Clinical trial NCT04066114: Treg Modulation With CD28 and IL-6 Receptor Antagonists
Official title: Regulatory T Cell Modulation in Kidney Transplantation With Biologic Blockade of Dual Effector Pathways, CD28 and IL-6 (CTOT-24)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
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
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Bristol-Myers Squibb
name: Clinical Trials in Organ Transplantation
First posted: 2019-08-26
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: 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.
timeFrame: 6 months post-transplantation
Secondary outcomes:
measure: 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.
timeFrame: 12 months post-transplantation
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama School of Medicine: Transplantation
state: Alabama
city: San Francisco
country: United States
facility: University of California San Francisco School of Medicine: Transplantation
state: California
city: Aurora
country: United States
facility: University of Colorado (UC) Health Transplant Center - Anschutz
state: Colorado
city: Chicago
country: United States
facility: Northwestern Memorial Hospital: Transplantation
state: Illinois
city: Omaha
country: United States
facility: University of Nebraska Medical Center: Transplantation
state: Nebraska
city: Durham
country: United States
facility: Duke University Medical Center: Transplantation
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation: Transplantation
state: Ohio
Study officials:
affiliation: University of California San Francisco School of Medicine: Transplantation
name: Flavio Vincenti, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California San Francisco School of Medicine: Transplantation
name: Sindhu Chandran, M.D.
role: STUDY_CHAIR
References: