A Randomized, Double-blind, Placebo-controlled Phase III Multi-center Study of Azacitidine With or Without MBG453 for the Treatment of Patients With Intermediate, High or Very High Risk Myelodysplastic Syndrome (MDS) as Per IPSS-R, or Chronic Myelomonocytic Leukemia-2 (CMML-2)
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 530
- 试验地点
- 161
- 主要终点
- Overall Survival (OS) (Primary Efficacy Results)
研究概览
简要总结
This was a Phase III multi-center, randomized, two-arm parallel-group, double-blind, placebo-controlled study of MBG453 or placebo added to azacitidine in adult participants with intermediate, high or very high-risk myelodysplastic syndrome (MDS) as per IPSS-R, or Chronic Myelomonocytic Leukemia-2 (CMML-2) who are not eligible for intensive chemotherapy or hematopoietic stem cell transplantation (HSCT) according to medical judgment by the investigator.
The purpose of the current study was to assess clinical effects of MBG453 in combination with azacytidine in adult participants with IPSS-R intermediate, high, very high risk MDS and CMML-2.
详细描述
This was a Phase III multi-center, randomized, two-arm parallel-group, double-blind, placebo-controlled study of MBG453 or placebo added to azacitidine in adult participants with intermediate, high or very high-risk myelodysplastic syndrome (MDS) as per IPSS-R, or Chronic Myelomonocytic Leukemia-2 (CMML-2).
The primary objective of this study was to compare overall survival (OS) in the MBG453 plus azacitidine arm versus placebo plus azacitidine arm where OS was the time from randomization until death due to any cause.
Participants were randomized in a 1:1 ratio to treatment arms as follow: MBG453 800 mg IV Q4W plus azacitidine, Placebo IV Q4W plus azacitidine.
The randomization was stratified into 4 groups: intermediate risk MDS, high risk MDS, very high risk MDS and CMML-2.
All participants who discontinued both study treatments were to have entered a long-term post-treatment follow-up including response and PRO assessments, and/or survival follow-up for up to 5 years after the last participant was randomized.
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
- •Morphologically confirmed diagnosis of myelodysplastic syndrome (MDS) based on WHO 2016 classification (Arber et al 2016) by local investigator assessment with one of the following Prognostic Risk Categories, based on the revised International Prognostic Scoring System (IPSS-R):
- •Very high (> 6 points)
- •High (> 4.5 - ≤ 6 points)
- •Intermediate (> 3 - ≤ 4.5 points) Or Morphologically confirmed diagnosis of Chronic Myelomonocytic Leukemia -2 based on WHO 2016 classification (Arber et al 2016, including persistent monocytosis) by local investigator assessment with WBC < 13 x 109/L at time of initial diagnosis
- •Indication for azacitidine treatment according to the investigator, based on local standard medical practice and institutional guidelines for treatment decisions
- •Not eligible at time of screening for intensive chemotherapy according to the investigator, based on local standard medical practice and institutional guidelines for treatment decisions, including assessment of individual clinical factors such as age, comorbidities and performance status
- •Not eligible at 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, including assessment of individual clinical factors such as age, comorbidities, performance status, and donor availability
- •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 checkpoint inhibitors (e.g, anti-CTLA4, anti-PD-1, anti-PD-L1, or anti-PD-L2), cancer vaccines is allowed except if the drug was administered within 4 months prior to randomization
- •Previous first-line treatment for intermediate, high, very high risk myelodysplastic syndromes (based on IPSS-R) or CMML with any antineoplastic agents including for example chemotherapy, lenalidomide and hypomethylating agents (HMAs) such as decitibine and azacitidine. However, previous treatment with hydroxyurea or leukopheresis to reduce WBC count is allowed prior to randomization.
- •Investigational treatment received within 4 weeks or 5 half-lives of this investigational treatment, whatever is longer, prior to randomization. In case of a checkpoint inhibitor: a minimal interval of 4 months prior to randomization is necessary to allow randomization.
- •Subjects with Myelodysplastic syndrome (MDS) based on 2016 WHO classification (Arber et al 2016) with revised International Prognostic Scoring System (IPSS-R) ≤ 3
- •Diagnosis of acute myeloid leukemia (AML) including acute promyelocytic leukemia and extra-medullary acute myeloid leukemia, primary or secondary myelofibrosis based on WHO 2016 classification (Arber et al 2016)
- •Diagnosis of therapy related myeloid neoplasms based on WHO 2016 classification (Arber et al 2016)
- •History of organ or allogeneic hematopoietic stem cell transplant
研究组 & 干预措施
Sabatolimab (MBG453) + Azacitidine
Participants received sabatolimab plus Azacitidine
干预措施: Sabatolimab (Drug)
Sabatolimab (MBG453) + Azacitidine
Participants received sabatolimab plus Azacitidine
干预措施: Azacitidine (Drug)
Placebo + Azacitidine
Participants received placebo plus Azacitidine.
干预措施: Azacitidine (Drug)
Placebo + Azacitidine
Participants received placebo plus Azacitidine.
干预措施: Placebo (Drug)
结局指标
主要结局
Overall Survival (OS) (Primary Efficacy Results)
时间窗: up to approx. 39 months
OS is the time from randomization until death due to any cause.
Overall Survival (OS) (Final Efficacy Results)
时间窗: up to approx. 52 months
OS is the time from randomization until death due to any cause.
次要结局
- Key Secondary Endpoint 1: Time to Definitive Deterioration of Fatigue Using Functional Assessment of Cancer Therapy (FACIT)-Fatigue Score(up to approx. 52 months)
- Key Secondary Endpoint 2: Red Blood Cell (RBC) Annualized Transfusion Free Rate for Transfusion(up to approx. 52 months)
- Key Secondary Endpoint 3: Percentage of Participants With at Least 3 Point Confirmed Improvement From Baseline in FACIT-fatigue Scores(up to approx. 52 months)
- Key Secondary Endpoint 4: Percentage of Participants With at Least 10 Point Confirmed Improvement From Baseline in Physical Functioning Using European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC QLQ-C30)(up to approx. 52 months)
- Key Secondary Endpoint 5: Percentage of Participants With at Least 10 Point Confirmed Improvement From Baseline in Emotional Functioning Using EORTC-QLQ-C30(up to approx. 52 months)
- Percentage of Participants With Either CR, or mCR, or PR, or HI in Each Treatment Arm According to International Working Group for MDS (IWG-MDS) as Per Investigator Assessment(up to approx. 52 months)
- Percentage of Participants With Stable Disease (SD) According to International Working Group for MDS (IWG-MDS) as Per Investigator Assessment(up to approx. 52 months)
- Progression Free Survival (PFS)(up to approx. 52 months)
- Leukemia-free Survival (LFS)(up to approx. 52 months)
- Number of Participants Who Become Red Blood Cells (RBC) Transfusion Independent After Randomization(up to approx. 52 months)
- Number of Participants Who Become Platelets Transfusion Independent After Randomization(up to approx. 52 months)
- Pharmacokinetics of MBG453 (Parameter Cmax)(0 hr (pre-dose) & 2 hrs (post-dose) of Cycle (C) 1 Day (D) 8 and 0 hr (pre-dose) & 2 hrs (post-dose) of C3D8)
- Pharmacokinetics of MBG453 (Parameter AUC)(0 hr (pre-dose) & 2 hrs (post-dose) of Cycle (C) 1 Day (D) 8 and 0 hr (pre-dose) & 2 hrs (post-dose) of C3D8)
- ADA Prevalence at Baseline and ADA-positive Participants On-treatment(Baseline, up to approx. 39 months)
- Change From Baseline in the European Quality of Life (EuroQol) - 5 Dimensions, 5 Level Questionnaire (EQ-5D-5L) Score Over Time(Baseline, every 3 cycles up to C48D1 (1 cycle = 28 days))
- Change From Baseline in the European Quality of Life (EuroQoL) - 5 Dimensions, 5 Level Questionnaire (EQ-5D-5L) Visual Analogue Scale (VAS) Over Time(Baseline, every 3 cycles up to C48D1 (1 cycle = 28 days))
- Change From Baseline of Global Health Status/Quality of Life Scores Using European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQ-C30).(Up to Cycle 12 Day 1 (C12D1) (1 cycle = 28 days))