Daratumumab + Belatacept for Kidney Transplant Candidates

(ATTAIN 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

Disqualifiers: Invasive fungal infection, Malignancy, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 10-14 weeks

15 Participants Needed

Trial Summary

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

The trial information does not specify if you need to stop taking your current medications. However, if you are currently on a biological drug, you cannot participate in the trial.

What data supports the effectiveness of the drug Belatacept for kidney transplant candidates?

Research shows that Belatacept is an effective alternative to other drugs for kidney transplant patients, improving kidney function and reducing the risk of diabetes and high blood pressure compared to cyclosporine. ^{1 2 3 4 5}

Is the combination of Daratumumab and Belatacept safe for kidney transplant candidates?

Belatacept, used in kidney transplants, is generally well tolerated but can cause side effects like anemia, fever, and infections. It may also increase the risk of certain cancers and serious infections, especially in patients without prior exposure to the Epstein-Barr virus. Daratumumab's safety profile is not detailed here, but it is important to consult with healthcare providers for comprehensive safety information. ^{1 4 6 7 8}

How is the drug combination of Daratumumab and Belatacept unique for kidney transplant candidates?

The combination of Daratumumab and Belatacept is unique because Belatacept is a novel immunosuppressive drug that helps prevent organ rejection by blocking T-cell activation, potentially reducing long-term kidney damage compared to traditional treatments. This combination may offer a new approach by integrating Daratumumab, which is typically used in other conditions, to enhance the effectiveness of Belatacept in kidney transplants. ^{1 3 4 6 8}

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 on waitlist. The purpose of this study is to find out whether two drugs, daratumumab (Darzalex®), and belatacept (Nulojix®), can make these kidney transplant candidates less sensitized, and make it easier and quicker to find a kidney donor for them.

Research Team

Flavio G. Vincenti

Principal Investigator

UCSF Kidney Transplant Research

Eligibility Criteria

This trial is for kidney transplant candidates who are highly sensitized (cPRA ≥99.9% or >98% with long wait times) and on hemodialysis, able to consent, HIV and Hepatitis C negative, immune to certain viruses like EBV and TB, not pregnant or nursing, willing to use contraception. Excluded are those with serious diseases besides kidney failure, past transplants or immunodeficiencies, recent infections requiring hospitalization or antibiotics.

Inclusion Criteria

Evidence of established immunity to Epstein-Barr Virus (EBV) as demonstrated by serologic testing

I understand the study and can give my consent.

I am on the UNOS list for a transplant with a high antibody level or long wait time.

Exclusion Criteria

Previous non-kidney solid organ or bone marrow transplant

Treatment with any investigational agent within 4 weeks (or 5 half-lives of investigational drug, whichever is longer) of screening

Past or current medical problems or findings from physical examination or laboratory testing not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, interfere with the subject's ability to comply with study requirements, or impact the quality or interpretation of the data obtained from the study

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive infusions of daratumumab and belatacept over a 10-week period in Cohort 1 or a 14-week period in Cohort 2

10-14 weeks

Weekly visits for infusions

Follow-up

Participants are monitored for safety and effectiveness after treatment, including HLA antibody assessments and bone marrow aspiration

42-56 weeks

Regular follow-up visits

Post-transplant Follow-up

Participants who receive a kidney transplant are monitored for 52 weeks post-transplant

52 weeks

Treatment Details

Interventions

• Belatacept
• Bone marrow aspiration
• Daratumumab

Trial Overview The study tests if daratumumab (Darzalex®) and belatacept (Nulojix®), along with a bone marrow aspiration procedure can reduce the immune system's sensitivity in prospective kidney transplant recipients making it easier for them to find compatible donors.

Participant Groups

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

The enrollment of ten additional subjects is dependent on the results in Cohort 1. Multiple intravenous infusions of daratumumab and belatacept over 14 weeks:° * Daratumumab will be administered intravenously at a dose of 8 mg/kg for the first dose, then 16 mg/kg for subsequent given weekly for 3 weeks, then every 2 weeks for 2 doses (week 9 and week 11). The dose administered will be calculated based on the actual body weight of the subject at each visit. * Belatacept will be administered intravenously at a dose of 10 mg/kg every 2 weeks starting at week 8 (dosed at weeks 8, 10, 12, 14, 16 and 18). The total infusion dose of belatacept will be based on the actual body weight of the subject at the baseline visit and will not be modified during the course of therapy, unless there is a change in body weight of greater than 10%. * Was modified based on the safety and efficacy analysis of Cohort 1.

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

Multiple intravenous infusions of daratumumab and belatacept over 10 weeks: * Daratumumab will be administered intravenously at a dose of 8 mg/kg weekly for 4 weeks, then every other week for 4 weeks (week 9 and week 11). The dose administered will be calculated based on the actual body weight of the subject at each visit. * Belatacept will be administered intravenously at a dose of 10 mg/kg every 2 weeks starting at week 8 (dosed at weeks 8, 10, 12, and 14). The total infusion dose of belatacept will be based on the actual body weight of the subject at the baseline visit, and will not be modified during the course of therapy, unless there is a change in body weight of greater than 10%.

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+

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

Immune Tolerance Network (ITN)

Collaborator

Trials

68

Recruited

7,900+

Rho Federal Systems Division, Inc.

Industry Sponsor

Trials

44

Recruited

15,000+

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

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

Findings from Research

Early conversion to belatacept-based immunosuppression after kidney transplantation significantly improved kidney function, as measured by eGFR, from 26.73 to 45.3 ml/min/1.73 m² within one year, while late conversion showed no significant change.

Both early and late conversion groups had a one-year allograft survival rate of 100%, but early conversion was associated with a higher rate of acute T-cell-mediated rejections, suggesting that the choice of immunosuppressants may influence rejection types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early conversion to belatacept-based immunosuppression regimen promotes improved long-term renal graft function in kidney transplant recipients. Moein, M., Dvorai, RH., Li, BW., et al.[2023]

In a study involving 666 kidney-transplant recipients over 7 years, both more-intensive and less-intensive belatacept regimens significantly reduced the risk of death or graft loss by 43% compared to cyclosporine.

Patients receiving belatacept also experienced improved renal function, as indicated by an increase in mean estimated glomerular filtration rate (eGFR), while those on cyclosporine showed a decline in eGFR.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belatacept and Long-Term Outcomes in Kidney Transplantation. Vincenti, F., Rostaing, L., Grinyo, J., et al.[2022]

Belatacept significantly improves renal function in kidney transplant recipients compared to traditional cyclosporine-based therapy, with a notable increase in estimated glomerular filtration rate (eGFR) of 13-15 mL/min at 1 year and 23-27 mL/min at 7 years, as shown in the BENEFIT study involving standard criteria donors.

In addition to enhancing kidney function, belatacept therapy is associated with lower rates of hypertension, high cholesterol, and new-onset diabetes compared to cyclosporine, although concerns about the risk of posttransplantation lymphoproliferative disorder and the cost of treatment may limit its widespread use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belatacept for the prophylaxis of organ rejection in kidney transplant patients: an evidence-based review of its place in therapy. Hardinger, KL., Sunderland, D., Wiederrich, JA.[2020]

Belatacept is as effective as cyclosporine in preventing organ rejection in kidney transplant patients, with similar rates of patient and graft survival and acute rejection, while showing a significant advantage in reducing renal impairment after 12 months.

Patients treated with belatacept experienced fewer serious side effects, including lower rates of new-onset diabetes and better blood pressure and lipid levels compared to those on cyclosporine, indicating a potentially safer profile for long-term use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belatacept: in adult kidney transplant recipients. Garnock-Jones, KP.[2016]

Converting from tacrolimus to belatacept in kidney transplant patients with stable low eGFR (< 40 mL/min) resulted in a significant improvement in eGFR, with an average increase of 11.0 mL/min compared to 4.8 mL/min in the control group over 4 months.

However, while the belatacept group showed a modest increase in kidney function, there was a higher incidence of acute rejection (16.7%) compared to the control group, indicating potential safety concerns with this conversion strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early Conversion to Belatacept in Kidney Transplant Recipients With Low Glomerular Filtration Rate. Abdelwahab Elhamahmi, D., Heilman, RL., Smith, B., et al.[2022]

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]

Belatacept, a new immunosuppressive drug for kidney transplantation, shows better cardiovascular and metabolic profiles compared to cyclosporin A, including lower blood pressure and serum lipids, and a reduced risk of new onset diabetes after transplantation.

While about 20% of patients on belatacept experienced adverse effects like anemia and infections, it does not appear to increase the risk of infections compared to cyclosporin A, making it a promising option for immunosuppressive therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Introduction to the use of belatacept: a fusion protein for the prevention of posttransplant kidney rejection. Ippoliti, G., D'Armini, AM., Lucioni, M., et al.[2023]

In a study of 316 kidney transplant recipients over 2 years, belatacept-based immunosuppression showed a significantly lower incidence of reduced kidney function (eGFR <45 ml/min) compared to tacrolimus, indicating better long-term kidney health.

However, belatacept was associated with a higher rate of biopsy-proven acute rejection compared to tacrolimus, suggesting a trade-off between reduced nephrotoxicity and increased rejection risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Belatacept for Simultaneous Calcineurin Inhibitor and Chronic Corticosteroid Immunosuppression Avoidance: Two-Year Results of a Prospective, Randomized Multicenter Trial. Kaufman, DB., Woodle, ES., Shields, AR., et al.[2023]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Early conversion to belatacept-based immunosuppression regimen promotes improved long-term renal graft function in kidney transplant recipients. [2023]

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

Belatacept and Long-Term Outcomes in Kidney Transplantation. [2022]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Belatacept for the prophylaxis of organ rejection in kidney transplant patients: an evidence-based review of its place in therapy. [2020]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Belatacept: in adult kidney transplant recipients. [2016]

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

Early Conversion to Belatacept in Kidney Transplant Recipients With Low Glomerular Filtration Rate. [2022]

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

Belatacept in kidney transplantation. [2018]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Introduction to the use of belatacept: a fusion protein for the prevention of posttransplant kidney rejection. [2023]

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

Belatacept for Simultaneous Calcineurin Inhibitor and Chronic Corticosteroid Immunosuppression Avoidance: Two-Year Results of a Prospective, Randomized Multicenter Trial. [2023]