High-Dose Post-Transplant Medication for Preventing Transplant Complications
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Northwell Health
Disqualifiers: Pregnancy, Heart failure, Recent malignancy, others
No Placebo Group
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.12345
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.46789
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.1011121314
Research Team
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 β€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.
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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.
See 7 more
Trial 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 (Biological)
- Bortezomib (Other)
Trial OverviewThe 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:
πͺπΊ Approved in European Union as Orencia for:
- Rheumatoid arthritis
- Polyarticular juvenile idiopathic arthritis
- Psoriatic arthritis
πΊπΈ Approved in United States as Orencia for:
- Rheumatoid arthritis
- Polyarticular juvenile idiopathic arthritis
- Psoriatic arthritis
π¨π¦ Approved in Canada as Orencia for:
- Rheumatoid arthritis
- Polyarticular juvenile idiopathic arthritis
π―π΅ Approved in Japan as Orencia for:
- Rheumatoid arthritis
- Polyarticular juvenile idiopathic arthritis
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Zuckerberg Cancer CenterLake Success, NY
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Who Is Running the Clinical Trial?
Northwell Health
Lead Sponsor
Trials
481
Patients Recruited
470,000+
References
Proteasome inhibitor treatment of antibody-mediated allograft rejection. [2015]Bortezomib is a first-in-class proteasome inhibitor that was originally Food and Drug Administration approved for the treatment of multiple myeloma. In the past few years, off-label use in solid organ transplant recipients has demonstrated its ability to provide plasma cell-targeted therapy in humans. The purpose of this review is to provide an update of recent basic science and clinical results with bortezomib in treating antibody-mediated rejection (AMR) that occurs in solid organ transplant recipients.
The use of bortezomib as a rescue treatment for acute antibody-mediated rejection: report of three cases and review of literature. [2015]Antibody-mediated rejection (AMR) typically occurs early after transplantation in approximately 5%-7% of recipients. The literature reports suggest that 12%-37% of kidney transplant recipients with acute AMR do not respond to treatment and eventually lose their grafts. The proteasome inhibitor bortezomib is currently approved by the Food and Drug Administration for the treatment of multiple myeloma. It has been demonstrated both in vitro and in vivo to possess apoptotic properties against mature plasma cells. Herein we have described a series of 3 patients with positive cross-matches who developed early AMR after kidney transplantation. Bortezomib rescue treatment was administered after the patients failed to respond to plasmapheresis/intravenous immunoglobulin and splenectomy. All 3 patients responded with full, durable recovery of renal function. In conclusion, bortezomib is useful to treat refractory AMR after kidney transplantation.
Bortezomib successfully reduces monoclonal serum free light chain levels in a patient with recurrent myeloma and cast nephropathy in the renal transplant. [2017]Bortezomib can be used to successfully treat acute kidney injury in the renal transplant allograft due to light chain cast nephropathy from recurrent multiple myeloma.
Bortezomib as an adjuvant to conventional therapy in the treatment of antibody mediated rejection (AMR): the full spectrum. [2015]Antibody-mediated rejection (AMR) is a well-known complication of kidney transplantation. Its incidence is higher in HLA and ABO incompatible transplant recipients and in patients who develop de novo HLA antibodies. Different clinical and histological phenotypes of HLA-related AMR have been described with variable responses to conventional AMR treatment (Plasmapheresis, IVIG, thymoglobulin (ATG), and anti-CD20 antibodies). Regardless of the phenotype, once the HLA primed B cells have differentiated into antibody producing long-lived plasma cells, they become less vulnerable to conventional AMR treatment. Bortezomib (Velcade) is a proteasome inhibitor approved by the FDA for the treatment of multiple myeloma. It targets mature plasma cells, and hence it is intriguing to study its role in the suppression of long-lived plasma cells. Several previous reports have suggested effectiveness of Bortezomib in the treatment of AMR. We report our experience with Bortezomib as an adjuvant to conventional therapy in five distinct phenotypes of AMR: early acute AMR in the context of desensitization; subclinical acute AMR in the context of desensitization; late acute AMR due to de novo HLA antibody; late ACR and acute AMR due to de novo HLA antibody and chronic AMR due to de novo HLA antibody.
Bortezomib is effective to treat acute humoral rejection after liver transplantation. [2015]Acute humoral rejection (AHR), a rare complication in orthotopic liver transplantation (OLT), responds poorly to conventional therapies. Bortezomib, a proteasome inhibitor, has been shown to be effective in treating plasma cell-derived tumors and acute rejection episodes after renal transplantation. Herein, we have reported our clinical experience with bortezomib as a novel approach to treat AHR after OLT.
Bortezomib-induced skin eruption. [2015]Bortezomib (Velcad) is a proteasome inhibitor recently developed and mainly used for the treatment of multiple myeloma. Bortezomib represents a novel class of drugs functioning as proteasome inhibitors. Skin complications of bortezomib treatment are very frequent but poorly characterized. We describe the case of a patient who developed erythematous and edematous plaques after treatment with bortezomib. This case illustrates one of the potential reactions associated with bortezomib administration and underlines the need to recognize and report cutaneous side effects of this new drug.
A summary of bortezomib use in transplantation across 29 centers. [2015]Despite the substantial effects and promise of bortezomib-based regimens, there is still much to be learned. Finding an effective approach to removing antibodies is an ultimate goal. At this time it seems that bortezomib is a key element in improving the treatment for rejection (both acute and chronic) and in desensitization. In regard to such clinical outcomes as achieving transplant and stabilizing allograft function, bortezomib-based regimens have shown in the cases presented here to have a high success rate, albeit lower with desensitization and chronic rejection than with acute rejection. Bortezomib, even in combination regimens, has also shown a good safety profile, although side effects such a thrombocytopenia, gastrointestinal disturbances, and even peripheral neuropathy have been reported in transplant patients following treatment. In addition, bortezomib's safety regarding viral reactivation of cytomegalovirus, Epstein Barr virus, and BK virus are not clearly known, therefore precautions must be taken (especially in combination regimens). Moving forward, continual data collection and trials will be needed to answer questions about bortezomib. Hopefully, this effort and future efforts to collectively gather data and collaborate with a common goal of treating antibodies will lead us to improved long term allograft survival.
Bortezomib in multiple myeloma: a practice guideline. [2015]Bortezomib (Velcadeβ’, PS-341), a first-in-class proteasome inhibitor, has been extensively studied either alone or in combination with other agents for the treatment of multiple myeloma. We created a provincial guideline for the use of bortezomib, in newly diagnosed individuals (both eligible and ineligible for transplant) and in individuals with relapsed or refractory multiple myeloma.
Clinical update: proteasome inhibitors in hematologic malignancies. [2019]The proteasome inhibitor bortezomib (VELCADE; formerly PS-341, LDP-341, MLN341) is a novel dipeptide boronic acid. In cell culture and xenograft models, bortezomib showed potent activity, enhanced the sensitivity of cancer cells to traditional chemotherapeutics, and appeared to overcome drug resistance. In vitro, bortzomib downregulated the NF-kappaB pathway. NF-kappaB is a transcription factor that enhances the production of growth factors (e.g., IL-6), cell-adhesion molecules, and anti-apoptotic factors, all of which contribute to the growth of the tumor cell and/or protection from apoptosis. Phase II trials have been conducted in patients with relapsed and refractory multiple myeloma (SUMMIT trial, 202 patients) or relapsed myeloma (CREST trial, n=54) using a 1.3mg/m(2) dose given twice weekly for 2 weeks (days 1, 4, 8, 11; rest days 12-21). Both trials showed responses (including complete responses) with manageable toxicities, forming the basis for an ongoing phase III trial comparing response to bortezomib versus high-dose dexamethasone.
Belatacept. [2019]Immunosuppressive therapy designed to prevent kidney graft rejection usually consists of a triple-drug combination including a corticosteroid, a calcineurin inhibitor (ciclosporin or tacrolimus) and a drug that inhibits cell proliferation (azathioprine or mycophenolate mofetil). Belatacept is closely related to abatacept, an immunosuppressant marketed for rheumatic diseases. It is now authorised in the European Union for the prevention of kidney graft rejection, as a replacement for the calcineurin inhibitor. Two randomised controlled trials compared belatacept (2 doses) versus ciclosporin as part of the immunosuppressive regimen in respectively 666 and 534 patients. After 3 years of follow-up, survival with a functioning graft did not differ between the groups (about 80% in the trial closest to European protocols). Only the use of a high dose of belatacept instead of ciclosporin resulted in better preservation of renal function, but this is not the authorised dose. Lymphomas, particularly those affecting the central nervous system, were more frequent with belatacept in both trials (1.4% versus 0.9%). The risk was particularly high in patients receiving the high dose of belatacept, and in patients who were seronegative for Epstein-Barr virus. Overall, the risk of infections seems to be similar with belatacept and ciclosporin, but certain severe infections were more frequent with belatacept, including progressive multifocal leukoencephalopathy and tuberculosis. Unlike ciclosporin, belatacept plasma concentrations do not need to be monitored. However, intravenous belatacept administration is less convenient than oral ciclosporin administration, especially during long-term treatment. Overall, it is better to continue to use ciclosporin, a better-documented drug, as part of immunosuppressive therapy after kidney transplantation.
Abatacept as rescue immunosuppression after calcineurin inhibitor treatment failure in renal transplantation. [2023]A majority of kidney transplant recipients receive calcineurin inhibitor-based immunosuppression. However, some do not tolerate calcineurin inhibitors and require other immunosuppressive strategies. Until recently, alternative approaches have been associated with inferior outcomes, but recent methods have effectively utilized belatacept in calcineurin inhibitor-intolerant patients. Though promising, belatacept uptake has been limited by higher acute rejection rates, unavailability due to production shortages, and logistical challenges as a result of intravenous infusion requirements. Interestingly, its predecessor abatacept is clinically available in subcutaneous formulation to treat autoimmune disorders but has not been used in clinical transplantation. Here we report on a series of 9 calcineurin inhibitor-intolerant transplant recipients converted to abatacept early after transplant as rescue immunosuppression during periods of belatacept unavailability. Retrospective review revealed successful allograft salvage and 100% patient and graft survival (median 115 months) after conversion to abatacept. Patients received abatacept for a median duration of 82 months with stable, long-term renal allograft function, a single cellular rejection episode, and no clinically apparent protective immunity concerns. Hence our findings suggest that future clinical studies utilizing abatacept either de novo or as conversion therapy in transplant recipients should be considered.
Time-varying belatacept exposure and its relationship to efficacy/safety responses in kidney-transplant recipients. [2015]Belatacept is the first T-cell costimulation blocker to be approved for the prophylaxis of organ rejection in adult kidney-transplant recipients (KTRs) and represents an alternative to calcineurin inhibitors, which are known to be nephrotoxic. After transplant, the risk of acute rejection (AR) decreases with time. Accordingly, belatacept exposures were reduced over time by changes in dose and dosing interval in the two treatment regimens tested in two phase III studies. Time-varying belatacept exposures were characterized by developing and applying a population pharmacokinetic model. Clearance and volume of central and peripheral compartments increased with baseline body weight, but there was no effect of age, gender, race, renal/hepatic function, diabetes, patient type (healthy/KTR), or dialysis on belatacept clearance. Exposure-response analyses showed that lower exposures did not compromise efficacy (as measured by AR), whereas higher exposures were associated with increased serious infections and central nervous system events.
A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT study). [2023]Recipients of extended criteria donor (ECD) kidneys are at increased risk for graft dysfunction/loss, and may benefit from immunosuppression that avoids calcineurin inhibitor (CNI) nephrotoxicity. Belatacept, a selective costimulation blocker, may preserve renal function and improve long-term outcomes versus CNIs. BENEFIT-EXT (Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial-EXTended criteria donors) is a 3-year, Phase III study that assessed a more (MI) or less intensive (LI) regimen of belatacept versus cyclosporine in adult ECD kidney transplant recipients. The co-primary endpoints at 12 months were composite patient/graft survival and a composite renal impairment endpoint. Patient/graft survival with belatacept was similar to cyclosporine (86% MI, 89% LI, 85% cyclosporine) at 12 months. Fewer belatacept patients reached the composite renal impairment endpoint versus cyclosporine (71% MI, 77% LI, 85% cyclosporine; p = 0.002 MI vs. cyclosporine; p = 0.06 LI vs. cyclosporine). The mean measured glomerular filtration rate was 4-7 mL/min higher on belatacept versus cyclosporine (p = 0.008 MI vs. cyclosporine; p = 0.1039 LI vs. cyclosporine), and the overall cardiovascular/metabolic profile was better on belatacept versus cyclosporine. The incidence of acute rejection was similar across groups (18% MI; 18% LI; 14% cyclosporine). Overall rates of infection and malignancy were similar between groups; however, more cases of posttransplant lymphoproliferative disorder (PTLD) occurred in the CNS on belatacept. ECD kidney transplant recipients treated with belatacept-based immunosuppression achieved similar patient/graft survival, better renal function, had an increased incidence of PTLD, and exhibited improvement in the cardiovascular/metabolic risk profile versus cyclosporine-treated patients.
Belatacept: a novel biologic for maintenance immunosuppression after renal transplantation. [2021]In the past decade, the availability of new immunosuppressive maintenance therapies for use in solid organ transplantation has remained limited. Patients and clinicians have relied on immunosuppressive drugs that require a significant amount of therapeutic monitoring and are associated with a variety of adverse effects that affect both quality of life and allograft function. Belatacept is an investigational intravenous biologic agent for long-term use in renal transplant recipients. The costimulatory pathway (signal 2) of T-cell activation and proliferation is produced by stimulation of the T-cell surface marker, CD28, and is essential to the immune system's cellular response and ability to recognize an allograft as foreign. Belatacept is a potent antagonist of B7-1 (CD80) and B7-2 (CD86) ligands present on antigen-presenting cells that are responsible for activation of CD28. Recent phase III trials describe various dosing strategies of belatacept versus a standard cyclosporine protocol in recipients of both living- and deceased-donor renal transplants, as well as in patients receiving kidneys transplanted from extended-criteria donors. Compared with cyclosporine, belatacept has been shown to be noninferior in both patient and allograft survival rates. However, the rate of biopsy-proven acute cellular rejection occurred more frequently in the belatacept groups. Also, compared with standard calcineurin-based regimens, the risk of posttransplant lymphoproliferative disorder is increased in patients receiving belatacept, with the greatest risk in transplant recipients who are Epstein-Barr virus seronegative before transplantation. However, this investigational immunosuppressive agent may avert common adverse effects experienced with standard immunosuppressive protocols including renal dysfunction, metabolic disorders, neurotoxicities, glucose abnormalities, and cosmetic effects. More data on the long-term risks of belatacept are needed to better define its role as immunosuppressive maintenance therapy. Aside from an increased risk of malignancy, belatacept's limited adverse-effect profile and convenient dosing strategy may make it an attractive option for immuno-suppressive maintenance for both the patient and clinician.