Cyclophosphamide + Abatacept for Graft-versus-Host Disease

Overseen By Jessika Reiner

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Dimitrios Tzachanis, MD PhD

Must not be taking: Investigational agents

Disqualifiers: Active infection, Heart failure, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

43 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to investigate whether the combination of cyclophosphamide and abatacept versus the treatment used in standard of care will reduce the incidence of moderate and severe chronic graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation. GVHD occurs when the cells from your donor (the graft) see your body's cells (the host) as different and attack them.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, you cannot be on any other investigational agents in the last 28 days before joining the trial.

What data supports the effectiveness of the drug abatacept for graft-versus-host disease?

Research shows that abatacept can help prevent severe acute graft-versus-host disease and improve outcomes in patients with chronic graft-versus-host disease who do not respond to steroids. In clinical trials, abatacept was well-tolerated and led to significant improvements in patient conditions, including reduced need for other medications. ^{1 2 3 4 5}

Is the combination of Cyclophosphamide and Abatacept safe for treating Graft-versus-Host Disease?

Abatacept has been shown to be generally safe in clinical trials for treating graft-versus-host disease, with no serious side effects reported and no dose-limiting toxicities. Cyclophosphamide's safety in patients with organ dysfunctions is less clear, but abatacept has been well-tolerated in various studies, including those involving heavily pretreated patients. ^{1 2 3 4 5}

How is the drug combination of Cyclophosphamide and Abatacept unique for treating graft-versus-host disease?

The combination of Cyclophosphamide and Abatacept is unique because Abatacept acts as a T cell costimulation blocker, which helps prevent severe acute graft-versus-host disease by modulating the immune response, and Cyclophosphamide is used post-transplant to manage organ dysfunctions, making this combination a novel approach for patients with high-risk conditions. ^{1 2 3 4 6}

Research Team

Divya Koura, MD

Principal Investigator

University of California, San Diego

Dimitrios Tzachanis, MD PhD

Principal Investigator

University of California, San Diego

Eligibility Criteria

This trial is for people with high-risk blood cancers needing a stem cell transplant and who have a perfectly matched or half-matched donor. They should not be pregnant, breastfeeding, or on other experimental drugs recently. People with active cancer relapse, short life expectancy, certain leukemia types in early stages, or uncontrolled infections and heart problems can't join.

Inclusion Criteria

Creatinine clearance > 40

I have a high-risk blood cancer needing a stem cell transplant.

My liver is working well.

Exclusion Criteria

My blood cancer can be treated with options other than a transplant.

I cannot find a perfectly matched or half-matched donor for a transplant.

My cancer has come back after treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning

Participants undergo a conditioning regimen with Busulfan/Fludarabine or Total Body Irradiation

1-2 weeks

Treatment

GVHD prophylaxis with high dose Cyclophosphamide on Days +3 and +4 followed by abatacept for 6 months in the experimental arm, or methotrexate and tacrolimus in the standard of care arm

6 months

Multiple visits for drug administration on specified days

Follow-up

Participants are monitored for the occurrence of moderate and severe chronic GVHD and other outcomes

1 year

Treatment Details

Interventions

• Abatacept
• Cyclophosphamide

Trial Overview The study compares the effectiveness of Cyclophosphamide and Abatacept combination to standard treatments in preventing severe chronic graft-versus-host disease after stem cell transplantation. This condition happens when transplanted cells attack the patient's own body cells.

Participant Groups

Group I: Cyclophosphamide and abatacept Experimental Treatment 2 Interventions

The GVHD prophylaxis regimen on the experimental arm will consist of high dose Cyclophosphamide on Days +3 and +4 followed by abatacept for 6 months. Abatacept at a dose of 10mg/kg will be administered on days +5, +14 and +28, +56, +84, +112, +140, +168

Group II: methotrexate and tacrolimus Active Control 2 Interventions

The GVHD prophylaxis regimen on the standard of care arm will consist of methotrexate on Days +1,+3, +6 and +11 and tacrolimus

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?

Dimitrios Tzachanis, MD PhD

Lead Sponsor

Trials

1

Recruited

40+

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 case report involving 4 pediatric patients undergoing haplo-hematopoietic cell transplantation, the addition of abatacept (Aba) for graft-versus-host disease (GVHD) prophylaxis resulted in reliable engraftment and acceptable levels of GVHD, even in patients with organ dysfunction.

All 4 patients remained alive with full donor chimerism, and 3 of them were able to discontinue immunosuppressants, suggesting that an Aba-based regimen can be a safe and effective alternative when traditional posttransplant cyclophosphamide is not feasible.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abatacept-based Graft-Versus-Host Disease Prophylaxis in Haplo-identical Hematopoietic Cell Transplant in a High-risk Cohort. Raffa, EH., Srinivasan, A., Wall, DA., et al.[2022]

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]

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]

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 study of 75 patients aged 2-20 years who underwent T replete haploidentical transplantation, 13% developed hyperacute steroid-refractory graft-versus-host disease (SR-GVHD), highlighting the serious challenges in treating this condition.

The treatment regimen combining Abatacept with anti-cytokine agents showed promising results, achieving a 100% response rate at day 29 and leading to long-term disease-free survival in two patients, suggesting this approach may be worth further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T cell costimulation blockade for hyperacute steroid refractory graft versus-host disease in children undergoing haploidentical transplantation. Jaiswal, SR., Zaman, S., Chakrabarti, A., et al.[2018]

References

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

Abatacept-based Graft-Versus-Host Disease Prophylaxis in Haplo-identical Hematopoietic Cell Transplant in a High-risk Cohort. [2022]

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

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

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

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

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. England pubmed.ncbi.nlm.nih.gov

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

6. Netherlands pubmed.ncbi.nlm.nih.gov

T cell costimulation blockade for hyperacute steroid refractory graft versus-host disease in children undergoing haploidentical transplantation. [2018]