An Open-Label Phase IIa Trial Exploring the Safety, Tolerability, and Efficacy of the T-Cell Engager OM336 for Desensitization of Kidney Transplant Candidates
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 12
- 试验地点
- 2
- 主要终点
- Incidence of Treatment-Emergent Adverse Events (TEAE) [Safety and Tolerability]
研究概览
简要总结
This investigator-initiated, single-arm, open-label Phase IIa pilot study will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of OM336 in highly HLA-sensitized adults with chronic kidney disease awaiting kidney transplantation. The study will enroll 12 participants who have either a very low likelihood of receiving a compatible deceased donor kidney because of broad HLA sensitization or unacceptable donor-specific antibodies against a potential living donor.
Participants will receive one 4-week course of subcutaneous OM336, with the option of a second 4-week course based on the change in virtual panel-reactive antibody (vPRA) levels after the initial treatment period. Participants will subsequently be followed for up to 24 months and, if transplantation occurs, for at least 12 months after transplantation.
The primary objectives are to evaluate the safety and tolerability of OM336 through Week 24 and (co-primary endpoint) its effect on HLA sensitization, assessed by changes in vPRA levels at Week 24. Secondary and exploratory objectives include assessment of the durability of changes in vPRA and donor-specific antibodies, the number of potential compatible donors, transplantation rates, OM336 pharmacokinetics and immunogenicity, and effects on B-cell and plasma-cell immunity and antibody characteristics. An optional substudy will assess B-cell immunity in bone marrow and lymph-node samples.
详细描述
This investigator-initiated, prospective, single-arm, open-label Phase IIa pilot trial will evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and preliminary immunologic effects of OM336 in highly sensitized adults with chronic kidney disease who are awaiting kidney transplantation. The study will characterize the effects of treatment on HLA sensitization and on cellular components of humoral immunity over a follow-up period of up to 24 months.
The study addresses the substantial barriers to transplantation associated with HLA sensitization. Highly sensitized kidney transplant candidates may have prolonged waiting times because of a restricted pool of immunologically compatible donors, while candidates with a potential living donor may have donor-specific antibodies (DSA) that preclude transplantation because of the associated risk of antibody-mediated rejection. Existing desensitization approaches, including antibody removal and therapies targeting B cells or plasma cells, may provide incomplete or transient reductions in alloantibody levels. A therapeutic approach capable of reducing the cellular sources responsible for persistent alloantibody production could therefore potentially increase access to transplantation.
OM336 is an investigational, humanized IgG4 (κ/λ) bispecific T-cell engager directed against B-cell maturation antigen (BCMA) and CD3. BCMA is expressed on plasmablasts and plasma cells, with lower expression on memory and naïve B-cell subsets. OM336 is designed to simultaneously bind BCMA-expressing cells and CD3-positive T cells, promoting T-cell-dependent cellular cytotoxicity and depletion of BCMA-expressing target cells independently of conventional antigen presentation. Mutations in the Fc domain are intended to prevent antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complement deposition, while retaining FcRn binding to support a prolonged serum half-life. The study will investigate whether this mechanism can reduce alloantibody-producing plasma-cell populations and thereby decrease the level and breadth of HLA sensitization.
Twelve participants will be enrolled at two European kidney transplant centers. Participants will be broadly sensitized deceased-donor kidney transplant candidates with persistently high virtual panel-reactive antibody (vPRA) levels or living-donor candidates with unacceptable DSA against the intended donor, according to the study-specific eligibility criteria. The trial is exploratory and is not designed to provide confirmatory evidence of efficacy.
OM336 will be administered by weekly subcutaneous injections using a fractionated dosing regimen during a 4-week treatment course, consisting of two step-up doses followed by three weekly 40-mg doses through Day 28. The initial treatment course will be followed by a 5-month observation period. At Month 6, HLA antibody profiles will be reassessed and vPRA recalculated. Participants with a vPRA reduction of less than 5 percentage points may receive a second 4-week treatment course with step-up dosing and weekly administration through approximately Week 30. Participants will subsequently be followed through Month 24. If transplantation occurs during the study, additional post-transplantation safety follow-up will be performed for at least 12 months.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Biologic male or female, 18 to 70 years of age at the time of informed consent.
- •Capable of and willing to provide signed informed consent (ICF); subject must sign ICF indicating that he or she understands the purpose of procedures required for the study and is willing to participate in the study. Consent is to be obtained prior to the initiation of any study-related tests or procedures that are not part of standard-of-care for the subject's disease.
- •Willing and able to comply with the visits, treatments, procedures, laboratory tests, and other requirements according to the current protocol, with a high probability for adherence and completion of the study.
- •Presensitized patient
- •Deceased kidney donor transplant candidate Broadly sensitized recipient on deceased donor waiting list: inclusion in the AM program (>85% vPRA) for ≥24 months or inclusion in the ETKAS scheme and >95% vPRA for ≥24 months, but not fulfilling the criteria in the AM program (panel reactivity includes specificities that are not acceptable by the local center; e.g. HLA antibodies with an MFI >10.000 but no prior sensitizing event documented).
- •A dilution of the baseline serum obtained at screening by 1:100 must lead to a considerable decrease in HLA antibody MFI, with a decrease in vPRA levels by at least 1.0%.
- •Living donor kidney transplant candidate Living donor transplant candidate with, according to local policy, unacceptable DSA against the scheduled donor and no option of kidney paired donation (KPD) transplantation, or within a KPD program with no transplant offer after 12 months of listing.
- •A dilution of the baseline serum obtained at screening by 1:100 must lead to a negative DSA result or to a considerable decrease in DSA MFI to permissive levels per local lab.
- •Women of childbearing potential (WOCBP) must have a negative pregnancy test at screening using a highly sensitive pregnancy test. Women of childbearing potential and fertile men who are sexually active must agree to use a highly effective method of contraception (<1% / year failure rate) during the study and for 150 days after the last dose of study drug. Women and men must agree not to donate eggs (ova, oocytes) or sperm, respectively, during the study and for 90 days after the last dose of study drug.
- •Within 4 weeks prior to inclusion, participants should be up to date on all vaccinations recommended by the local country or regional public health authority, as determined by the Investigator.
排除标准
- •Prior treatment with any therapy that is targeted to BCMA or any other CD3-redirecting drug.
- •Treatment with prohibited medications during the timeframes detailed below.
- •History of severe allergic reaction (per investigator judgment) or anaphylactic reaction to monoclonal antibody-based therapies or any components of OM
- •Congenital immunodeficiency with recurrent severe infections over the last 12 months.
- •Prior desensitization treatment within 6 months prior to inclusion:
- •Apheresis therapy (plasmapheresis or immunoadsorption)
- •CD20 mAb, e.g. rituximab or other
- •CD38 mAb, e.g. daratumumab or other
- •Proteasome inhibitor (bortezomib, carfilzomib)
- •Tocilizumab
- •Any other investigational agent
- •WOCBP: Pregnant, or breastfeeding, unwilling to practice adequate contraception.
- •Pulmonary compromise requiring chronic supplemental oxygen use to maintain adequate oxygenation.
- •Systemic herpes simplex (HSV) or symptomatic herpes zoster virus (HZV) (infection within 3 months prior to screening, or a history of disseminated or ophthalmic or central nervous system (CNS) infection with herpes zoster.
- •Active or latent tuberculosis based on a positive QuantiFERON-TB Gold Plus test or equivalent test, medical history, examination, and chest X-ray.
- •Active infection with hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency virus (HIV).
- •Clinically significant infection (e.g., requiring hospitalization or parenteral antimicrobial therapy) within 3 months prior to screening.
- •Any infection requiring oral antimicrobial therapy within 2 weeks prior to inclusion.
- •A history of malignancy within the past 5 years (except for successfully treated basal or squamous cell carcinoma of the skin, or successfully treated carcinoma in situ of the cervix, with no evidence of recurrence). Note: low-grade prostate cancer (Gleason score of 6 or less, confined to the prostate and under surveillance/monitoring without need for imminent surgical intervention) is permitted, per judgment of the investigator.
- •Live vaccine within 3 months prior to screening.
- •Uncontrolled psychiatric conditions (eg, alcohol or drug abuse), dementia, or altered mental status precluding study enrollment according to the judgment of the investigators
- •Inadequate liver function at Screening: Total bilirubin >2 × the upper limit of normal (ULN) except if due to Gilbert syndrome; Alanine transaminase (ALT) and/or aspartate aminotransferase (AST) >3 × ULN
- •Currently enrolled in or participated in another clinical research study with investigational drug or device within 30 days or 5 drug half-lives of the investigational product (whichever is longer), prior to screening.
- •Any clinically significant underlying illness that, in the opinion of the Investigator, may compromise study participation, present a safety risk to the participant, or may confound the interpretation of the study results, including general non-adherence to medication
- •Known allergy to dexametasone and its excipients, diphenhydramine and its excipients, acetaminophen and its excipients or to valacyclovir and its excipients.
研究组 & 干预措施
OM336 treatment
HLA-sensitized participants will receive one or (If there is a less than 5.0% reduction in vPRA after 6 months) two 4-week cycles of OM336, followed by observation through Month 24.
干预措施: OM3436 (Biological)
结局指标
主要结局
Incidence of Treatment-Emergent Adverse Events (TEAE) [Safety and Tolerability]
时间窗: 24 weeks
Number and percentage of participants experiencing TEAE through Week 24, including serious adverse events (SAE) and adverse events of special interest (AESI). Adverse events will be summarized by relationship to study treatment, severity, System Organ Class (SOC), and Preferred Term (PT). The number of participants experiencing each event and the number of events will be reported. Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).
Level of vPRA
时间窗: 24 weeks
Co-primary EP: Assessment of vPRA levels at week 24.
次要结局
- Incidence of Treatment-Emergent Adverse Events (TEAE) through the end of the study(24 months)
- Level of vPRA through 24 months.(24 months)
- Donor frequency according to ET Donor calculator through 24 months.(24 months)
- Number of unacceptable antigens(24 months)
- DSA MFI(24 months)
- Level of vPRA>MFI 1000(24 months)
- Level of vPRA>MFI 3000(24 months)
- Level of vPRA>MFI 10000(24 months)
- Course of MFI of HLA Single Antigen Fluorescent Bead (SAFB) reactivities that are >1000 at baseline(24 months)
- Titer course of HLA Single Antigen Fluorescent Bead (SAFB) reactivity(24 months)
- Number of complement (C1q)-fixing HLA Single Antigen Fluorescent Bead (SAFB) reactivities(24 months)
- Rate of Crossmatch (XM) conversion(24 months)
- Levels of IgG, IgM, IgA(24 months)
- Levels of free light chains(24 months)
- Blood group and xeno-reactive antibodies(24 months)
- Vaccination titers(24 months)
- Torque Teno virus (TTV) load(24 months)
- Counts of peripheral blood B cell (sub)populations(24 months)
- Counts of peripheral blood T cells and T cell (sub)populations(24 months)
- Change from baseline in gene set enrichment in peripheral blood(24 months)
- Level of serum soluble BCMA (sBCMA)(24 months)
- Level of serum CXCL10(24 months)
- Transplantation rate(24 months)
- Incidence of Anti-Drug Antibodies (ADA) to OM336(9 months)
- Maximum Plasma Concentration (Cmax) of OM336(9 months)
- Area Under the Plasma Concentration-Time Curve (AUC) of OM336(9 months)
- Terminal Half-Life (t½) of OM336(9 months)
- Plasma Clearance (CL) of OM336(9 months)
- Volume of Distribution (Vd) of OM336(9 months)
研究者
Georg Böhmig
Principal Investigator
Medical University of Vienna