Felzartamab in Late Antibody-Mediated Rejection

Farsad Eskandary22 enrolled

Overview

This prospective trial will assess the safety, tolerability, pharmacokinetics, immunogenicity, pharmacodynamics and efficacy of the fully human CD38 monoclonal antibody felzartamab in kidney transplant recipients with late active or chronic-active ABMR. The study is designed as a randomized, controlled, double-blind pilot phase 2 trial. Participants will be randomized to receive either felzartamab or placebo for a period of six months, and then followed for another six months. After six and twelve months, study participants will be subjected to follow-up allograft biopsies.

This prospective bi-center study (University of Vienna, Charité Universitätsmedizin Berlin; Sponsor: Medical University of Vienna, Vienna, Austria; Funder: MorphoSys AG, Planegg, Germany) is an investigator-driven pilot trial designed to assess the safety\&tolerability (primary endpoint), pharmacokinetics, immunogenicity, pharmacodynamics and efficacy (preliminary assessment) of the fully human CD38 monoclonal antibody felzartamab in kidney transplant recipients diagnosed with late active or chronic-active antibody-mediated rejection (ABMR) after kidney transplantation. Adult renal allograft recipients with anti-HLA donor-specific antibodies (DSA) and biopsy-proven ABMR (Banff 2019 classification) ≥180 days post-transplantation will be identified and recruited at the kidney transplantation outpatient services of the two center sites. The primary endpoint will be safety and tolerability. Participants will be randomized to receive either felzartamab (intravenous administration) or placebo (1:1 randomization stratified by study site and according to ABMR categories) for a period of 6 months (administration of felzartamab/placebo at day 0, 7, 14, 21, and thereafter in 4-weekly intervals. After six (week 24) and twelve months (week 52), study participants will be subjected to follow-up allograft biopsies. Primary goals of the trial are to assess the safety, pharmacokinetics and pharmacodynamics (peripheral blood plasma cell and natural killer cell depletion) of a 6-month course of treatment over a period of 12 months. The trial will in addition provide first data on efficacy (progression/activity of rejection, blood biomarkers) and potential associations of treatment with parameters reflecting clinical progression of allograft dysfunction, including the course of estimated glomerular filtration rate.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Antibody-mediated Rejection

Interventions

FelzartamabDRUG

Intravenous infusion in regular intervals over 6 months

PlaceboDRUG

Intravenous infusion in regular intervals over 6 months

Eligibility

Sex: ALLMin age: 19 YearsMax age: 80 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Voluntary written informed consent * Age \>18 years (maximum: 80 years) * Functioning living or deceased donor allograft after ≥180 days post-transplantation * eGFR ≥20 ml/min/1.73 m2 (CKD-EPI formula) * HLA class I and/or II antigen-specific antibodies (preformed and/or de novo DSA). * Active or chronic/active ABMR (±C4d in PTC) according to the Banff 2019 classification * Molecular ABMR score (MMDx) ≥0.2 Exclusion Criteria: * Patients actively participating in another clinical trial * Age ≤18 years * Female subject is pregnant or lactating or not on adequate contraceptive therapy * ABO-incompatible transplant * Index biopsy results: * T-cell-mediated rejection classified Banff grade ≥I * De novo or recurrent severe thrombotic microangiopathy * Polyoma virus nephropathy * De novo or recurrent glomerulonephritis * Acute rejection treatment ≤3 month before screening * Previous treatment with other CD38 monoclonal antibodies (e.g. daratumumab) * Previous treatment with other immunomodulatory monoclonal/polyclonal antibodies (e.g. CD20 Ab rituximab, IL-6/IL-6R Ab) ≤3 months before study treatment * Total bilirubin \>2×the upper limit of normal \[ULN\], alanine transaminase and aspartate aminotransferase \>2·5×ULN * Haemoglobin \<8 g/dL * Thrombocytopenia: Platelets \<100 G/L * Leukopenia: Leukocytes \<3 G/L * Neutropenia: Neutrophils \< 1.5 G/L * Hypogammaglobulinemia: Serum IgG \<400 mg/dL * Active viral, bacterial or fungal infection precluding intensified immunosuppression * Active malignant disease precluding intensified immunosuppressive therapy * Latent or active tuberculosis (positive QuantiFERON-TB-Gold test) * Administration of a live vaccine within 6 weeks of screening * History of alcohol or illicit substance abuse * Serious medical or psychiatric illness likely to interfere with participation in the study

Locations (2)

Medical University of Vienna

Vienna, Austria

Charité University

Berlin, Germany

Outcomes

Primary Outcomes

Incidence of treatment-emergent adverse events

(Serious) adverse events will be classified using the Medical Dictionary for Regulatory Activities (MedDRA). Documentation of an AE will include the assessment of its relationship with the study drug (unrelated, related) and the severity of AE will be graded on a three-point scale (mild, moderate, severe).

Time frame: 12 months

Secondary Outcomes

Felzartamab serum concentration

Total felzartamab serum concentration (ELISA, ng/mL)

Time frame: At day 0, week 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 44, 48 and 52

Anti-Felzartamab antibodies

Concentration of anti-felzartamab antibodies in serum (ELISA, ng/mL)

Time frame: At day 0, week 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 44, 48 and 52

Morphologic ABMR categories

Phenotyping of renal transplant biopsies: active ABMR vs. chronic active ABMR vs. chronic inactive ABMR

Time frame: At week 24 and at week 52

Serum donor-specific antibody (DSA) levels

Mean fluorescence intensity (MFI) of the immunodominant DSA (Luminex)

Time frame: Week 0, 12, 24, and 52

Serum immunoglobulin levels

Ig (sub)classes (ELISA, Nephelometry, mg/dL)

Time frame: Week 0, 12, 24, and 52

Leukocyte subsets in peripheral blood

Counts of circulating plasma cells, natural killer cells, T and B cell subpopulations (flow cytometry, cell counts)

Data from ClinicalTrials.gov

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