Treg Modulation With CD28 and IL-6 Receptor Antagonists

NCT04066114 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: DAIT CTOT-24NIAID CRMS ID#: 38581
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 7

Brief Summary

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

Conditions

Living-Donor Kidney Transplant; Kidney Transplant Recipients

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

Outcome Measures

Primary Outcomes (1)

• The Proportion of Participants Who Remain Free of Biopsy-proven Acute T-cell Mediated or Antibody-mediated Rejection (as Defined by Banff Criteria) at 6 Months Post-transplantation.

  Acute T-cell mediated rejection was defined using the Banff 2007 criteria. Participants with a Banff grade of greater than or equal to 1A were determined to have met the endpoint. Severity is graded as 1A, 1B, 2A, 2B, or 3, with 1A being the mildest form of cellular rejection and 3 being the most severe form of cellular rejection. Antibody mediated rejection was defined as diffusely positive staining for C4d, presence of circulating anti-donor antibodies, and morphologic evidence of acute tissue injury. Clinical rejection occurring prior to 6 months, defined as treated rejection without biopsy confirmation was included as acute rejection with respect to the endpoint.

  6 months post-transplantation

Secondary Outcomes (1)

• The Proportion of Participants Who Remain Free of Biopsy-proven Acute T-cell Mediated or Antibody-mediated Rejection (as Defined by Banff Criteria) at 12 Months Post-transplantation.

  12 months post-transplantation

Study Arms (1)

lulizumab pegol + novel ISR

EXPERIMENTAL

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

Biological: lulizumab pegol; Biological: antithymocyte globulin (rabbit); Drug: methylprednisolone; Biological: tocilizumab; Drug: Prednisone; Drug: everolimus; Biological: belatacept; Drug: mycophenolate mofetil; Drug: mycophenolic acid

Interventions

lulizumab pegol BIOLOGICAL

25 mg subcutaneously (SC) on Day 1 post transplantation then 12.5 mg SC weekly through day 77 (Week 11)

Also known as: BMS-931699

lulizumab pegol + novel ISR

antithymocyte globulin (rabbit) BIOLOGICAL

Study participants are administered four doses of rabbit anti-thymocyte globulin, total dose 6 mg/kg given in divided doses on the day of transplantation and days 1-3.

Also known as: ATG (rabbit), Thymoglobulin®

lulizumab pegol + novel ISR

methylprednisolone DRUG

500 mg (IV) on Day 0 (day of transplantation), 250 mg (IV) on Day 1 and 125 mg (IV) on Day 2

Also known as: Solu-Medrol ®

lulizumab pegol + novel ISR

tocilizumab BIOLOGICAL

8 mg/kg (IV) on Day 2 post transplantation followed by 162 mg (SC) every 2 weeks through day 168 (Week 24)

Also known as: Actemra®

lulizumab pegol + novel ISR

Prednisone DRUG

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

Also known as: prednisone tablets, Rayos®

lulizumab pegol + novel ISR

everolimus DRUG

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.

Also known as: Zortress®

lulizumab pegol + novel ISR

belatacept BIOLOGICAL

5 mg/kg (IV) every 4 weeks starting on Day 84 (Week 12) and continuing through Day 364 (Week 52)

Also known as: Nulojix®

lulizumab pegol + novel ISR

mycophenolate mofetil DRUG

mycophenolate mofetil is started no later than one day after transplant at 1000mg PO twice daily provided WBC count permits, staying on it until everoliumus level is within therapeutic range. Participants that do no tolerate everolimus can stay on or switch back to mycophenolate mofetil 1000 mg twice daily and remain in trial.

Also known as: MMF, CellCept®

lulizumab pegol + novel ISR

mycophenolic acid DRUG

mycophenolic acid is started no later than one day after transplant at 720mg PO twice daily provided WBC count permits, staying on it until everoliumus level is within therapeutic range. Participants that do not tolerate everolimus can stay on or switch back to 720 mg twice daily of mycophenolic acid and remain in trial.

Also known as: Myfortic®

lulizumab pegol + novel ISR

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Individuals who meet all the following criteria are eligible for enrollment as study participants:
• Able to understand and provide informed consent
• 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).
• Recipient of primary, nonhuman leukocyte antigen identical living donor kidney transplant
• No donor specific antibodies prior to transplant that are considered to be of clinical significance by the site investigator

You may not qualify if:

• Individuals who meet any of these criteria are not eligible for enrollment as study participants-
• Prisoners or subjects who are compulsorily detained
• Inability or unwillingness of a participant to give written informed consent or comply with study protocol
• Candidate for a multiple solid organ or tissue transplants
• Prior history of organ or cellular transplantation
• Known to have idiopathic focal segmental glomerulosclerosis (FSGS) as the underlying cause of kidney failure (ESRD)
• Requirement for uninterrupted anticoagulation therapy, including Plavix.
• Known hypersensitivity to mechanistic target of rapamycin (mTOR) inhibitors or contraindication to everolimus (including history of wound healing complications)
• History of severe allergic and/or anaphylactic reactions to humanized or murine monoclonal antibodies
• Hypersensitivity to rabbit proteins or rabbit anti-thymocyte Globulin (ATG)
• Known hypersensitivity to ACTEMRA® (tocilizumab) or lulizumab pegol (BMS-931699)
• The human immunodeficiency virus (HIV) infected subjects, including those who are well controlled on antiretrovirals
• Positive hepatitis B surface antigen (HBSAg), or hepatitis B core antibody (HBcAB) serology
• 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
• Subjects with a previous history of active Tuberculosis (TB)

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Bristol-Myers Squibb: collaborator
• Clinical Trials in Organ Transplantation: collaborator

Study Sites (7)

University of Alabama School of Medicine: Transplantation

Birmingham, Alabama, 35233, United States

Location

University of California San Francisco School of Medicine: Transplantation

San Francisco, California, 94143, United States

Location

University of Colorado (UC) Health Transplant Center - Anschutz

Aurora, Colorado, 80045, United States

Location

Northwestern Memorial Hospital: Transplantation

Chicago, Illinois, 60611, United States

Location

University of Nebraska Medical Center: Transplantation

Omaha, Nebraska, 68105, United States

Location

Duke University Medical Center: Transplantation

Durham, North Carolina, 27710, United States

Location

Cleveland Clinic Foundation: Transplantation

Cleveland, Ohio, 44195, United States

Location

Related Links

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

MeSH Terms

Interventions

lulizumab pegol; thymoglobulin; Methylprednisolone; Methylprednisolone Hemisuccinate; tocilizumab; Prednisone; Everolimus; Abatacept; Mycophenolic Acid

Intervention Hierarchy (Ancestors)

Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Pregnadienediols; Sirolimus; Macrolides; Lactones; Organic Chemicals; Immunoconjugates; Antibodies; Immunoglobulins; Serum Globulins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Globulins; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids

Results Point of Contact

• Title: Director, Clinical Research Operations Program
• Organization: DAIT/NIAID

DAITClinicalTrialsGov@niaid.nih.gov

301-594-7669

Study Officials

• Flavio Vincenti, M.D.

  University of California San Francisco School of Medicine: Transplantation

  PRINCIPAL INVESTIGATOR

• Sindhu Chandran, M.D.

  University of California San Francisco School of Medicine: Transplantation

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 21, 2019
• First Posted: August 26, 2019
• Study Start: December 11, 2019
• Primary Completion: September 14, 2023
• Study Completion: September 14, 2023
• Last Updated: October 9, 2024
• Results First Posted: October 9, 2024

Record last verified: 2024-10

Locations

US (7)