Clinical trial NCT03504241: Tolerance by Engaging Antigen During Cellular Homeostasis
Official title: Donor-derived Mesenchymal Stromal Cells, Alemtuzumab, Co-stimulation Blockade and Sirolimus for Tolerance Induction in Adult Kidney Allograft Recipients (ITN062ST)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Kidney Transplantation
Renal Transplantation
Renal Transplant Recipient
Keywords: mesenchymal stromal cells (MSCs)
anti-rejection drugs
operational tolerance
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Immune Tolerance Network (ITN)
name: PPD Development, LP
name: Rho Federal Systems Division, Inc.
First posted: 2018-04-20
Enrollment: 8
Sex: ALL
Minimum age (years): 19
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Anti-rejection medicines, also known as immunosuppressive drugs, are prescribed to organ transplant recipients to prevent rejection of the new organ. Long-term use of these medicines places transplant recipients at higher risk of serious infections and certain types of cancer.

The purpose of this study is to determine if:

* it is safe to give mesenchymal stromal cells (MSCs) to kidney transplant recipients, and
* the combination of the immunosuppressive (anti-rejection) study drugs plus the MSCs can allow a kidney transplant recipient to slowly reduce and/or then completely stop all anti-rejection drugs, without rejection of their kidney (renal) allograft, a process called "immunosuppression withdrawal".

Detailed description: Background:The most common problem following a kidney transplant is the development of acute or chronic rejection. Rejection is the immunologic reaction in which the body refuses to accept the transplanted organ. The body's immune system will make destructive antibodies that will attempt to attack the transplanted organ.

In order to prevent organ rejection, all patients receiving an allograft (a graft transplanted between genetically non-identical individuals of the same species) must take anti-rejection (immunosuppressive) therapy. These medications function by lowering the body's natural immune system. Often these medications are associated with significant side effects ranging from infections to cancer.

Study:

This is a single center, open label, dose-escalation clinical trial in 6 adult recipients of Human Leukocyte Antigen (HLA)- non-identical, living-donor renal allografts. All participants will receive induction therapy with alemtuzumab followed by maintenance therapy with sirolimus and belatacept.

A total of 2 dosing cohorts of 2 recipients each will receive 12 infusions of donor-derived MSCs starting on Day 42 post-transplant and every 4 weeks starting on Day 56 post-transplant, with a minimum of 7 days between the first and second MSC infusions.

The primary objective is to determine whether immune reconstitution after lymphocyte depletion in the setting of co-stimulatory blockade and systemic MSC-derived donor antigen can promote operational tolerance in recipients of kidney allografts.

Participants will be evaluated for eligibility for sirolimus withdrawal any time between week 52 and week 104 post-transplant. Participants who successfully complete sirolimus withdrawal will remain on belatacept monotherapy for at least 24 weeks before being assessed for eligibility to discontinue belatacept. Participants who successfully complete Immunosuppression Withdrawal (ISW) will then undergo 24 weeks of high frequency follow up followed by 132 weeks of standard follow up.

Study participation may continue for up to seven (7) years after kidney transplant surgery.

\*\*\* IMPORTANT NOTICE: \*\*\* The National Institute of Allergy and Infectious Diseases and the Immune Tolerance Network 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:

Recipient:

* Adult candidates of an human leukocyte antigen (HLA)-non-identical, living-donor kidney transplant:

  --Candidates must meet the United Network for Organ Sharing (UNOS) criteria, including laboratory criteria, for transplant listing;
* Evidence of established immunity to Epstein-Barr Virus (EBV) as demonstrated by serologic testing;
* Serological evidence of prior Cytomegalovirus (CMV) infection if donor is CMV positive;
* For women of child bearing potential:

  * A negative serum or urine pregnancy test with sensitivity of less than 50 mIU/mL within 72 hours of start of study medication; and
  * Agreement to use contraception:

    --- According to the FDA Office of Women's Health (http://www.fda.gov/birthcontrol), there are a number of birth control methods that are more than 80% effective

    ----Female recipients of child-bearing potential must consult with their physician and determine the most suitable method(s) from this list to be used for 18 months after the first dose of study therapy.

Donor:

* Meets institutional selection criteria for organ and bone marrow donation:

  --All donors will be screened and tested in accordance with:
  * (i) FDA 21 CRF 1271.85 requirements for donors of human cells, tissues, and cellular- and tissue-based products (HCT/P); and
  * (ii) standards for living kidney donors testing for infection established by the United Network for Organ Sharing (UNOS).
* Ability to understand and provide informed consent for all study procedures including kidney transplant and bone marrow harvest.

Exclusion Criteria:

Recipient:

* History of any immunodeficiency syndrome (including Human Immunodeficiency Virus-1 (HIV-1) and HIV-2);
* Positive anti-Hepatitis C Virus (HCV) Polymerase Chain Reaction (PCR), anti-Hepatitis C Virus (HBV) PCR, or HBV surface antigen;
* History of malignancy within 5 years of enrollment or any history of hematogenous malignancy or lymphoma; --Exception: Participants with curatively treated non-melanomatous skin cancer or curatively treated cervical carcinoma in situ may be enrolled.
* Underlying renal disease with high likelihood of recurrence, including but not limited to:

  * primary focal segmental glomerulosclerosis (FSGS),
  * Type I or II membranoproliferative glomerulonephritis (MPGN),
  * hemolytic-uremic syndrome and
  * thrombotic thrombocytopenic purpura (HUS/TTP) syndrome. ---Subject(s) with end-stage renal disease (ESRD) of unknown etiology and/or has no histologically confirmed diagnosis, may be enrolled into the study as long as there are no clinical signs or symptoms consistent with excluded clinical diagnoses.
* History of active M. tuberculosis:

  --Participants with a history of latent M. tuberculosis (LTB) as defined by positive testing for tuberculosis using an approved IGRA blood test, such as QuantiFERON®-Gold TB or T-SPOT-TB assay must:
  * have completed treatment for LTB and
  * have a negative chest x-ray. ----All participants will undergo IGRA testing for M tuberculosis within 3 months prior to transplant.
* Current or historical evidence of donor-specific antibody;
* Immunosuppressive drug therapy within one year prior to enrollment.
* May not be taking or have taken prednisone, cyclosporine A, tacrolimus, azathioprine, Mycophenolate Mofetil (MMF), cyclophosphamide, methotrexate, infliximab, etanercept, or other agents which have a primary therapeutic effect of immunosuppression in the year prior to transplantation.
* May not have taken depletional anti-lymphocyte agents at any time.

  ---Exceptions:
  * Short (≤ 30 days) courses of topical or inhaled steroids are permitted, as are
  * Short oral or parental pulses for a documented hypersensitivity reaction.
* Active autoimmune disease requiring ongoing immunosuppressive therapy or other conditions in which there is an anticipated need for immunosuppressive maintenance therapy;
* Uncompensated congestive heart failure, pulmonary edema, or symptomatic pulmonary hypertension;
* Active severe infection within a month of the screening visit;
* Use of an investigational drug within 30 days of the screening visit;
* Presence of any medical condition that the investigator deems incompatible with trial participation; or
* Inability or unwillingness to comply with protocol monitoring and therapy.

Donor:

* History of blood donation to the recipient;
* Evidence of prior Cytomegalovirus (CMV) infection if the recipient is CMV negative;
* History of HIV-1/HIV-2 infection;
* Positive HCV PCR, HBV PCR or HBV surface antigen;or
* Presence of any medical condition that the investigator deems incompatible with trial participation.

Primary outcomes:
measure: Proportion of Participants who Achieve Operational Tolerance
timeFrame: 52 weeks after completion of Immunosuppression Withdrawal (ISW)
Secondary outcomes:
measure: Proportion of Participants who Remain Off Immunosuppression
timeFrame: From ISW completion to end of study participation (up to approximately 5 years)
measure: Proportion of Participants who Return to Immunosuppression
timeFrame: From ISW completion to end of study participation (up to approximately 5 years)
measure: Proportion of Participants who Achieve Belatacept Monotherapy
timeFrame: 48 weeks from the time of last sirolimus dose
measure: Proportion of Participants who Die
timeFrame: From kidney transplant with alemtuzumab induction to to completion of study (up to approximately 6.5 years)
measure: Time from Transplant to the First Episode of Rejection
timeFrame: From kidney transplantation to completion of study (up to approximately 7 years)
measure: Incidence of Participants who Develop Donor Specific Antibody (DSA)
timeFrame: From study enrollment to completion of study (up to approximately 7 years)
measure: Incidence of Adverse Events Attributable to Mesenchymal Stromal Cells (MSC) Administration
timeFrame: From initial MCS infusion (day 42 post kidney transplant) to end of study participation (up to 7 years)
measure: Frequency of Select Adverse Events (AEs)
timeFrame: From kidney transplantation to completion of study (up to approximately 7 years)
measure: Incidence of Post-Transplant Diabetes
timeFrame: From post kidney transplantation to completion of study (up to approximately 7 years)
measure: Frequency of Antibody-Mediated Acute Cellular Rejection
timeFrame: From kidney transplant to completion of study (up to approximately 7 years)
measure: Frequency of Antibody-Mediated Chronic Rejection
timeFrame: From kidney transplant to completion of study (up to approximately 7 years)
Other outcomes:
Locations:
city: Durham
country: United States
facility: Duke University Health System
state: North Carolina
Study officials:
affiliation: Duke University Medical Center: Transplantation
name: Allan D. Kirk, M.D., Ph.D.
role: STUDY_CHAIR
References: