A Randomized, Double-blind, Placebo-controlled Phase II Multi-center Study of Intravenous MBG453 Added to Hypomethylating Agents in Adult Subjects With Intermediate, High or Very High Risk Myelodysplastic Syndrome (MDS) as Per IPSS-R Criteria
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 127
- 试验地点
- 55
- 主要终点
- Complete Remission (CR) Rate
研究概览
简要总结
This Phase II was a multicenter, randomized, two-arm parallel-group, double-blind, placebo-controlled study of MBG453 or placebo added to hypomethylating agents (azacitidine or decitabine) in adult subjects with IPSS-R intermediate, high or very high risk myelodysplastic syndrome (MDS) not eligible for Hematopoietic Stem Cell Transplant (HSCT) or intensive chemotherapy.
详细描述
The 2 primary objectives were as follows:
To determine if MBG453 combined with standard HMA therapy improved complete remission in subjects with intermediate, high, or very high risk MDS.
To determine if MBG453 combined with standard HMA therapy improved progression free survival (PFS) in subjects with intermediate, high or very high risk MDS.
This Phase II study was a multicenter, randomized, two-arm parallel-group, double-blind, placebo-controlled study of MBG453 or placebo added to hypomethylating agents (azacitidine or decitabine, as per investigators' choice based on local standard of care (SOC)) in adult subjects with IPSS-R intermediate, high or very high risk MDS not eligible for HSCT or intensive chemotherapy. A total of 127 subjects were randomized in a 1:1 ratio to treatment arms as follows:
- MBG453 400 mg IV Q2W and decitabine or azacitidine
- Placebo IV Q2W and decitabine or azacitidine
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
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Signed informed consent must be obtained prior to participation in the study.
- •Age ≥ 18 years at the date of signing the informed consent form (ICF)-. Morphologically confirmed diagnosis of a myelodysplastic syndrome (MDS) based on 2016 WHO classification (Arber et al 2016) by investigator assessment with one of the following Prognostic Risk Categories, based on the International Prognostic Scoring System (IPSS-R):
- •Very high
- •Intermediate with at least ≥ 5% bone marrow blast
- •Not eligible at the time of screening, for intensive chemotherapy according to the investigator, based on local standard medical practice and institutional guidelines for treatment decisions
- •Not eligible at the time of screening, for hematopoietic stem-cell transplantation (HSCT) according to the investigator, based on local standard medical practice and institutional guidelines for treatment decisions.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
排除标准
- •Prior exposure to TIM-3 directed therapy at any time. Prior therapy with immune check point inhibitors (e.g. anti-CTLA4, anti-PD-1, anti-PD-L1, or anti-PD-L2), cancer vaccines are allowed except if the drug was administered within 4 months prior to randomization.
- •Previous first-line treatment for higher risk MDS with chemotherapy or any other antineoplastic agents including lenalidomide and hypomethylating agent (HMAs) such as decitabine or azacitidine.
- •History of severe hypersensitivity reactions to any ingredient of the study treatment (azacitidine, decitabine or MGB453) or their excipients, or to monoclonal antibodies (mAbs).
- •Currently using or used within 14 days prior to randomization of systemic, steroid therapy (> 10 mg/day prednisone or equivalent) or any immunosuppressive therapy. Topical, inhaled, nasal, ophthalmic steroids are allowed. Replacement therapy, steroids given in the context of a transfusion are allowed and not considered a form of systemic treatment.
- •Investigational treatment for MDS received within 4 weeks prior to randomization. In case of a checkpoint inhibitor: 4 months minimum prior to randomization interval is necessary to allow enrollment.
- •Active autoimmune disease requiring systemic therapy (e.g.corticosteroids).
- •Live vaccine administered within 30 Days prior to randomization.
研究组 & 干预措施
MBG453 + hypomethylating agents
Patients are taking MBG453 plus hypomethylating agents
干预措施: MBG453 (Drug)
MBG453 + hypomethylating agents
Patients are taking MBG453 plus hypomethylating agents
干预措施: Hypomethylating agents (Drug)
Placebo + hypomethylating agents
Patients are taking placebo plus hypomethylating agents
干预措施: Placebo (Drug)
Placebo + hypomethylating agents
Patients are taking placebo plus hypomethylating agents
干预措施: Hypomethylating agents (Drug)
结局指标
主要结局
Complete Remission (CR) Rate
时间窗: average of 7 months
CR: where the Bone marrow: ≤ 5% blasts with normal maturation of all cell lineages and Peripheral blood: where Hgb ≥ 10 g/dL AND Platelets ≥ 100\*109/L AND Neutrophils ≥ 1.0\*109/L AND Peripheral blasts 0%. Modified response criteria According to International Working Group (IWG) and as per World Health Organization (WHO) criteria for Myelodysplastic syndromes (MDS) as per investigator assessment.
Progression Free Survival (PFS)
时间窗: approx. 32 months
PFS is defined as time from randomization to disease progression (including transformation to acute leukemia per WHO 2016 classification), relapse from CR according to IWG-MDS or death due to any cause, whichever occurs first, as per investigator assessment.
次要结局
- Progression Free Survival (PFS) - Final PFS(approx. 48 months)
- Overall Survival (OS)(approx. 48 months)
- Event-free Survival (EFS)(approx. 48 months)
- Leukemia-free Survival (LFS)(approx. 48 months)
- Response Rate of Complete Remission (CR)/Marrow Complete Remission (mCR)/Partial Remission (PR)/Hematopoietic Improvement (HI))(approx. 32 months)
- Duration of Complete Remission(approx. 48 months)
- Time to Complete Remission(Average of 7 months)
- Percent of Participants Who Are Red Blood Cells (RBC)/Platelets Transfusion Independent After Randomization as Per IWG-MDS(approx. 48 months)
- Red Blood Cells (RBC) Transfusion Independence Duration After Randomization(approx. 48 months)
- Platelets Transfusion Independence Duration After Randomization(approx. 48 months)
- Serum Concentrations for MBG453(0hr pre-dose on Day 8 of each cycle until cycle 6 and on Day 8 of cycles 9, 12, 18 and 24, 2hr post-dose on Day 8 of C1 and C3, EOT (approx. 48 months) and up to 150 day of the safety follow up period; 1 cycle = 28 days)
- Immunogenicity (IG) of MBG453 When Given in Combination of Hypomethylating Agents: ADA Prevalence(at baseline)
- Immunogenicity of MBG453 When Given in Combination of Hypomethylating Agents: ADA-positive Participants(approx. 48 months)