Carfilzomib + Belatacept for Kidney Transplant Compatibility

(ADAPT Trial)

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must not be taking: Biological drugs, Oral contraceptives

Disqualifiers: Invasive fungal infection, Hepatitis B, Uncontrolled hypertension, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 24 weeks

15 Participants Needed

Trial Summary

What is the purpose of this trial?

Some kidney transplant candidates have a very low chance of getting a kidney transplant because their immune systems are "highly sensitized" to most kidney donors. Being "highly sensitized" means that they will likely have to wait a long time (more than 5 years) before an acceptable donor is found for them or, they never receive a compatible donor, and die while on the kidney transplant waitlist. The purpose of this study is to find out whether two drugs, carfilzomib (Kyprolis®),and belatacept (Nulojix®), can make these kidney transplant candidates less sensitized, and make it easier and quicker to find a kidney donor for them.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are currently on any biological drugs or medications that increase the risk of blood clots, like oral contraceptives.

What data supports the effectiveness of the drug Belatacept in kidney transplant compatibility?

Belatacept has been approved by the FDA for preventing organ rejection in kidney transplant patients, showing it can help maintain the transplanted kidney's health. It is used as part of a maintenance treatment to prevent acute rejection, which means the body attacking the new kidney. ^{1 2 3 4 5}

Is the combination of Carfilzomib and Belatacept safe for humans?

Belatacept, used in kidney transplants, is generally safe but may increase the risk of infections and acute rejection. Carfilzomib, used for other conditions, has its own safety profile, but specific safety data for the combination of these two drugs is not available. ^{1 2 3 6 7}

How is the drug Carfilzomib + Belatacept unique for kidney transplant compatibility?

The combination of Carfilzomib and Belatacept for kidney transplant compatibility is unique because Carfilzomib, a second-generation proteasome inhibitor, effectively reduces HLA antibodies and depletes plasma cells, which are crucial for reducing transplant rejection risk. Unlike first-generation proteasome inhibitors, Carfilzomib has a better safety profile with less neurotoxicity, making it a promising option for desensitizing highly sensitized kidney transplant candidates. ^{8 9 10 11 12}

Research Team

Stuart J. Knechtle, MD

Principal Investigator

Duke Department of Surgery, Duke University School of Medicine

Annette M. Jackson, PhD

Principal Investigator

Duke Department of Surgery, Duke University School of Medicine

Eligibility Criteria

This trial is for kidney transplant candidates who are highly sensitized to potential donors, meaning they have a low chance of finding a compatible donor. Participants must be on dialysis, listed for a transplant with high antibody levels against most donors, and free from serious infections like HIV or hepatitis C. They should not have severe heart issues or recent cancer history and must agree to use contraception.

Inclusion Criteria

Evidence of established immunity to Epstein-Barr virus (EBV)

I am a woman who can have children and I have a negative pregnancy test.

Negative result for SARS-CoV-2

Exclusion Criteria

Liver function test abnormalities

Immunodeficiency conditions

Current tobacco use

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive carfilzomib and belatacept to reduce sensitization to kidney donors

24 weeks

Multiple visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

52 weeks

Regular follow-up visits

Post-transplant Follow-up

Participants who undergo kidney transplantation are followed up for safety and graft success

52 weeks

Treatment Details

Interventions

• Belatacept
• Carfilzomib

Trial Overview The study tests if carfilzomib (Kyprolis®) and belatacept (Nulojix®), along with bone marrow aspiration, can reduce immune sensitivity in patients awaiting kidney transplants. The goal is to increase their chances of finding a suitable donor more quickly.

Participant Groups

Group I: Cohort 2 (N=10 Subjects) Experimental Treatment 3 Interventions

The enrollment of ten additional subjects and dosing regimen is dependent on the results in Cohort 1.° Per protocol, Carfilzomib administered intravenously: * Cycle 1 will consist of 2 doses in week 4 (Day 28 and 29). If tolerated, the dose will be increased and administered twice a week in weeks 5 (Day 35 and 36) and 6 (Day 42 and 43). * Cycle 2 will consist of a total of 6 doses, administered twice weekly in weeks 12 (Day 84 and 85), 13 (Day 91 and 92) and 14 (Day 98 and 99). Per protocol, Belatacept: -Belatacept will be administered intravenously on days 28 (week 4), 33 (week 5), and weeks 6, 8, 12, 16, then at a lower dose at week 20, 24, 28, 32, 36, 40, 44, 48, 52, and 56. Dosing is based on the recommended dose in the package insert. ° May be modified based on the safety and efficacy analysis of Cohort 1.

Group II: Cohort 1 (N=5 Subjects) Experimental Treatment 3 Interventions

The two investigational agents used in this study are carfilzomib and belatacept. Per protocol, Carfilzomib administered intravenously: * Cycle 1 will consist of 2 doses in week 4 (Day 28 and 29). If tolerated, the dose will be increased and administered twice a week in weeks 5 (Day 35 and 36) and 6 (Day 42 and 43). * Cycle 2 will consist of a total of 6 doses, administered twice weekly in weeks 12 (Day 84 and 85), 13 (Day 91 and 92) and 14 (Day 98 and 99). Per protocol, Belatacept: -Belatacept will be administered intravenously on days 29 (week 4), 33 (week 5), and weeks 6, 8, 12, 16, then at a lower dose at week 20, 24, 28, 32, 36, 40, 44, 48, 52, and 56. Dosing is based on the recommended dose in the package insert.

Belatacept is already approved in United States, European Union for the following indications:

Approved in United States as Nulojix for:

• Prophylaxis of organ rejection in adult patients receiving a kidney transplant

Approved in European Union as Nulojix for:

• Prophylaxis of organ rejection in adult patients receiving a kidney transplant

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Rho Federal Systems Division, Inc.

Industry Sponsor

Trials

44

Recruited

15,000+

PPD DEVELOPMENT, LP

Industry Sponsor

Trials

167

Recruited

38,000+

David Simmons

PPD DEVELOPMENT, LP

Chief Executive Officer since 2012

BSc in Applied Science from Georgia Institute of Technology

Martina Flammer

PPD DEVELOPMENT, LP

Chief Medical Officer since 2024

MD

PPD Development, LP

Industry Sponsor

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

Immune Tolerance Network (ITN)

Collaborator

Trials

68

Recruited

7,900+

PPD

Industry Sponsor

Trials

162

Recruited

36,600+

Dr. Austin Smith

PPD

Chief Medical Officer since 2020

Doctor of Medicine from the Royal College of Surgeons in Ireland

David Simmons

PPD

Chief Executive Officer since 2012

Bachelor’s degree in Applied Mathematics and Industrial Management from Carnegie Mellon University

Findings from Research

Belatacept is an effective immunosuppressant for kidney transplant recipients, showing noninferior patient and allograft survival compared to cyclosporine in Phase 3 trials, with improved kidney function over three years.

While belatacept may offer benefits like better renal function and cardiometabolic health, it carries a risk of higher early rejection rates and potential increased risk of posttransplant lymphoproliferative disease, particularly in certain patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belatacept in kidney transplantation. Wojciechowski, D., Vincenti, F.[2018]

An accurate and precise assay for measuring belatacept serum concentrations was developed, showing a measurement range of 0.9-30 mg/L and high accuracy (91%-99%).

This assay was applied in a pharmacokinetic study involving 5 renal transplant recipients, allowing for the visualization of belatacept concentrations over time, which is crucial for optimizing immunosuppressive therapy post-transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Fully Automated Method for the Determination of Serum Belatacept and Its Application in a Pharmacokinetic Investigation in Renal Transplant Recipients. Klaasen, RA., Egeland, EJ., Chan, J., et al.[2019]

In a study of 280 kidney transplant patients switched to belatacept (bela), 12.1% experienced opportunistic infections (OPI), with cytomegalovirus (CMV) disease and pneumocystis pneumonia being the most common.

The risk of OPI was notably higher in patients who switched to bela within 6 months post-transplant, indicating a need for careful monitoring and possible prophylactic treatment for infections like CMV and pneumocystis pneumonia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Opportunistic infections after conversion to belatacept in kidney transplantation. Bertrand, D., Chavarot, N., Gatault, P., et al.[2020]

Belatacept, a CNI-free immunosuppressive option for kidney transplant patients, has shown improvements in renal function and a lower incidence of chronic allograft nephropathy compared to traditional treatments like cyclosporine.

Patients treated with belatacept also exhibited a more favorable metabolic profile and reduced formation of donor-specific antibodies, suggesting potential long-term benefits for kidney transplant outcomes, although further studies are needed to confirm these effects over time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A safety evaluation of belatacept for the treatment of kidney transplant. Garcia, VD., Meinerz, G., Keitel, E.[2017]

In a study of 108 kidney transplant recipients, converting from calcineurin inhibitors (CNI) to belatacept showed no significant difference in rejection-free, patient, or graft survival over 5 years between HLA-sensitized (HS) and non-HLA-sensitized (non-HS) groups.

However, HS recipients who were converted to belatacept within the first year post-transplant had lower rejection-free survival rates, indicating that this conversion should be approached with caution in patients at high immunologic risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes of Conversion From Calcineurin Inhibitor to Belatacept-based Immunosuppression in HLA-sensitized Kidney Transplant Recipients. Sethi, S., Najjar, R., Peng, A., et al.[2021]

A 61-year-old woman experienced acute vascular rejection of her kidney transplant 56 days after receiving belatacept, highlighting a potential risk associated with this immunosuppressive therapy.

The rejection was characterized by a predominance of cytotoxic memory T cells, suggesting that these cells may be resistant to the effects of belatacept, indicating a need for further investigation into the mechanisms of rejection in patients treated with this drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Acute Cellular Rejection With Detrimental Outcome Occurring Under Belatacept-Based Immunosuppressive Therapy: An Immunological Analysis. de Graav, GN., Hesselink, DA., Dieterich, M., et al.[2022]

Switching to belatacept from calcineurin inhibitors (CNI) within 3 months of kidney transplantation resulted in a decrease in naive T cells and an increase in terminally differentiated effector memory T cells, but did not significantly alter immune responses compared to control patients.

Patients on belatacept showed a lower incidence of donor-specific antibody (DSA) development compared to those on CNI, indicating a potential benefit in preventing alloimmune responses while maintaining antiviral immunity against viruses like cytomegalovirus (CMV) and Epstein-Barr virus (EBV).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preservation of Antiviral Immunologic Efficacy Without Alloimmunity After Switch to Belatacept in Calcineurin Inhibitor-Intolerant Patients. Schaenman, J., Rossetti, M., Pickering, H., et al.[2023]

Carfilzomib, a selective proteasome inhibitor, is well tolerated in patients with relapsed and refractory multiple myeloma (MM) who also have renal dysfunction, making it a promising treatment option for this population.

The presence of renal complications in MM patients is a negative prognostic factor, highlighting the importance of therapies like carfilzomib that have favorable renal safety profiles to avoid under-dosing and maintain treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence and management of renal adverse events in patients with relapsed and/or refractory multiple myeloma treated with single-agent carfilzomib. Shah, JJ.[2014]

Carfilzomib, a selective proteasome inhibitor, showed consistent pharmacokinetics and safety across patients with varying degrees of renal impairment, including those on chronic hemodialysis, indicating it can be safely administered regardless of kidney function.

The study found that carfilzomib achieved a 25.5% overall response rate in patients with multiple myeloma, even among those who were resistant to other treatments, with a median duration of response of 7.9 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carfilzomib in multiple myeloma patients with renal impairment: pharmacokinetics and safety. Badros, AZ., Vij, R., Martin, T., et al.[2022]

Carfilzomib, a second-generation proteasome inhibitor, was well tolerated in 13 highly HLA-sensitized kidney transplant candidates, showing a safety profile similar to bortezomib without neurotoxicity, and only one participant required a permanent dose reduction due to toxicity.

The treatment led to a significant reduction in HLA antibodies, with a median reduction of 72.8%, and effectively depleted about 69.2% of plasma cells in the bone marrow, indicating its potential efficacy in desensitizing patients for kidney transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A prospective, iterative, adaptive trial of carfilzomib-based desensitization. Tremblay, S., Driscoll, JJ., Rike-Shields, A., et al.[2023]

Carfilzomib, a proteasome inhibitor approved for relapsing multiple myeloma, was associated with a case of fatal pulmonary toxicity in a 61-year-old male patient, highlighting a potential serious side effect of the drug.

The patient developed acute respiratory distress syndrome and diffuse alveolar hemorrhage shortly after starting carfilzomib, suggesting a direct link between the medication and the severe lung complications, which had not been previously reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fatal pulmonary toxicity due to carfilzomib (Kyprolis™). Lataifeh, AR., Nusair, A.[2020]

Rutin, a bioflavonoid with antioxidant properties, effectively protects against nephrotoxicity caused by the proteasome inhibitor carfilzomib (CFZ) in a study involving Wistar albino rats, suggesting its potential as a protective agent in patients undergoing CFZ treatment.

The study demonstrated that rutin administration significantly reduced oxidative stress and inflammation markers associated with CFZ-induced kidney damage, indicating that it works through the NOS-mediated NF-κB signaling pathway to ameliorate renal injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rutin inhibits carfilzomib-induced oxidative stress and inflammation via the NOS-mediated NF-κB signaling pathway. Al-Harbi, NO., Imam, F., Al-Harbi, MM., et al.[2021]

References

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

Belatacept in kidney transplantation. [2018]

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

A Fully Automated Method for the Determination of Serum Belatacept and Its Application in a Pharmacokinetic Investigation in Renal Transplant Recipients. [2019]

3. England pubmed.ncbi.nlm.nih.gov

Opportunistic infections after conversion to belatacept in kidney transplantation. [2020]

4. England pubmed.ncbi.nlm.nih.gov

A safety evaluation of belatacept for the treatment of kidney transplant. [2017]

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

Outcomes of Conversion From Calcineurin Inhibitor to Belatacept-based Immunosuppression in HLA-sensitized Kidney Transplant Recipients. [2021]

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

An Acute Cellular Rejection With Detrimental Outcome Occurring Under Belatacept-Based Immunosuppressive Therapy: An Immunological Analysis. [2022]

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

Preservation of Antiviral Immunologic Efficacy Without Alloimmunity After Switch to Belatacept in Calcineurin Inhibitor-Intolerant Patients. [2023]

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

Incidence and management of renal adverse events in patients with relapsed and/or refractory multiple myeloma treated with single-agent carfilzomib. [2014]

9. England pubmed.ncbi.nlm.nih.gov

Carfilzomib in multiple myeloma patients with renal impairment: pharmacokinetics and safety. [2022]

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

A prospective, iterative, adaptive trial of carfilzomib-based desensitization. [2023]

11. England pubmed.ncbi.nlm.nih.gov

Fatal pulmonary toxicity due to carfilzomib (Kyprolis™). [2020]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Rutin inhibits carfilzomib-induced oxidative stress and inflammation via the NOS-mediated NF-κB signaling pathway. [2021]