Safety, Tolerability and Efficacy of Monoclonal CD38 Antibody Felzartamab in Late Antibody-Mediated Renal Allograft Rejection - A Phase 2 Pilot Trial
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 22
- 试验地点
- 2
- 主要终点
- Incidence of treatment-emergent adverse events
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 19 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Felzartamab (Drug)
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.
干预措施: Placebo (Drug)
结局指标
主要结局
Incidence of treatment-emergent adverse events
时间窗: 12 months
(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).
次要结局
- Felzartamab serum concentration(At day 0, week 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 44, 48 and 52)
- Leukocyte subsets in peripheral blood(Week 0, 1, 4, 8, 12, 24, and 52)
- Serum immunoglobulin levels(Week 0, 12, 24, and 52)
- Proteinuria(At day 0, week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 44, 48 and 52)
- Transplant glomerulopathy score(At week 24 and at week 52)
- C4d score(At week 24 and at week 52)
- Molecular ABMR score(At week 24 and at week 52)
- Morphologic ABMR categories(At week 24 and at week 52)
- Serum donor-specific antibody (DSA) levels(Week 0, 12, 24, and 52)
- eGFR(At day 0, week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 44, 48 and 52)
- Anti-Felzartamab antibodies(At day 0, week 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 44, 48 and 52)
- Torque Teno virus(Week 0, 12, 24, and 52)
- Immunologic biomarkers(Week 0, 12, 24, and 52)
- Graft loss(12 months)
- Death(12 months)
- Glomerulitis plus peritubular capillaritis sum score(At week 24 and at week 52)
- Molecular ABMR categories(At week 24 and at week 52)
研究者
Farsad Eskandary
Ass. Prof. Dr.
Medical University of Vienna