Clinical trial NCT05021484: Felzartamab in Late Antibody-Mediated Rejection
Official title: Safety, Tolerability and Efficacy of Monoclonal CD38 Antibody Felzartamab in Late Antibody-Mediated Renal Allograft Rejection - A Phase 2 Pilot Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Antibody-mediated Rejection
Keywords: CD38
Kidney transplantation
Lead sponsor: Medical University of Vienna
Sponsor class: OTHER
Collaborators: name: Charite University, Berlin, Germany
name: University of Alberta
name: Biogen
First posted: 2021-08-25
Enrollment: 22
Sex: ALL
Minimum age (years): 19
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Incidence of treatment-emergent adverse events
timeFrame: 12 months
Secondary outcomes:
measure: Felzartamab serum concentration
timeFrame: At day 0, week 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 44, 48 and 52
measure: Anti-Felzartamab antibodies
timeFrame: At day 0, week 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 44, 48 and 52
measure: Morphologic ABMR categories
timeFrame: At week 24 and at week 52
measure: Serum donor-specific antibody (DSA) levels
timeFrame: Week 0, 12, 24, and 52
measure: Serum immunoglobulin levels
timeFrame: Week 0, 12, 24, and 52
measure: Leukocyte subsets in peripheral blood
timeFrame: Week 0, 1, 4, 8, 12, 24, and 52
measure: Immunologic biomarkers
timeFrame: Week 0, 12, 24, and 52
measure: Torque Teno virus
timeFrame: Week 0, 12, 24, and 52
measure: eGFR
timeFrame: At day 0, week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 44, 48 and 52
measure: Proteinuria
timeFrame: At day 0, week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 44, 48 and 52
measure: Graft loss
timeFrame: 12 months
measure: Death
timeFrame: 12 months
measure: Glomerulitis plus peritubular capillaritis sum score
timeFrame: At week 24 and at week 52
measure: Transplant glomerulopathy score
timeFrame: At week 24 and at week 52
measure: C4d score
timeFrame: At week 24 and at week 52
measure: Molecular ABMR score
timeFrame: At week 24 and at week 52
measure: Molecular ABMR categories
timeFrame: At week 24 and at week 52
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: Medical University of Vienna
city: Berlin
country: Germany
facility: Charité University
Study officials:
affiliation: Department of Internal Medicine III, Medical University of Vienna
name: Georg A Böhmig, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Doberer K, Klager J, Gualdoni GA, Mayer KA, Eskandary F, Farkash EA, Agis H, Reiter T, Reindl-Schwaighofer R, Wahrmann M, Cohen G, Haslacher H, Bond G, Simonitsch-Klupp I, Halloran PF, Bohmig GA. CD38 Antibody Daratumumab for the Treatment of Chronic Active Antibody-mediated Kidney Allograft Rejection. Transplantation. 2021 Feb 1;105(2):451-457. doi: 10.1097/TP.0000000000003247.
citation: Raab MS, Engelhardt M, Blank A, Goldschmidt H, Agis H, Blau IW, Einsele H, Ferstl B, Schub N, Rollig C, Weisel K, Winderlich M, Griese J, Hartle S, Weirather J, Jarutat T, Peschel C, Chatterjee M. MOR202, a novel anti-CD38 monoclonal antibody, in patients with relapsed or refractory multiple myeloma: a first-in-human, multicentre, phase 1-2a trial. Lancet Haematol. 2020 May;7(5):e381-e394. doi: 10.1016/S2352-3026(19)30249-2. Epub 2020 Mar 11.
citation: Mayer KA, Doberer K, Eskandary F, Halloran PF, Bohmig GA. New concepts in chronic antibody-mediated kidney allograft rejection: prevention and treatment. Curr Opin Organ Transplant. 2021 Feb 1;26(1):97-105. doi: 10.1097/MOT.0000000000000832.
citation: Mayer KA, Budde K, Halloran PF, Doberer K, Rostaing L, Eskandary F, Christamentl A, Wahrmann M, Regele H, Schranz S, Ely S, Firbas C, Schorgenhofer C, Kainz A, Loupy A, Hartle S, Boxhammer R, Jilma B, Bohmig GA. Safety, tolerability, and efficacy of monoclonal CD38 antibody felzartamab in late antibody-mediated renal allograft rejection: study protocol for a phase 2 trial. Trials. 2022 Apr 8;23(1):270. doi: 10.1186/s13063-022-06198-9.