Extended vs Short-Term Abatacept Dosing for Graft-versus-Host Disease

(ABA3 Trial)

Recruiting in Cincinnati (<99 mi)

+14 other locations

Overseen By Brandi M Bratrude, BA

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Boston Children's Hospital

Must be taking: Calcineurin inhibitors, Methotrexate

Disqualifiers: Chronic lymphocytic leukemia, Myeloma, Primary myelofibrosis, others

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 4-8 weeks

160 Participants Needed

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.

Will 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.

What 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. ^{1 2 3 4 5}

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. ^{1 2 3 4 5}

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. ^{1 2 3 4 6}

Eligibility 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

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.

I am mostly able to carry out normal activities without assistance.

If the patient does not meet defined eligibility requirements, the PI/study committee must be contacted to determine eligibility.

Exclusion Criteria

Pregnancy (positive serum b-HCG) or breastfeeding.

Exclusion Criteria Prior to Randomization (prior to 5th dose of abatacept/placebo):

My MDS does not have more than 5% blasts.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 4 doses of abatacept on Days -1, +5, +14, +28, followed by randomization to either 4 additional doses of placebo or 4 more doses of abatacept

4-8 weeks

Follow-up

Participants are monitored for severe AGVHD-free, severe CGVHD-free, relapse-free survival (SGRFS) with a minimum follow-up of one year post-transplant

1 year

Long-term follow-up

Participants continue to be monitored for outcomes such as severe chronic GVHD, non-relapse mortality, and relapse-free survival until 2 years post-transplant

1 year

Treatment Details

Interventions

• Abatacept
• Placebo

Trial Overview 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.

Participant Groups

Group I: Standard GVHD Prophylaxis + Abatacept Extended dosing Experimental Treatment 1 Intervention

Standard GVHD prophylaxis of calcineurin inhibitor (cyclosporine or tacrolimus) and methotrexate + 8 doses of Abatacept.

Group II: Standard GVHD Prophylaxis + Abatacept + Placebo Placebo Group 2 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

Who Is Running the Clinical Trial?

Boston Children's Hospital

Lead Sponsor

Trials

801

Recruited

5,584,000+

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Findings from Research

In a phase 2 study involving 36 patients with steroid-refractory chronic graft-versus-host disease (cGVHD), abatacept demonstrated an overall response rate of 58%, with all responders achieving a partial response, indicating its efficacy as a treatment option.

Abatacept was well tolerated, showing few serious infections, and it positively impacted the immune system by reducing levels of inflammatory markers like IL-1α and TNF-α, suggesting it modifies the immune microenvironment in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 clinical trial evaluating abatacept in patients with steroid-refractory chronic graft-versus-host disease. Koshy, AG., Kim, HT., Liegel, J., et al.[2023]

In a phase 1 clinical trial involving 16 patients with steroid-refractory chronic graft-versus-host disease (SR-cGVHD), the immunomodulatory drug abatacept was found to be safe and well-tolerated, with no dose-limiting toxicities reported.

Abatacept led to a 44% clinical partial response rate and a significant 51.3% reduction in prednisone usage among responders, indicating its potential as an effective treatment option for SR-cGVHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 clinical trial evaluating abatacept in patients with steroid-refractory chronic graft-versus-host disease. Nahas, MR., Soiffer, RJ., Kim, HT., et al.[2021]

Abatacept has been shown to effectively prevent moderate to severe acute graft-versus-host disease (GvHD) when used alongside traditional treatments in allogeneic hematopoietic stem cell transplants, particularly with unrelated donors.

Emerging evidence suggests that abatacept may also protect against chronic GvHD and can be beneficial in treating steroid-refractory cases, indicating its potential for broader applications in GvHD management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of abatacept in the prevention of graft-versus-host disease: current perspectives. Ngwube, A., Rangarajan, H., Shah, N.[2023]

In a first-in-disease trial involving patients undergoing unrelated-donor hematopoietic cell transplantation, the addition of abatacept significantly inhibited the proliferation and activation of CD4(+) T cells, particularly the effector memory subpopulation, compared to a control group.

The use of abatacept resulted in a low incidence of acute graft-versus-host disease (aGVHD), with only 2 out of 10 patients developing grade II-IV aGVHD by day +100, and no related deaths or transplantation-related mortality, suggesting its potential as an effective adjunct therapy for aGVHD prevention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vivo T cell costimulation blockade with abatacept for acute graft-versus-host disease prevention: a first-in-disease trial. Koura, DT., Horan, JT., Langston, AA., et al.[2015]

In the ABA2 study, the T-cell costimulation blockade agent abatacept was found to be safe and effective in preventing acute graft-versus-host disease (aGVHD) after unrelated-donor hematopoietic cell transplant, leading to its FDA approval.

A higher trough concentration of abatacept (≥39 μg/mL) was associated with a significantly reduced risk of grade 2-4 aGVHD, while no safety concerns were linked to this higher concentration, indicating a favorable risk-benefit profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Higher abatacept exposure after transplant decreases acute GVHD risk without increasing adverse events. Takahashi, T., Al-Kofahi, M., Jaber, M., et al.[2023]

In a phase 1 trial involving 10 pediatric patients with nonmalignant diseases undergoing unrelated donor hematopoietic cell transplantation, the addition of abatacept (Aba) to standard GVHD prophylaxis was found to be safe and well-tolerated, with no severe acute or chronic graft-versus-host disease (GVHD) observed.

The trial showed promising preliminary efficacy, as 9 out of 10 patients successfully engrafted and 8 were off systemic immunosuppression after one year, indicating that Aba may help in preventing GVHD without negatively impacting immune reconstitution.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abatacept GVHD prophylaxis in unrelated hematopoietic cell transplantation for pediatric bone marrow failure. Stenger, EO., Watkins, B., Rogowski, K., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

Phase 2 clinical trial evaluating abatacept in patients with steroid-refractory chronic graft-versus-host disease. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Phase 1 clinical trial evaluating abatacept in patients with steroid-refractory chronic graft-versus-host disease. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Role of abatacept in the prevention of graft-versus-host disease: current perspectives. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

In vivo T cell costimulation blockade with abatacept for acute graft-versus-host disease prevention: a first-in-disease trial. [2015]

5. United States pubmed.ncbi.nlm.nih.gov

Higher abatacept exposure after transplant decreases acute GVHD risk without increasing adverse events. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Abatacept GVHD prophylaxis in unrelated hematopoietic cell transplantation for pediatric bone marrow failure. [2023]