A Study to Evaluate the Safety and Effectiveness of Clazakizumab for the Treatment of Chronic Active Antibody-Mediated Rejection in Kidney Transplant Recipients

Overview

About this study

The purpose of this study is to investigate whether clazakizumab (an anti-interleukin (IL)-6 monoclonal antibody (mAb)) may be beneficial for the treatment of CABMR in recipients of a kidney transplant by inhibiting the production of Donor Specific Antibodies (DSA) and re-shaping T cell alloimmune responses.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Unless specified otherwise, all eligibility criteria time-intervals are assessed with respect to the screening visit.

Inclusion Criteria:

  • Age 18-70 years old.
  • Living donor/deceased donor kidney transplant recipients ≥6 months from time of transplant.
  • Diagnosis of CABMR (according to Banff 2015 diagnostic criteria) to include all of the following: 
    • Biopsy-proven CABMR (i.e., chronic glomerulopathy (cg) >0) with/without C4d staining. Repeat biopsy to be performed if previous biopsy is not within 6 months of the start of the screening period. The local pathologist's diagnosis will be reviewed by a central pathologist to confirm eligibility for entry into the study. Subjects without evidence of chronic tissue injury on light microscopy but who have glomerular basement membrane double contours on electron microscopy (cg1a) are eligible.  Positive for human leukocyte antigen (HLA) DSA (using single-antigen bead based assays) post-transplant. Local laboratory DSA results will be reviewed by the central HLA reviewer to confirm eligibility for entry into the study. A single antigen bead MFI >1,000 will be considered positive. If presence of HLA DSA is confirmed within 6 months of the start of the screening period, the test does not need to be repeated for eligibility. 
      • Note: Treatments for ABMR (including CABMR) or TCMR are not allowed within 3 months of the start of screening (see Exclusion Criterion 3). If a subject has received one of these treatments at any time prior, a repeat biopsy and repeat DSA must be performed after halting/completing treatment (to show continuing CABMR).
  • Written informed consent obtained from subject (or legally acceptable representative) before any trial-related procedures.

Exclusion Criteria:

  • Participant is unable or unwilling to comply with study procedures in the opinion of the Investigator.
  • Multi-organ transplant recipient or cell transplant (islet, bone marrow, stem cell) recipient.
  • Treatment for ABMR (including CABMR) or TCMR within 3 months of the start of screening.
  • Received T cell depleting agents (e.g., alemtuzumab, anti-thymocyte globulin) within 3 months of the start of screening.
  • Treatment with mTOR inhibitors within 4 weeks of the start of screening.
  • Biopsy showing pure TCMR or advanced interstitial fibrosis (ci3), advanced tubular atrophy (ct3), vascular fibrous intimal thickening (cv3) or other significant causes of renal dysfunction (e.g., polyoma BK virus (BKV) nephropathy, glomerulonephritis).
  • Impaired renal function due to disorders in the transplanted allograft (e.g., renal artery stenosis, hydronephrosis).
  • eGFR < 25 mL/min/1.73 m2 or > 65 mL/min/1.73 m2 (MDRD4).
  • Nephrotic range proteinuria defined as spot urine albumin creatinine ratio (UACR) ≥ 2,200 mg/g (≥ 220 mg/mmol). If spot UACR is above defined limits, repeat test on separate day to confirm ineligibility (or collect 24-hour urine to confirm nephrotic range proteinuria (≥ 3.0 g/day)).
  • Pregnant, breastfeeding, or unwillingness to practice highly effective birth control during the study and for 5 months after last dose of investigational drug.
  • History of anaphylaxis.
  • Abnormal liver function tests (LFTs) (alanine aminotransferase (ALT)/aspartate aminotransferase (AST)/bilirubin > 1.5 x upper limit of normal) or other significant liver disease.
  • History of active tuberculosis (TB).
  • History of latent TB (e.g., positive QuantiFERON-TB test) without history of active TB unless subject has completed a full course of prophylactic treatment.
  • History of human immunodeficiency virus (HIV) infection or positive for HIV.
  • Seropositive for hepatitis B surface antigen (HBsAg).
  • Hepatitis C virus (HCV) RNA positive.
  • Known Epstein-Barr virus (EBV) mismatch: donor seropositive, recipient seronegative.
  • History of gastrointestinal perforation, diverticular disease or diverticulitis, or inflammatory bowel disease.
  • Neutropenia (< 1,000/mm3) or thrombocytopenia (< 50,000/mm3).
  • Active infections requiring systemic antimicrobial agents and unresolved prior to screening.
  • History of or current invasive fungal infection or other opportunistic infection, including (but not limited to) the following: a nontuberculous mycobacterial infection, aspergillosis, pneumocystosis, and toxoplasmosis.
  • Active viral infections such as BKV, CMV, or EBV based on polymerase chain reaction (PCR) testing.
  • Current or recent (within 3 months) participation in an interventional trial.
  • Administration of a live vaccine within 6 weeks of the start of screening, including but not limited to the following:
    • Adenovirus;
    • Measles, mumps, and rubella;
    • Oral polio;
    • Oral typhoid;
    • Rotavirus;
    • Varicella zoster;
    • Yellow fever .
  • History of alcohol or illicit substance (including marijuana) abuse.
  • Present or previous (within 3 years) malignancy except for basal cell carcinoma, fully excised squamous cell carcinoma of the skin, or non-recurrent (within 5 years) cervical carcinoma in-situ.
  • Presence of a condition or abnormality (i.e., clinically significant endocrine, autoimmune, metabolic, neurological, psychiatric/psychological, renal, gastrointestinal, hepatic, and hematological or any other system abnormalities that are uncontrolled with standard treatment) that in the opinion of the Investigator would compromise the safety or life expectancy of the patient or the quality of the data.
  • History of intolerance to trimethoprim and/or sulfamethoxazole. This criterion does not apply if subject is already taking another suitable Investigator-approved alternative for PJP prophylaxis, or if subject is willing to begin taking an Investigator-approved alternative prophylactic therapy at least 1 week prior to the Day 1 Baseline visit (Visit 2).
  • Prior exposure to clazakizumab, tocilizumab, or other IL-6/IL-6R blockers.
  • ABO-incompatible transplant recipient.
  • Severe hypogammaglobulinemia (defined as immunoglobulin G (IgG) < 400 mg/dL).
  • Prior exposure to proteasome inhibitors (e.g., bortezomib).

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Scottsdale/Phoenix, Ariz.

Mayo Clinic principal investigator

Hasan Khamash, M.D.

Open for enrollment

Contact information:

Emily Frank R.N., CCRN

(480)342-3484

Frank.Emily1@mayo.edu

Rochester, Minn.

Mayo Clinic principal investigator

Carrie Schinstock, M.D.

Open for enrollment

Contact information:

Nong Braaten L.P.N.

(507)538-9617

Braaten.Nong@mayo.edu

More information

Publications

Publications are currently not available

Study Results Summary

Not yet available

Supplemental Study Information

Not yet available