Felzartamab in Late Antibody-Mediated Rejection

Antibody-mediated Rejection Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05021484
• Other study ID #: EK1161/2021
• Secondary ID: 2021-000545-40
• Status: Completed
• Phase: Phase 2
• Start date: October 6, 2021
• Est. completion date: March 7, 2024

Study information

• Verified date: April 2024
• Source: Medical University of Vienna
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 22
• Est. completion date: March 7, 2024
• Est. primary completion date: March 7, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 19 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Antibody-mediated Rejection

Intervention

Drug:
• Felzartamab
Intravenous infusion in regular intervals over 6 months
• Placebo
Intravenous infusion in regular intervals over 6 months

Locations

Country	Name	City	State
Austria	Medical University of Vienna	Vienna
Germany	Charité University	Berlin

Sponsors (4)

Lead Sponsor	Collaborator
Farsad Eskandary	Charite University, Berlin, Germany, HI-Bio, University of Alberta

Countries where clinical trial is conducted

Austria,  Germany, 

References & Publications (3)

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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	Serum donor-specific antibody (DSA) levels	Mean fluorescence intensity (MFI) of the immunodominant DSA (Luminex)	Week 0, 12, 24, and 52
Secondary	Serum immunoglobulin levels	Ig (sub)classes (ELISA, Nephelometry, mg/dL)	Week 0, 12, 24, and 52
Secondary	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
Secondary	Immunologic biomarkers	CXCL9 and CXCL10 levels in blood and urine, BAFF levels in blood (ELISA, Luminex)	Week 0, 12, 24, and 52
Secondary	Torque Teno virus	Torque Teno virus (TTV) levels in plasma (quantitative PCR)	Week 0, 12, 24, and 52
Secondary	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
Secondary	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
Secondary	Graft loss	Graft failure: time (months) to event (Kaplan Meier)	12 months
Secondary	Death	Patient death: time (months) to event (Kaplan Meier)	12 months
Secondary	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
Secondary	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
Secondary	C4d score	Grading of renal transplant biopsies using a semiquantitative score (c4d 0-3); higher = worse prognosis	At week 24 and at week 52
Secondary	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
Secondary	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