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

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

74 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing three new treatments to prevent a complication called GvHD in adults with blood cancers receiving stem cell transplants. It targets patients at high risk of GvHD due to their transplant type. The treatments work by calming the immune system to prevent it from attacking the body.

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.

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

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 achieving a partial response. It was well tolerated and showed promising effects on the immune system, suggesting it could be an effective treatment option. ^{1 2 3 4 5}

Is the combination of Cyclophosphamide, Bortezomib, and Abatacept safe for humans?

Abatacept has been shown to be generally safe in humans, with studies indicating it is well-tolerated and has few serious side effects when used for graft-versus-host disease. Cyclophosphamide and Bortezomib have also been used in various treatments, but specific safety data for this exact combination is not detailed in the available research. ^{1 2 3 4 6}

What makes the drug combination of Cyclophosphamide, Bortezomib, and Abatacept unique for treating graft-versus-host disease?

This drug combination is unique because it includes Abatacept, which is a novel immunomodulatory drug that inhibits T-cell activation, potentially reducing the severity of graft-versus-host disease. Abatacept has shown promise in reducing the need for steroids and improving patient outcomes in cases where other treatments have failed. ^{1 3 4 5 6}

Research Team

A. Samer Al-Homsi, MD, MBA

Principal Investigator

Northwell Health

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

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 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 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 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]

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]

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

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

3. 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]

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

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

5. Netherlands pubmed.ncbi.nlm.nih.gov

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

6. England pubmed.ncbi.nlm.nih.gov

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