Cyclophosphamide Therapy for Refractory Antibody-Mediated Rejection (AMR) in Kidney Transplants

Study Overview
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Brief Summary
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The study hypothesis is that short-term low dose cyclophosphamide therapy will be effective in resolving inflammation in patients with late phase antibody-mediated rejection refractory to current standard of care treatment.

Detailed Description
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There is no consensus on the optimal treatment of de novo donor specific antibody-mediated rejection. Optimizing baseline immunosuppression (calcineurin inhibitor (CNI), anti-proliferative agent, and anti-inflammatory) is considered foundational but is insufficient. Pulse steroids are routinely used. A number of immunosuppressive approaches have been tried in uncontrolled trials. The strongest evidence, at least for early antibody-mediated rejection (< 6 months from transplant), exists for plasmapheresis, with or without low dose IVIg, or high dose IVIg alone. However, as noted in a recent FDA workshop, while the literature suggests that [these agents] have evidence of efficacy for the management of acute antibody-mediated rejection, and could be considered as standard of care, treatment regimes have not been standardized or optimized. Moreover the evidence supporting efficacy of this approach in late, as opposed to early antibody-mediated rejection is distinctly lacking.

Official Title
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Phase II Pilot Study of Cyclophosphamide Therapy for Refractory Antibody-Mediated Rejection in Kidney Transplantation

Conditions
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Antibody Mediated Rejection

Intervention / Treatment
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* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with a living or deceased donor kidney transplant Failed current standard of care for late antibody-mediated rejection Persistent de novo donor specific antibody and a concurrent biopsy with histologic evidence of acute antibody-mediated inflammation Adults with reproductive potential must agree to use approved methods of birth control while in the study Exclusion Criteria: Leukopenia (WBC) < 3.0 x 109/L Creatinine Clearance less than or equal to 25 ml/min/1.73m2 HCV or HBV positive BKV or CMV viremia assessed by PCR Any active infection Use of other investigational drugs within 4 weeks of study Pregnancy/breast feeding/unwilling or unable to take birth control Active malignancy de novo DSA occurring equal to or greater than15 years after kidney transplant Screening biopsy with equal to or greater than cg2 on Banff criteria Cumulative/lifetime dose of cyclophosphamide, including anticipated total study dose (calculated according to Creatinine Clearance and mg/kg/day) equal to or greater than 36 g. Any condition that, in the opinion of the investigator, would pose risk to the subject's safe participation in the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cyclophosphamide<br>Cyclophosphamide 1.5 mg/kg orally daily for 180 days (26 weeks) adjusted for renal function. | Drug: Cyclophosphamide<br>* Cyclophosphamide 1.5 mg/kg orally daily for 180 days adjusted for renal function<br>* Other names: Procytox;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Microvascular inflammation | Histologic resolution of acute antibody-mediated inflammation in a 6 month post-treatment biopsy (Banff histology scores: g, v, ptc, C4d +ve) | month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| titre of donor specific antibody (DSA) | Change in the level of de novo DSA between enrolment and at 6 and 12 months post-enrollment | 6 and 12 months | 
| antibody-mediated tissue injury | Change in antibody-mediated tissue injury between the enrollment and post-treatment kidney transplant biopsy samples | month 6 | 
| Urine Albumin/Creatinine ratios | Change in urine albumin/creatinine ratio between enrolment and 6 and 12 month post-enrolment samples | month 6 and 12 | 
| Creatinine Clearance and estimated GFR | Evaluation of Creatinine Clearance, and estimated GFR using the Chronic Kidney Disease Epidemiology (CKR-EPI) equation | month 6 and 12 | 
| Graft Survival |  | month 6 and 12 | 
| Patient Survival |  | month 6 and 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Transplantation