Felzartamab in Late Antibody-Mediated Rejection

Safety, Tolerability and Efficacy of Monoclonal CD38 Antibody Felzartamab in Late Antibody-Mediated Renal Allograft Rejection - A Phase 2 Pilot Trial

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.

Study Overview

• Status: Completed
• Conditions: Antibody-mediated Rejection
• Intervention / Treatment: Drug: Felzartamab; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Georg A Böhmig, MD; Phone Number: 43630 +43 1 40400; Email: georg.boehmig@meduniwien.ac.at
• Study Contact Backup: Name: Farsad F Eskandary, MD; Phone Number: 43630 +43 1 40400; Email: farsad.eskandary@meduniwien.ac.at

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Medical University of Vienna
• Germany
  • Berlin, Germany, 10117
    • Charité University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 17 years to 78 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Felzartamab; 9 doses of felzartamab as an intravenous infusion over 6 treatment cycles at 28 days each. Dosing occurs every week in cycle 1 and every four weeks in cycles 2-6.	Drug: Felzartamab; Intravenous infusion in regular intervals over 6 months; Other Names: MOR202, CD38 monoclonal antibody
Placebo Comparator: Placebo; 9 doses of placebo as an intravenous infusion over 6 treatment cycles at 28 days each. Dosing occurs every week in cycle 1 and every four weeks in cycles 2-6.	Drug: Placebo; Intravenous infusion in regular intervals over 6 months; Other Names: 0.9% Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Felzartamab serum concentration	Total felzartamab serum concentration (ELISA, ng/mL)	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)	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	At week 24 and at week 52
Serum donor-specific antibody (DSA) levels	Mean fluorescence intensity (MFI) of the immunodominant DSA (Luminex)	Week 0, 12, 24, and 52
Serum immunoglobulin levels	Ig (sub)classes (ELISA, Nephelometry, mg/dL)	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)	Week 0, 1, 4, 8, 12, 24, and 52
Immunologic biomarkers	CXCL9 and CXCL10 levels in blood and urine, BAFF levels in blood (ELISA, Luminex)	Week 0, 12, 24, and 52
Torque Teno virus	Torque Teno virus (TTV) levels in plasma (quantitative PCR)	Week 0, 12, 24, and 52
eGFR	Estimated GFR (CKD-EPI, mL/min/1.73m2)	At day 0, week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 44, 48 and 52
Proteinuria	Urinary protein excretion in spot urine (protein/creatinine ratio in mg/g)	At day 0, week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 44, 48 and 52
Graft loss	Graft failure: time (months) to event (Kaplan Meier)	12 months
Death	Patient death: time (months) to event (Kaplan Meier)	12 months
Glomerulitis plus peritubular capillaritis sum score	Grading of renal transplant biopsies using a semiquantitative score (g+ptc 0-6); higher = worse prognosis	At week 24 and at week 52
Transplant glomerulopathy score	Grading of renal transplant biopsies using a semiquantitative score (cg 0-3); higher = worse prognosis	At week 24 and at week 52
C4d score	Grading of renal transplant biopsies using a semiquantitative score (c4d 0-3); higher = worse prognosis	At week 24 and at week 52
Molecular ABMR score	ABMR score (0.0-1.0, dimensionless number) assessed via the Molecular Microscope Diagnostic Platform (MMDx); higher = worse prognosis	At week 24 and at week 52
Molecular ABMR categories	Molecular archetype analysis of rejection phenotypes using the Molecular Microscope Diagnostic Platform (MMDx). Phenotypes: early-stage ABMR; fully developed ABMR; late-stage ABMR	At week 24 and at week 52

Collaborators and Investigators

• Sponsor: Farsad Eskandary
• Collaborators: Charite University, Berlin, Germany; University of Alberta; HI-Bio
• Investigators: Principal Investigator: Georg A Böhmig, MD, Department of Internal Medicine III, Medical University of Vienna

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): October 6, 2021
• Primary Completion (Actual): March 7, 2024
• Study Completion (Actual): March 7, 2024

Study Registration Dates

• First Submitted: August 12, 2021
• First Submitted That Met QC Criteria: August 19, 2021
• First Posted (Actual): August 25, 2021

Study Record Updates

• Last Update Posted (Actual): April 18, 2024
• Last Update Submitted That Met QC Criteria: April 17, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Kidney transplantation; CD38
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Felzartamab
• Other Study ID Numbers: EK1161/2021; 2021-000545-40 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No