临床试验/NCT02631070

NCT02631070已完成3 期

A Phase 3, Double-blind, Randomized Study to Compare the Efficacy and Safety of Luspatercept (ACE-536) Versus Placebo for the Treatment of Anemia Due to the IPSS-R Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes in Subjects With Ring Sideroblasts Who Require Red Blood Cell Transfusions.

Celgene74 个研究点分布在 7 个国家目标入组 229 人开始时间: 2016年2月9日最近更新: 2021年12月17日

适应症

干预措施

试验速览

阶段: 3 期
状态: 已完成
发起方: Celgene
入组人数: 229
试验地点: 74
主要终点: Percentage Of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 to Week 24

研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验相关资讯

研究概览

简要总结

The study will be conducted in compliance with the International Council on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical Practice (GCP) and applicable regulatory requirements.

This is a Phase 3, double-blind, randomized, placebo-controlled, multicenter study to determine the efficacy and safety of luspatercept (ACE-536) versus placebo in participants with anemia due to the Revised International Prognostic Scoring System (IPSS-R) very low, low, or intermediate MDS with ring sideroblasts who require red blood cell (RBC) transfusions.

详细描述

Anemia is considered to be one of the most prevalent cytopenias in patients who have myelodysplastic syndromes, an umbrella term used to describe disorders relating to the ineffective production of red blood cells, white blood cells, and/or platelets. Ranging in severity from mild (asymptomatic) to severe, anemia can result in patients requiring regular red blood cell (RBC) transfusions, which can lead to further complications from iron overload. The goal of this study is to assess the safety and efficacy of luspatercept versus placebo in anemic patients who are categorized as International Prognostic Scoring System-Revised (IPSS-R) very low, low, or intermediate risk Myelodysplastic syndrome (MDS), have ring sideroblasts present, and require constant RBC transfusions. The design of the study will allow a period of initial randomization of patients into either the luspatercept or placebo arm, followed by a double-blind treatment period, and then an MDS disease assessment visit. For those patients that are determined to be experiencing clinical benefit as judged from the study Investigator by this disease assessment visit, they will be permitted to enter the double-blind Extension Phase of the study. Once patients are discontinued from study treatment, they will enter a post treatment follow-up period.

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: 18 Years 至 —（Adult, Older Adult）
性别: All
接受健康志愿者: 否

入选标准

•Subjects must satisfy the following criteria to be enrolled in the study:
•Subject is ≥ 18 years of age the time of signing the informed consent form (ICF).
•Documented diagnosis of MDS according to World Health Organization (WHO)/French American British (FAB) classification that meets IPSS R classification of very low, low, or intermediate risk disease, and:
•Ring sideroblast ≥ 15% of erythroid precursors in bone marrow or ≥ 5% (but < 15%) if SF3B1 mutation is present.
•< 5% blasts in bone marrow
•Peripheral blood white blood cell (WBC) count < 13,000/µL
•Requires red blood cell RBC transfusions
•Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2
•Subjects who are refractory/intolerant/ineligible to prior erythropoietin-stimulating agents (ESA) treatment, defined as:
•Refractory to prior - erythropoietin stimulating agents treatment: documentation of non-response or response that is no longer maintained to prior ESA-containing regimen, either as single agent or combination (eg, with granulocyte colony stimulating factor (G-CSF); ESA regimen must have been either recombinant human erythropoietin (rHu EPO) ≥ 40,000 IU/wk for at least 8 doses or equivalent OR darbepoetin alpha ≥ 500 μg Q3W for at least 4 doses or equivalent
•Intolerant to prior ESA treatment: documentation of discontinuation of prior ESA-containing regimen, either as single agent or combination (eg, with G-CSF), at any time after introduction due to intolerance or an adverse event
•ESA ineligible: low chance of response to ESA base on endogenous serum erythropoietin level > 200 U/L for subjects not previously treated with ESAs

排除标准

•The presence of any of the following will exclude a subject from enrollment:
•Prior therapy with disease modifying agents for underlying MDS disease.
•Previously treated with either luspatercept (ACE-536) or sotatercept (ACE-011)
•MDS associated with del 5q cytogenetic abnormality
•Secondary MDS, ie, MDS that is known to have arisen as the result of chemical injury or treatment with chemotherapy and/or radiation for other diseases.
•Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding
•iron deficiency to be determined by serum ferritin less than or equal to 15 ug/L and additional testing if clinically indicated (eg, calculated transferrin saturation [iron/total iron binding capacity less than or equal to 20%] or bone marrow aspirate stain for iron).
•Prior allogeneic or autologous stem cell transplant
•Known history of diagnosis of acute myeloid leukemia (AML)
•Use of any of the following within 5 weeks prior to randomization:
•anticancer cytotoxic chemotherapeutic agent or treatment
•corticosteroid, except for subjects on a stable or decreasing dose for ≥ 1 week prior to randomization for medical conditions other than MDS
•iron-chelating agents, except for subjects on a stable or decreasing dose for at least 8 weeks prior to randomization
•other RBC hematopoietic growth factors (eg, Interleukin-3)
•investigational drug or device, or approved therapy for investigational use. If the half-life of the previous investigational product is known, use within 5 times the half-life prior to randomization or within 5 weeks, whichever is longer is excluded.
•Prior history of malignancies, other than MDS, unless the subject has been free of the disease (including completion of any active or adjuvant treatment for prior malignancy) for ≥ 5 years. However, subjects with the following history/concurrent conditions are allowed:
•Basal or squamous cell carcinoma of the skin
•Carcinoma in situ of the cervix
•Carcinoma in situ of the breast
•Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system)
•Major surgery within 8 weeks prior to randomization. Subjects must have completely recovered from any previous surgery prior to randomization

研究组 & 干预措施

Experimental Arm - Luspatercept (ACE-536)

Experimental

Starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks

干预措施: Luspatercept (Drug)

Control Arm: Placebo

Placebo Comparator

Subcutaneous injection every 3 weeks

干预措施: Placebo (Other)

结局指标

主要结局

Percentage Of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 to Week 24

时间窗: From Week 1 through Week 24 of study treatment

RBC-TI response was defined as the absence of any Red Blood Cells (RBC) transfusion during any consecutive 56-day (8-week) period (ie, Days 1 to 56, Days 2 to 57, Days 3 to 58, etc.) during the first 24 weeks of study treatment. Participants had to have at least 56 days (≥ 8 weeks) of transfusion independence prior to (and including) the Week 24 cut-off date to qualify as a responder. Participants who failed to achieve RBC-TI at least 56 days prior to or on the cut-off date were counted as non-responders.

次要结局

Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 24(From Week 1 through Week 24 of study treatment)
Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 48(From Week 1 through Week 48 of study treatment)
Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 24(From start of study treatment to 16 weeks after last dose, up to approximately 93 weeks)
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score(Baseline and Cycle 3, Day 1 (C3 D1), C5 D1, C7 D1, Week 25, every other cycle during extension phase (C1 D1, C3 D1, C5 D1, etc. up to C59 D1) and end of treatment. Each cycle is composed of 21 days.)
Change From Baseline in Mean Daily Dose of Iron Chelation Therapy (ICT)(Baseline and Week 9 through Week 24 and Week 33 through Week 48 of study treatment)
Time to Acute Myeloid Leukemia (AML) Progression(From randomization to study completion (up to approximately 57 months))
Change From Baseline in Mean Serum Ferritin(Baseline and Week 9 through Week 24 and Week 33 through Week 48)
Percentage of Participants Who Progressed to Acute Myeloid Leukemia (AML)(From randomization to study completion (up to approximately 57 months))
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Area Under the Curve at Steady State for Starting Dose (AUC^ss)(Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.)
Participants With Pre-Existing and/or Treatment-Emergent Antidrug Antibodies (ADA)(From randomization to 1 year post first dose)
Change From Baseline in RBC Units Transfused Over Fixed 16-Week Period(At Baseline (16 weeks prior to first dose of study treatment) and Weeks 9 to 24 or Weeks 33 to 48)
Percentage of Participants Who Achieved a Modified Hematologic Erythroid Response (mHI-E) Over Any Consecutive 56-Day Period(Week 1 through 24 or Week 1 Through Week 48)
Overall Survival(From randomization to study completion (up to approximately 57 months))
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Volume of Distribution of the Central Compartment (V1/F)(Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.)
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Elimination Half-life (t1/2)(Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.)
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Time to Reach Maximum Concentration (Tmax)(Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.)
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Starting Dose (Cmax) at Steady State(Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.)
Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 Through Week 48(From Week 1 through Week 48 of study treatment)
Percentage of Participants Who Achieved a Hematologic Improvement in Neutrophil Response (HI-N) Over Any Consecutive 56-day Period(Week 1 through Week 24 or Week 1 Through Week 48 of study treatment)
Percentage of Participants Who Achieved a Hematologic Improvement in Platelet Response (HI-P) Over Any Consecutive 56-day Period(Week 1 through Week 24 or Week 1 Through Week 48 of study treatment)
Time to Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 24(From first dose to Week 24 of study treatment)
Time to Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 48(From first dose to Week 48 of study treatment)
Percentage of Participants Who Achieved a Mean Hemoglobin (Hgb) Increase of at Least 1.0 g/dL Over Any Consecutive 56-Day Period in Absence of Red Blood Cells (RBC) Transfusions(Week 1 though Week 24 and Week 1 through 48)
Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 48(From start of study treatment to 16 weeks after last dose, up to approximately 93 weeks)
Number of Participants With Treatment Emergent Adverse Events (TEAEs)(From date of first dose up to 42 days after the last dose (up to approximately 83 weeks))
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Clearance (CL/F)(Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.)
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the First Dose (Cmax)(Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.)

研究者

发起方

Celgene

申办方类型

Industry

责任方

Sponsor

研究点 (74)

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