheumatoid arthritis
- Polyarticular juvenile idiopathic arthritis
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Oregon Health and Sciences UniversityPortland, OR
Children's Hospital of PhiladelphiaPhiladelphia, PA
University of RochesterRochester, NY
Washington University St. LouisSaint Louis, MO
More Trial Locations
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Who is running the clinical trial?
Boston Children's HospitalLead Sponsor
Bristol-Myers SquibbIndustry Sponsor
References
In vivo T cell costimulation blockade with abatacept for acute graft-versus-host disease prevention: a first-in-disease trial. [2015]We performed a first-in-disease trial of in vivo CD28:CD80/86 costimulation blockade with abatacept for acute graft-versus-host disease (aGVHD) prevention during unrelated-donor hematopoietic cell transplantation (HCT). All patients received cyclosporine/methotrexate plus 4 doses of abatacept (10 mg/kg/dose) on days -1, +5, +14, +28 post-HCT. The feasibility of adding abatacept, its pharmacokinetics, pharmacodynamics, and its impact on aGVHD, infection, relapse, and transplantation-related mortality (TRM) were assessed. All patients received the planned abatacept doses, and no infusion reactions were noted. Compared with a cohort of patients not receiving abatacept (the StdRx cohort), patients enrolled in the study (the ABA cohort) demonstrated significant inhibition of early CD4(+) T cell proliferation and activation, affecting predominantly the effector memory (Tem) subpopulation, with 7- and 10-fold fewer proliferating and activated CD4(+) Tem cells, respectively, at day+28 in the ABA cohort compared with the StdRx cohort (P
Phase 1 clinical trial evaluating abatacept in patients with steroid-refractory chronic graft-versus-host disease. [2021]Steroid-refractory chronic graft-versus-host disease (SR-cGVHD) remains a major cause of morbidity and mortality after allogeneic stem cell transplantation. Innovative immunotherapeutic strategies are urgently needed for the treatment of SR-cGVHD. We conducted a phase 1 clinical trial to evaluate the safety, efficacy, and immune effects of abatacept, a novel immunomodulatory drug that acts as an inhibitor of T-cell activation via costimulatory blockade, in the treatment of SR-cGVHD. The study followed a 3+3 design with 2 escalating abatacept doses: 3 mg/kg and 10 mg/kg, with an expansion cohort treated at 10 mg/kg. Abatacept was well-tolerated with no dose-limiting toxicities. Of the 16 evaluable patients, 44% achieved a clinical partial response per 2005 National Institutes of Health Consensus Criteria. Importantly, abatacept resulted in a 51.3% reduction in prednisone usage in clinical responders (mean baseline, 27 vs 14 mg; P = .01). Increased PD-1 expression on circulating CD4 (P = .009) and CD8 (P = .007) T cells was observed in clinical responders. In summary, abatacept was safe and led to a marked improvement in National Institutes of Health cGVHD scores and a significant reduction in prednisone use. In this cohort of heavily pretreated patients, the results suggest abatacept may be a promising therapeutic agent for SR-cGVHD, and a phase 2 trial has been initiated. This trial was registered at www.clinicaltrials.gov as #NCT01954979.
Abatacept GVHD prophylaxis in unrelated hematopoietic cell transplantation for pediatric bone marrow failure. [2023]Hematopoietic cell transplantation (HCT) is the only readily available cure for many life-threatening pediatric nonmalignant diseases (NMD), but most patients lack a matched related donor and are at higher risk for graft-versus-host disease (GVHD). Use of abatacept (Aba) to target donor T-cell activation has been safe and effective in preventing GVHD after unrelated donor (URD) HCT for malignant diseases (Aba2 trial). Our primary objective was to evaluate the tolerability of Aba added to standard GVHD prophylaxis (cyclosporine and mycophenolate mofetil) in pediatric patients with NMD undergoing URD HCT. In this single-arm, single-center phase 1 trial, 10 patients receiving reduced intensity or nonmyeloablative conditioning underwent URD HCT. Immune reconstitution was assessed longitudinally via flow cytometry and compared to pediatric patients on Aba2. Nine patients successfully engrafted, with 1 primary graft rejection in the setting of inadequate cell dose; secondary graft rejection occurred in 1 patient with concurrent cytomegalovirus viremia. Two deaths occurred, both unrelated to Aba. One patient developed probable posttransplant lymphoproliferative disease, responsive to rituximab and immune suppression withdrawal. No patients developed severe acute or chronic GVHD, and 8 patients were off systemic immunosuppression at 1 year. Immune reconstitution did not appear to be impacted by Aba, and preservation of naïve relative to effector memory CD4+ T cells was seen akin to Aba2. Thus, 4 doses of Aba were deemed tolerable in pediatric patients with NMD following URD HCT, with encouraging preliminary efficacy and supportive immune correlatives in this NMD cohort.
Role of abatacept in the prevention of graft-versus-host disease: current perspectives. [2023]Administration of abatacept following transplantation has been reported to inhibit graft rejection and graft-versus-host-disease (GvHD) in mouse models associated with allogeneic hematopoietic stem cell transplant (HSCT). This strategy has recently been adopted in clinical practice for GvHD prevention in human allogeneic HSCT and offers a unique approach to optimizing GvHD prophylaxis following alternative donor HSCTs. When combined with calcineurin inhibitors and methotrexate, abatacept had shown to be safe and effective in preventing moderate to severe acute GvHD in myeloablative HSCT using human leukocyte antigen (HLA) unrelated donors. Equivalent results are being reported in recent studies using alternative donors, in reduced-intensity conditioning HSCT and nonmalignant disorders. These observations have led to hypothesizing that even in the setting of increasing donor HLA disparity, abatacept when given with traditional GvHD prophylaxis does not worsen general outcomes. In addition, in limited studies, abatacept have being protective against the development of chronic GvHD through extended dosing and in the treatment of steroid-refractory chronic GvHD. This review summarized all the limited reports of this novels approach in the HSCT setting.
Phase 2 clinical trial evaluating abatacept in patients with steroid-refractory chronic graft-versus-host disease. [2023]Steroid-refractory chronic graft-versus-host disease (cGVHD) after allogeneic transplant remains a significant cause of morbidity and mortality. Abatacept is a selective costimulation modulator, used for the treatment of rheumatologic diseases, and was recently the first drug to be approved by the US Food and Drug Administration for the prophylaxis of acute graft-versus-host disease. We conducted a phase 2 study to evaluate the efficacy of abatacept in steroid-refractory cGVHD. The overall response rate was 58%, seen in 21 out of 36 patients, with all responders achieving a partial response. Abatacept was well tolerated with few serious infectious complications. Immune correlative studies showed a decrease in interleukin -1α (IL-1α), IL-21, and tumor necrosis factor α as well as decreased programmed cell death protein 1 expression by CD4+ T cells in all patients after treatment with abatacept, demonstrating the effect of this drug on the immune microenvironment. The results demonstrate that abatacept is a promising therapeutic strategy for the treatment of cGVHD. This trial was registered at www.clinicaltrials.gov as #NCT01954979.
Higher abatacept exposure after transplant decreases acute GVHD risk without increasing adverse events. [2023]In the ABA2 study, the T-cell costimulation blockade agent, abatacept, was safe and effective in preventing acute graft-versus-host disease (aGVHD) after unrelated-donor hematopoietic cell transplant (HCT), leading to US Food and Drug Administration approval. Here, we performed a determination of abatacept pharmacokinetics (PK), which enabled an examination of how abatacept exposure-response relationships affected clinical outcomes. We performed a population PK analysis of IV abatacept using nonlinear mixed-effect modeling and assessed the association between abatacept exposure and key transplant outcomes. We tested the association between the trough after dose 1 (Ctrough_1) and grade (GR) 2 or 4 aGVHD (GR2-4 aGVHD) through day +100. An optimal Ctrough_1 threshold was identified via recursive partitioning and classification tree analysis. This demonstrated that abatacept PK was characterized by a 2-compartment model with first-order elimination. The ABA2 dosing regimen was based on previous work targeting a steady-state abatacept trough of 10 μg/mL. However, a higher Ctrough_1 (≥39 μg/mL, attained in ∼60% of patients on ABA2) was associated with a favorable GR2-4 aGVHD risk (hazard ratio, 0.35; 95% confidence interval, 0.19-0.65; P