High-Dose Post-Transplant Medication for Preventing Transplant Complications

Overseen By Kelli Cole

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)

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

Compensation: Varies

Number of Visits: Unknown

10 Participants Needed

Trial Summary

What is the purpose of this trial?

The study will be conducted in two phases. The phase I portion will employ a 3+3 dose-escalation design to define the maximum tolerated dose (MTD) of abatacept added to PTCy and bortezomib following HSCT. The phase II portion will consist of two single-arm, open-label, optimal 2-stage Simon design studies conducted in two separate strata for HLA-matched and HLA-mismatched donor transplants.

Do I need to stop my current medications to join the trial?

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 Bortezomib in preventing transplant complications?

Research shows that Bortezomib, originally used for treating multiple myeloma, has been effective in treating antibody-mediated rejection (AMR) in kidney and liver transplant patients, especially when other treatments failed. It works by targeting plasma cells, which are involved in the rejection process, leading to recovery of organ function. ^{1 2 3 4 5}

Is bortezomib safe for use in humans?

Bortezomib, used for treating multiple myeloma and in transplant cases, generally has a good safety profile, but can cause side effects like skin reactions, low platelet counts, stomach issues, and nerve damage. Its safety regarding certain viral reactivations is not fully known, so caution is advised. ^{4 6 7 8 9}

How is the drug combination of Abatacept and Bortezomib unique for preventing transplant complications?

The combination of Abatacept and Bortezomib is unique because Abatacept, similar to its relative Belatacept, is a T-cell costimulation blocker that can be used as an alternative to calcineurin inhibitors, which are known to be harmful to the kidneys. Abatacept is available in a subcutaneous form, making it more convenient than intravenous options, and has shown promise in patients who cannot tolerate traditional treatments. ^{10 11 12 13 14}

Eligibility Criteria

This trial is for individuals who have undergone a hematopoietic stem cell transplant (HSCT) and are at risk of developing graft-versus-host disease (GVHD). Participants must meet certain health criteria to be eligible.

Inclusion Criteria

ALP ≤250 IU/L

I am willing and able to follow the study rules and attend all required visits.

I am mostly able to care for myself.

Exclusion Criteria

I haven't had cancer, except for certain skin cancers or low-risk prostate cancer treated over 3 years ago.

Serious medical or psychiatric illness is likely to interfere with participation in this clinical study.

I am a male willing to use contraception or abstain from sex for 90 days after the last dose.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I Treatment

3+3 dose-escalation design to define the maximum tolerated dose (MTD) of abatacept added to PTCy and bortezomib following HSCT

8 weeks

Phase II Treatment

Two single-arm, open-label, optimal 2-stage Simon design studies conducted in two separate strata for HLA-matched and HLA-mismatched donor transplants

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Treatment Details

Interventions

• Abatacept
• Bortezomib

Trial Overview The study tests high doses of post-transplant medication, specifically abatacept combined with PTCy and bortezomib. It aims to find the safest dose that prevents GVHD after HSCT, using two separate study phases for different donor matches.

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?

Northwell Health

Lead Sponsor

Trials

481

Recruited

470,000+

Findings from Research

Bortezomib, a proteasome inhibitor, is effective in treating antibody-mediated rejection (AMR) in solid organ transplant recipients, particularly when AMR is diagnosed early after transplantation.

While bortezomib shows promise as both primary and rescue therapy for AMR in kidney and heart transplant recipients, its effectiveness decreases for late AMR, likely due to the presence of long-lived plasma cells in the bone marrow.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Proteasome inhibitor treatment of antibody-mediated allograft rejection. Woodle, ES., Alloway, RR., Girnita, A.[2015]

Bortezomib, a proteasome inhibitor typically used for multiple myeloma, has shown effectiveness in treating refractory antibody-mediated rejection (AMR) in kidney transplant patients who did not respond to standard treatments.

In a series of 3 cases, all patients with early AMR experienced full and durable recovery of renal function after receiving bortezomib, suggesting it could be a valuable option for managing this complication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The use of bortezomib as a rescue treatment for acute antibody-mediated rejection: report of three cases and review of literature. Tzvetanov, I., Spaggiari, M., Joseph, J., et al.[2015]

Bortezomib is effective in treating acute kidney injury caused by light chain cast nephropathy in patients with recurrent multiple myeloma who have undergone renal transplantation.

This treatment demonstrates the potential of bortezomib to improve kidney function in transplant recipients affected by specific complications related to their underlying disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bortezomib successfully reduces monoclonal serum free light chain levels in a patient with recurrent myeloma and cast nephropathy in the renal transplant. Kumar, V., Elkins, S., Gaston, RS., et al.[2017]

Bortezomib, a proteasome inhibitor, shows promise as an adjuvant treatment for antibody-mediated rejection (AMR) in kidney transplantation, particularly in cases where conventional therapies are less effective due to the presence of long-lived plasma cells.

The study highlights the potential of Bortezomib in various phenotypes of AMR, suggesting it could enhance treatment outcomes for patients with complex rejection scenarios, although specific results from the five cases are not detailed in the abstract.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bortezomib as an adjuvant to conventional therapy in the treatment of antibody mediated rejection (AMR): the full spectrum. Al Meshari, K., Pall, A., Elgamal, H., et al.[2015]

In a study of 247 adult liver transplant patients, those treated with bortezomib for acute humoral rejection (AHR) had a significantly better survival rate compared to those who received conventional therapies, with 66.7% of bortezomib-treated patients surviving at a mean follow-up of 22.3 months.

All patients in the conventional treatment group (group A) died shortly after AHR, highlighting the potential of bortezomib as a novel and more effective treatment option for this serious complication in liver transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bortezomib is effective to treat acute humoral rejection after liver transplantation. Lee, CF., Eldeen, FZ., Chan, KM., et al.[2015]

Bortezomib, a proteasome inhibitor used primarily for treating multiple myeloma, can cause skin complications, which are common but not well understood.

A specific case is highlighted where a patient developed erythematous and edematous plaques after bortezomib treatment, emphasizing the importance of recognizing and reporting skin side effects associated with this medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bortezomib-induced skin eruption. Sanchez-Politta, S., Favet, L., Kerl, K., et al.[2015]

Bortezomib-based regimens have shown a high success rate in improving transplant outcomes and stabilizing allograft function, particularly effective against acute rejection, though less so for chronic rejection and desensitization.

While bortezomib has a generally good safety profile, it can cause side effects like thrombocytopenia and gastrointestinal issues, and there are concerns about its safety related to viral reactivation, necessitating caution in its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A summary of bortezomib use in transplantation across 29 centers. Everly, MJ.[2015]

Bortezomib is recommended for use in both newly diagnosed and relapsed/refractory multiple myeloma patients, whether they are eligible for autologous stem cell transplantation or not, based on a systematic review of evidence.

The guidelines also emphasize the importance of monitoring and managing potential toxicities associated with bortezomib treatment, such as the risk of herpes zoster reactivation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bortezomib in multiple myeloma: a practice guideline. Kouroukis, CT., Baldassarre, FG., Haynes, AE., et al.[2015]

Bortezomib, a proteasome inhibitor, has demonstrated strong anti-cancer activity in cell cultures and animal models, enhancing the effectiveness of traditional chemotherapy and overcoming drug resistance.

In Phase II trials involving 254 patients with relapsed multiple myeloma, bortezomib showed promising response rates and manageable side effects, leading to further investigation in a Phase III trial against high-dose dexamethasone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical update: proteasome inhibitors in hematologic malignancies. Richardson, P.[2019]

Belatacept, an immunosuppressant approved for preventing kidney graft rejection, showed similar graft survival rates compared to ciclosporin after 3 years in two large trials with over 1,200 patients, but only a high dose of belatacept improved renal function, which is not the authorized dose.

However, belatacept was associated with a higher risk of certain lymphomas and severe infections, such as progressive multifocal leukoencephalopathy and tuberculosis, making ciclosporin a more established and safer choice for long-term immunosuppressive therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belatacept. [2019]

In a study of 9 kidney transplant recipients who could not tolerate calcineurin inhibitors, switching to abatacept as a rescue immunosuppressive therapy resulted in 100% patient and graft survival over a median follow-up of 115 months.

Patients maintained stable renal function while on abatacept for a median of 82 months, with only one episode of cellular rejection, suggesting that abatacept could be a viable alternative for patients intolerant to traditional immunosuppressants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abatacept as rescue immunosuppression after calcineurin inhibitor treatment failure in renal transplantation. Badell, IR., Karadkhele, GM., Vasanth, P., et al.[2023]

Belatacept is an effective alternative to nephrotoxic calcineurin inhibitors for preventing organ rejection in adult kidney transplant recipients, as shown in two phase III studies.

Lower doses of belatacept did not reduce its effectiveness in preventing acute rejection, while higher doses increased the risk of serious infections and central nervous system events, highlighting the importance of dose management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Time-varying belatacept exposure and its relationship to efficacy/safety responses in kidney-transplant recipients. Zhou, Z., Shen, J., Hong, Y., et al.[2015]

In a 3-year study involving extended criteria donor kidney transplant recipients, belatacept showed similar patient and graft survival rates compared to cyclosporine, with 86% to 89% survival for belatacept versus 85% for cyclosporine at 12 months.

Belatacept treatment resulted in better renal function, with a mean glomerular filtration rate 4-7 mL/min higher than cyclosporine, although it was associated with a higher incidence of posttransplant lymphoproliferative disorder (PTLD).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT study). Durrbach, A., Pestana, JM., Pearson, T., et al.[2023]

Belatacept, an investigational immunosuppressive agent for kidney transplant recipients, has shown noninferior patient and allograft survival rates compared to standard cyclosporine treatment, but it is associated with a higher rate of acute cellular rejection.

While belatacept may reduce common adverse effects seen with traditional immunosuppressants, such as renal dysfunction and neurotoxicities, it carries an increased risk of posttransplant lymphoproliferative disorder, especially in Epstein-Barr virus seronegative patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belatacept: a novel biologic for maintenance immunosuppression after renal transplantation. Martin, ST., Tichy, EM., Gabardi, S.[2021]

References

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

Proteasome inhibitor treatment of antibody-mediated allograft rejection. [2015]

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

The use of bortezomib as a rescue treatment for acute antibody-mediated rejection: report of three cases and review of literature. [2015]

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

Bortezomib successfully reduces monoclonal serum free light chain levels in a patient with recurrent myeloma and cast nephropathy in the renal transplant. [2017]

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

Bortezomib as an adjuvant to conventional therapy in the treatment of antibody mediated rejection (AMR): the full spectrum. [2015]

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

Bortezomib is effective to treat acute humoral rejection after liver transplantation. [2015]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Bortezomib-induced skin eruption. [2015]

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

A summary of bortezomib use in transplantation across 29 centers. [2015]

8. England pubmed.ncbi.nlm.nih.gov

Bortezomib in multiple myeloma: a practice guideline. [2015]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Clinical update: proteasome inhibitors in hematologic malignancies. [2019]

10. France pubmed.ncbi.nlm.nih.gov

Belatacept. [2019]

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

Abatacept as rescue immunosuppression after calcineurin inhibitor treatment failure in renal transplantation. [2023]

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

Time-varying belatacept exposure and its relationship to efficacy/safety responses in kidney-transplant recipients. [2015]

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

A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT study). [2023]

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

Belatacept: a novel biologic for maintenance immunosuppression after renal transplantation. [2021]