Treg Modulation With CD28 and IL-6 Receptor Antagonists

Regulatory T Cell Modulation in Kidney Transplantation With Biologic Blockade of Dual Effector Pathways, CD28 and IL-6 (CTOT-24)

The purpose of this study is to evaluate the safety of using lulizumab pegol with tocilizumab, belatacept, and everolimus in kidney transplant recipients.

Study Overview

• Status: Completed
• Conditions: Kidney Transplant Recipients; Living-Donor Kidney Transplant
• Intervention / Treatment: Biological: lulizumab pegol; Biological: antithymocyte globulin (rabbit); Drug: methylprednisolone; Biological: tocilizumab; Drug: Prednisone; Drug: everolimus; Biological: belatacept; Drug: mycophenolate mofetil; Drug: mycophenolic acid

Detailed Description

This research study is for adults who are planning to have a kidney transplant from a living donor.

In Brief:

Those who have a transplant take immunosuppressive therapy to prevent the body from rejecting the transplanted organ. Rejection occurs when the body's defense system (immune cells) recognizes the transplant as a foreign object. These immune cells and the substances they produce can damage the transplanted kidney. It is important to prevent rejection episodes, so the kidney transplant lasts as long as possible.

Most transplant doctors in the United States give a combination of two or three drugs to prevent rejection. People with a transplant must take these drugs every day. Although kidney transplant recipients usually do well in the first five years after transplant, researchers want to find new ways to prevent rejection and avoid the side effects that the current drugs can cause.

This study will test a new combination of four drugs to evaluate whether this combination is safe for kidney transplant recipients:

• lulizumab pegol (BMS-931699)
• tocilizumab
• belatacept and
• everolimus.

Belatacept and everolimus are already approved for use as anti-rejection drugs in kidney transplant recipients. Lulizumab pegol and tocilizumab act on specific molecules (specifically CD28 and interleukin 6, respectively) on immune cells: these actions are different from how the older rejection drugs work.

Summary: This is a prospective multicenter open-label clinical trial of 10 living donor kidney transplant recipients. Safety of lulizumab pegol (BMS-931699) in the context of a novel immunosuppressive regimen (anti-thymocyte globulin (rabbit) (ATG), steroids,) Nulojix® (belatacept), Actemra® (tocilizumab), and Zortress®(everolimus)) will be assessed. Study participation involves a minimum of one year of follow-up post-transplant.

*** IMPORTANT NOTICE: *** The National Institute of Allergy and Infectious Diseases and the Clinical Trials in Organ Transplantation (CTOT) do not recommend the discontinuation of immunosuppressive therapy for recipients of cell, organ, or tissue transplants outside of physician-directed, controlled clinical studies. Discontinuation of prescribed immunosuppressive therapy can result in serious health consequences and should only be performed in certain rare circumstances, upon the recommendation and with the guidance of your health care provider.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama School of Medicine: Transplantation
  • California
    • San Francisco, California, United States, 94143
      • University of California San Francisco School of Medicine: Transplantation
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado (UC) Health Transplant Center - Anschutz
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern Memorial Hospital: Transplantation
  • Nebraska
    • Omaha, Nebraska, United States, 68105
      • University of Nebraska Medical Center: Transplantation
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center: Transplantation
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation: Transplantation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Individuals who meet all the following criteria are eligible for enrollment as study participants:

1. Able to understand and provide informed consent

2. Agreement to use highly effective (<1% failure rate) methods of contraception: Women of Childbearing Potential (WOCBP)-

   • Progestogen only hormonal contraception associated with inhibition of ovulation,
   • Hormonal methods of contraception including oral contraceptive pills containing a combination of estrogen + progesterone, vagina ring, injectables, implants and intrauterine devices (IUDs),
   • Non-hormonal IUDs,
   • Bilateral tubal occlusion,
   • Vasectomized partner,
   • Intrauterine hormone-releasing system (IUS), or
   • Complete abstinence.

   Note: Female participants of childbearing potential must consult with their physician and determine the most suitable method(s) from this list to be used for 12 months while on study drug regimen.

   Male Participants-

   --Must use a latex or other synthetic condom during any sexual activity with WOCBP until one month after the last dose of lulizumab (e.g., up to 3.5 months in duration).

3. Recipient of primary, nonhuman leukocyte antigen identical living donor kidney transplant
4. No donor specific antibodies prior to transplant that are considered to be of clinical significance by the site investigator
5. Epstein-Barr virus (EBV) positive serology
6. Cytomegalovirus (CMV) positive serology, unless donor-recipient pair are both CMV negative

7. Negative testing for latent Tuberculosis (TB) infection within 3 months prior to transplant

   • Testing should be conducted using either a purified protein derivative (PPD) or an interferon-gamma release assay blood test for TB (i.e. QuantiFERON®-TB Gold in-Tube test or T-SPOT® TB test)
   • Subjects with a positive test for latent TB infection must complete appropriate therapy for Latent tuberculosis infection (LTBI). ---A subject is considered eligible only if they have a negative test for LTBI within 3 months prior to transplant or, they have appropriately completed LTBI therapy prior to transplant.

   Note: Latent TB infection treatment regimens should be among those endorsed by the CDC (Division of TB Elimination, 2016).

8. In the absence of contraindication, vaccinations must be up to date for hepatitis B, influenza, pneumococcal, varicella and herpes zoster, and measles, mumps, and rubella (MMR)

9. Hepatitis C Virus (HCV) antibody positive subjects with negative HCV by PCR testing are eligible if they:

   • have spontaneously cleared infection, or
   • are in sustained virologic remission for at least 12 weeks after treatment for HCV.
10. Negative SARS-CoV-2 PCR test result performed within 2 weeks of transplant (SARS-CoV-2 is the virus that causes COVID-19)

Exclusion Criteria:

Individuals who meet any of these criteria are not eligible for enrollment as study participants-

1. Prisoners or subjects who are compulsorily detained
2. Inability or unwillingness of a participant to give written informed consent or comply with study protocol
3. Candidate for a multiple solid organ or tissue transplants
4. Prior history of organ or cellular transplantation
5. Known to have idiopathic focal segmental glomerulosclerosis (FSGS) as the underlying cause of kidney failure (ESRD)
6. Requirement for uninterrupted anticoagulation therapy, including Plavix.
7. Known hypersensitivity to mechanistic target of rapamycin (mTOR) inhibitors or contraindication to everolimus (including history of wound healing complications)
8. History of severe allergic and/or anaphylactic reactions to humanized or murine monoclonal antibodies
9. Hypersensitivity to rabbit proteins or rabbit anti-thymocyte Globulin (ATG)
10. Known hypersensitivity to ACTEMRA® (tocilizumab) or lulizumab pegol (BMS-931699)
11. The human immunodeficiency virus (HIV) infected subjects, including those who are well controlled on antiretrovirals
12. Positive hepatitis B surface antigen (HBSAg), or hepatitis B core antibody (HBcAB) serology
13. Hepatitis C virus antibody positive (HCV Ab+) subjects who have failed to demonstrate sustained viral remission for more than 12 weeks after anti-viral treatment
14. Subjects with a previous history of active Tuberculosis (TB)
15. Known active current viral, fungal, mycobacterial or other infections (including, but not limited to tuberculosis and atypical mycobacterial disease, Hepatitis B and C, and herpes zoster)

16. Donor or recipient residing in areas where the annual incidence ≥ 21 cases per 100,000) for coccidioidomycosis according to current CDC map: (https://www.cdc.gov/fungal/diseases/coccidioidomycosis/causes.html)

    • Donors or recipients residing in low risk zones (annual <21 cases per 100,000) will not require additional screening
17. History of malignancy except treated basal cell cancer of the skin
18. History of hemolytic-uremic syndrome/ thrombotic thrombocytopenia purpura
19. History of demyelinating disorders (e.g., multiple sclerosis, chronic inflammation demyelinating polyneuropathy)
20. History of gastrointestinal perforations, active inflammatory bowel disease or diverticulitis
21. Any previous treatment with alkylating agents such as chlorambucil, or with total lymphoid irradiation
22. Receipt of a live vaccine within 30 days prior to transplantation.

23. Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may:

    • pose additional risks from participation in the study,
    • may interfere with the participant's ability to comply with study requirements, or
    • that may impact the quality or interpretation of the data obtained from the study
24. Severe hyperlipidemia (defined by total cholesterol >350 mg/dL, LDL >190 mg/dL, or triglycerides >500 mg/dL)
25. Transaminase levels elevated more than 1.5 times the upper limit of normal (ULN) within 7 days prior to enrollment
26. The absolute neutrophil count (ANC) < 2,000 per mm^3 within 7 days prior to enrollment
27. Platelet count less than 100,000 per mm^3 within 7 days prior to enrollment
28. More than 50% CD8+/ CD28- T-cells in peripheral blood
29. A calculated panel reactive antibody (cPRA) ≥20%, as determined by each participating site's laboratory
30. Positive pregnancy test in women of child bearing potential, currently breastfeeding, or planning to become pregnant during the timeframe of the study or follow-up period
31. Participation in any other studies with investigational drugs or regimens in the preceding year
32. A history of a positive SARS-CoV-2 PCR test result (SARS-CoV-2 is the virus that causes COVID-19)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: lulizumab pegol + novel ISR; lulizumab pegol + novel ISR: lulizumab pegol plus immunosuppressive regimen (anti-thymocyte globulin (rabbit), steroids,) belatacept, tocilizumab, and everolimus)

Biological: lulizumab pegol; 25 mg subcutaneously (SC) on Day 1 post transplantation then 12.5 mg SC weekly through day 77 (Week 11); Other Names: BMS-931699; Biological: antithymocyte globulin (rabbit); 1.5 mg/kg intravenously (IV) on Day 0 (day of transplantation) and the day following (Day 1); Other Names: Thymoglobulin®; ATG (rabbit); Drug: methylprednisolone; 500 mg (IV) on Day 0 (day of transplantation), 250 mg (IV) on Day 1 and 125 mg (IV) on Day 2; Other Names: Solu-Medrol ®; Biological: tocilizumab; 8 mg/kg (IV) on Day 2 post transplantation followed by 162 mg (SC) every 2 weeks through day 168 (Week 24); Other Names: Actemra®; Drug: Prednisone; Beginning on Day 3 post transplantation, taken orally: 60 mg daily; Days 4 through 10: 30 mg daily; Days 11 through 17: 20 mg daily; Days 18 through 24: 10 mg daily; After Day 24: continued taper of dose to final maintenance dose of 5 mg, per protocol; Other Names: prednisone tablets; Rayos®; Drug: everolimus; Initial dose of 0.75 mg taken orally twice daily on Day 14 days after transplantation. Dose will be titrated to target trough levels 3-8 ng/mL.; Other Names: Zortress®; Biological: belatacept; 5 mg/kg (IV) every 4 weeks starting on Day 84 (Week 12) and continuing through Day 364 (Week 52); Other Names: Nulojix®; Drug: mycophenolate mofetil; An option for participants who do not tolerate everolimus: to be switched to either; mycophenolate mofetil 1000 mg administered orally twice daily or; mycophenolic acid; Other Names: MMF; CellCept®; Drug: mycophenolic acid; An option for participants who do not tolerate everolimus: to be switched to either; mycophenolic acid 720 mg taken orally twice daily or; mycophenolate mofetil; Other Names: Myfortic®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of participants who remain free of biopsy-proven acute T-cell mediated or antibody-mediated rejection as defined by Banff criteria	Definitions: Acute T cell Mediated Rejection: Biopsy proven rejection defined by histologic evidence of a Banff grade of ≥1A and clinical treatment for acute rejection.; Acute Antibody Mediated Rejection: Diffusely positive immunostaining staining for C4d, presence of circulating anti-donor antibodies, and morphologic evidence of acute tissue injury. Reference: Banff 2007 Classification Renal Allograft Pathology definition of terms.	6 months post transplantation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of participants who remain free of biopsy-proven acute T-cell mediated or antibody-mediated rejection as defined by Banff criteria	Definitions: Acute T cell Mediated Rejection: Biopsy proven rejection defined by histologic evidence of a Banff grade of ≥1A and clinical treatment for acute rejection.; Acute Antibody Mediated Rejection: Diffusely positive immunostaining staining for C4d, presence of circulating anti-donor antibodies, and morphologic evidence of acute tissue injury. Reference: Banff 2007 Classification Renal Allograft Pathology definition of terms.	12 months post transplantation

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
EXPLORATORY: Frequency of circulating T Regulatory Cells (Tregs)	Mechanistic assay. Evaluation of the frequency of circulating Tregs over time.Exploratory goal: To advance understanding in mechanisms of tolerance.	Day 0 (Pre-transplant) and -3, -6 and -12 months post transplantation
EXPLORATORY:T Regulatory Cells (Treg) suppressive activity	Mechanistic assay.Donor-specific suppression activity of recipient Tregs will be measured over time by using irradiated donor peripheral blood mononuclear cells (PBMCs) as stimulators. Exploratory goal: To advance understanding in mechanisms of tolerance.	Day 0 (Pre-transplant) and -3, -6 and -12 months post transplantation
EXPLORATORY:Alloreactive T cell frequency	Mechanistic assay that measures the frequency of circulating donor-reactive CD4 conventional T cells, CD8 T cells and Tregs analyzed over time. Exploratory goal: To advance understanding in mechanisms of tolerance.	Day 0 (Pre-transplant) and -3, -6 and -12 months post transplantation
EXPLORATORY:Expression of T cell checkpoint inhibition related genes	Methodology: Analysis of gene expression in peripheral blood mononuclear cells (PBMCs) stimulated with donor antigen presenting cells to explore genes implicated in T cell checkpoint inhibition (CTLA-4, SFASL, NFATC1, NFATC2, LAG3 and HAVCR2, as examples). Exploratory goal: To advance understanding in mechanisms of tolerance.	Day 0 (Pre-transplant) and -3, -6 and -12 months post transplantation

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Bristol-Myers Squibb; Clinical Trials in Organ Transplantation
• Investigators: Principal Investigator: Flavio Vincenti, M.D., University of California San Francisco School of Medicine: Transplantation; Study Chair: Sindhu Chandran, M.D., University of California San Francisco School of Medicine: Transplantation

Publications and helpful links

Helpful Links

• Division of Allergy, Immunology, and Transplantation
• National Institute of Allergy and Infectious Diseases
• Clinical Trials in Organ Transplantation (CTOT)

Study record dates

Study Major Dates

• Study Start (Actual): December 11, 2019
• Primary Completion (Actual): September 14, 2023
• Study Completion (Actual): September 14, 2023

Study Registration Dates

• First Submitted: August 21, 2019
• First Submitted That Met QC Criteria: August 21, 2019
• First Posted (Actual): August 26, 2019

Study Record Updates

• Last Update Posted (Actual): October 6, 2023
• Last Update Submitted That Met QC Criteria: October 5, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: adult living-donor kidney transplant recipients; novel immunosuppressive (IS) therapy regimen; lulizumab pegol (BMS-931699); CD28 and IL-6 biologic blockade; CD28 and IL-6 receptor antagonists; T regulatory cells (Treg) modulation
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Antineoplastic Agents, Immunological; Anti-Bacterial Agents; Protein Kinase Inhibitors; Antibiotics, Antineoplastic; Immune Checkpoint Inhibitors; Antitubercular Agents; Antibiotics, Antitubercular; MTOR Inhibitors; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisone; Mycophenolic Acid; Everolimus; Abatacept; Thymoglobulin; Antilymphocyte Serum
• Other Study ID Numbers: DAIT CTOT-24; NIAID CRMS ID#: 38581 (Other Identifier: DAIT NIAID)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No