Cyclophosphamide + Bortezomib + Abatacept for Graft-versus-Host Disease

Not currently recruiting at 1 trial location

Overseen By Emma Futamura

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Northwell Health

Disqualifiers: Pregnancy, Heart failure, Recent malignancy, others

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

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

Compensation: Varies

Number of Visits: Unknown

Duration: 16 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three drugs—cyclophosphamide (also known as Cytoxan, Neosar, or Endoxan), bortezomib (also known as Velcade), and abatacept (also known as Orencia)—to determine their effectiveness in preventing graft-versus-host disease (GvHD) in individuals receiving a stem cell transplant for blood cancers. GvHD occurs when the donor's immune cells attack the recipient's body, making prevention essential. The trial suits adults with blood cancers planning a stem cell transplant from a closely matched donor. Participants should not have ongoing infections or serious heart issues and must be able to follow the study's procedures. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to crucial advancements in GvHD prevention.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Research shows that the combination of cyclophosphamide, bortezomib, and abatacept is under evaluation for safety in preventing graft-versus-host disease (GvHD) after a stem cell transplant. Previous studies found that abatacept, one of the drugs in this combination, managed GvHD in 58% of patients who did not respond to steroids, meaning more than half of these patients had a positive response to the treatment.

Abatacept is already used in some cases to prevent GvHD, indicating a certain level of safety. Cyclophosphamide and bortezomib are also well-known drugs used in transplants. As this trial is in the early stages, researchers are carefully monitoring for any side effects. Although safety data is still being collected, this combination has shown enough potential to warrant further testing. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of cyclophosphamide, bortezomib, and abatacept for graft-versus-host disease (GvHD) because it offers a novel approach to preventing this serious complication after stem cell transplants. Unlike standard treatments like corticosteroids and calcineurin inhibitors, which broadly suppress the immune system, this combination targets specific pathways that contribute to GvHD, potentially reducing side effects and improving outcomes. Cyclophosphamide helps modulate immune responses, bortezomib disrupts protein degradation in immune cells, and abatacept specifically inhibits T-cell activation. This targeted approach could lead to more effective and safer prevention of GvHD, making it a promising option for patients undergoing stem cell transplantation.

What evidence suggests that this trial's treatments could be effective for GvHD?

Research has shown that a combination of three drugs—cyclophosphamide, bortezomib, and abatacept—can help prevent graft-versus-host disease (GvHD) in patients receiving stem cell transplants. In this trial, participants undergoing Allogeneic Hematopoietic Stem Cell Transplantation will receive this combination to reduce the rate of GvHD. GvHD occurs when the donor's immune cells attack the patient's body. Studies have found that these drugs, when used together, lower the risk of GvHD. Adding abatacept to the usual treatments has improved transplant results, especially when the donor and patient are not a perfect match. This drug combination calms the immune system, making transplants safer and more successful. ^{4 5 6 7 8}

Who Is on the Research Team?

A. Samer Al-Homsi, MD, MBA

Principal Investigator

Northwell Health

Are You a Good Fit for This Trial?

Adults with blood cancers eligible for a stem cell transplant from a matched donor can join. They must have good organ function, no severe infections, and be willing to follow the study plan. Pregnant women, those with recent heart issues or another cancer within 3 years (with some exceptions), or who cannot consent are excluded.

Inclusion Criteria

Total bilirubin <2 x the upper limit of normal (except for Gilbert's syndrome)

I do not have any worsening infections.

Creatinine clearance >50 mL/min/1.72m2

Exclusion Criteria

Inability to provide informed consent.

Prisoners

Participation in clinical trials with other investigational agents not included in this trial, within 14 days of the start of this trial and throughout the duration of this trial.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning and Transplantation

Participants receive a standard of care conditioning regimen followed by peripheral blood hematopoietic stem cells transplantation

1-2 weeks

Treatment

Participants receive investigational PTCy, bortezomib, and abatacept as GvHD prophylaxis

16 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including overall survival and GvHD outcomes

104 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Abatacept
• Bortezomib
• Cyclophosphamide

Trial Overview The trial tests high-dose Cyclophosphamide, Bortezomib, and Abatacept as preventatives for Graft-versus-Host Disease after allogeneic HSCT in adults. It's a phase I-II study assessing the safety and effectiveness of these drugs post-transplant.

How Is the Trial Designed?

Group I: Participants with hematological malignancies Experimental Treatment 3 Interventions

Participants undergoing Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) will receive a combination of cyclophosphamide, known commercially as Cytoxan®, abatacept, known as Orecia® and bortezomib commercially known as Velcade®, to reduce the rate of graft-versus-host disease (GvHD). These medications will be given for GvHD prevention during the transplant process.

Cyclophosphamide is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

Northwell Health

Lead Sponsor

Trials

481

Recruited

470,000+

NYU Langone Health

Lead Sponsor

Trials

1,431

Recruited

838,000+

Published Research Related to This Trial

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 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]

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 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]

Citations

1. 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) ...

2. cancer.gov cancer.gov/clinicaltrials/NCI-2022-02279

Cyclophosphamide, Bortezomib and Abatacept after Donor ... This phase I/II trial tests the safety, side effects, and best dose of abatacept when given together with cyclophosphamide and bortezomib, and tests whether ...

3. centerwatch.com centerwatch.com/clinical-trials/listings/NCT05289167/high-dose-post-transplant-cyclophosphamide-bortezomib-and-abatacept-for-the-prevention-of-graft-versus-host-disease-gvhd-following-allogenic-hematopoietic-stem-cell-transplantation-hsct-study

Post-Transplant Cyclophosphamide, Bortezomib and ... Post-Transplant Cyclophosphamide, Bortezomib and Abatacept for the Prevention of Graft-versus-Host-Disease (GvHD) | Clinical Research Trial ...

4. gvhdhub.com gvhdhub.com/medical-information/abatacept-ptcy-and-bortezomib-combination-for-gvhd-prophylaxis

Abatacept, PTCy, and bortezomib combination for ... Addition of abatacept to standard immunoprophylaxis can improve GvHD related transplant outcomes in mismatched unrelated donor HCT recipients.

5. clin.larvol.com clin.larvol.com/trial/NCT05289167

Post-Transplant Cyclophosphamide, Bortezomib and ... Post-Transplant Cyclophosphamide, Bortezomib and Abatacept for the Prevention of Graft-versus-Host-Disease (GvHD) ... Outcome Measure, Measure Description ...

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. withpower.com withpower.com/trial/phase-2-graft-vs-host-disease-2-2022-8f58d

Cyclophosphamide + Bortezomib + Abatacept for Graft- ... Research shows that abatacept, when used for steroid-refractory chronic graft-versus-host disease, led to a 58% response rate in patients, with all responders ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10435076/

Graft-versus-host disease: teaching old drugs new tricks at ... In this review article, we summarize the latest evidence on how we can continue to repurpose drugs for GVHD prophylaxis and treatment.