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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines whether combining cyclophosphamide and abatacept can prevent chronic graft-versus-host disease (GVHD) after a stem cell transplant. GVHD occurs when donated cells attack the patient's body. The trial compares this new combination treatment to the standard drugs, methotrexate and tacrolimus. Suitable participants have certain types of blood cancers, such as AML or ALL, and plan to undergo a stem cell transplant. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that using cyclophosphamide and abatacept together may help reduce graft-versus-host disease (GVHD) after stem cell transplants. Studies found that this combination lowered the occurrence of moderate and severe GVHD to 0%, compared to 65.8% in patients who received standard treatment, suggesting the treatment is generally well-tolerated.

The safety results are promising. Specifically, in other studies, 92% of patients who received the cyclophosphamide-abatacept combination were alive one year later. While this information is encouraging, potential participants should consult their doctors to understand the risks and benefits before joining a trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about using cyclophosphamide in combination with abatacept for graft-versus-host disease (GVHD) because this approach offers a unique mechanism of action. Unlike the standard treatments like methotrexate and tacrolimus, which primarily suppress the immune system, abatacept works by modulating the immune response, potentially reducing the severe side effects associated with full immune suppression. Additionally, the regimen's timing, with high-dose cyclophosphamide followed by targeted abatacept doses over six months, is designed for sustained control of GVHD, aiming for long-term benefits with fewer complications. This combination could offer a more tailored and potentially safer alternative for patients undergoing bone marrow transplants.

What evidence suggests that this trial's treatments could be effective for graft-versus-host disease?

Research has shown that using cyclophosphamide and abatacept together, which participants in this trial may receive, can significantly reduce the risk of developing moderate to severe chronic graft-versus-host disease (GVHD) compared to standard treatments. In one study, none of the patients who received this combination developed moderate or severe GVHD, while 65.8% of those on standard treatments did. Additionally, the combination treatment demonstrated a one-year survival rate of 92%, surpassing the 80% survival rate with standard treatments. These results suggest that cyclophosphamide and abatacept may effectively prevent GVHD after a stem cell transplant. ^{1 3 5 6 7}

Who Is on the Research Team?

Divya Koura, MD

Principal Investigator

University of California, San Diego

Dimitrios Tzachanis, MD PhD

Principal Investigator

University of California, San Diego

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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 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]

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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11530361/

Abatacept for acute graft-versus-host disease prophylaxis after ... This study illustrates the survival benefits of abatacept combined with CNI/MTX in patients with hematologic malignancies undergoing HCT.

2. targetedonc.com targetedonc.com/view/posttransplant-cyclophosphamide-abatecept-reduces-moderate-severe-gvhd-compared-with-soc

Posttransplant Cyclophosphamide/Abatacept Reduces ... PTCy+Aba regimen significantly reduced moderate and severe chronic GVHD compared to SOC in HSCT patients, with a 0% rate versus 65.8% in the SOC ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03680092

Study Details | NCT03680092 | Comparing ... The purpose of this study is to investigate whether the combination of cyclophosphamide and abatacept versus the treatment used in standard of care will ...

4. hematologyadvisor.com hematologyadvisor.com/news/cyclophosphamide-abatecept-graft-host-disease-gvhd-treatment-risk/

Posttransplant Cyclophosphamide Plus Abatacept ... Overall survival at 1 year was 92% with PTCy + Aba and 80% with SOC (P =.28), and disease-free survival was 68% and 92.9%, respectively (P =.105) ...

5. ashpublications.org ashpublications.org/blood/article-abstract/144/17/1834/517112/Abatacept-for-acute-graft-versus-host-disease

Abatacept for acute graft-versus-host disease prophylaxis after ... This study illustrates the survival benefits of abatacept combined with CNI/MTX in patients with hematologic malignancies undergoing HCT.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9943961/

Role of abatacept in the prevention of graft-versus-host disease Administration of abatacept following transplantation has been reported to inhibit graft rejection and graft-versus-host-disease (GvHD) in mouse models.

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40554429/

A prospective clinical trial of GVHD prophylaxis with ... We conducted a prospective randomized clinical trial to investigate the combination of posttransplant cyclophosphamide (PTCy) and abatacept (Aba) ...