A Phase 2, Open-Label, Single-Arm Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Subcutaneous Azacitidine in Adult Chinese Subjects With Higher-Risk Myelodysplastic Syndromes
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- Celgene
- 入组人数
- 72
- 试验地点
- 11
- 主要终点
- Percentage of Participants Achieving a Hematologic Improvement (HI) Based on 2000 IWG Response Criteria for MDS and Programmatically Assessed by the Sponsor Using Clinically Relevant Data.
研究概览
简要总结
The purpose of the study is to determine whether azacitidine is safe and effective in the treatment of Chinese patients with higher risk Myelodysplastic Syndromes (MDS).
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 —（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:
- •Chinese males and females of Asian descent ≥ 18 years of age at the time of signing the informed consent document;
- •Must have a documented diagnosis of refractory anemia with excess blasts (RAEB) or refractory anemia with excess blasts in transformation (RAEB-T) according to French-American-British (FAB) classification for Myelodysplastic Syndrome (MDS) and with an International Prognostic Scoring System (IPSS) score of intermediate-2 or high risk or a diagnosis of myelodysplastic chronic myelomonocytic leukemia (CMML) per modified FAB criteria meeting the following:
- •Monocytosis in peripheral blood > 1 x 10^9/L;
- •Dysplasia in one or more myeloid cell lines;
- •10% to 29% blasts in the bone marrow; and White blood cell (WBC) count < 13 x 10^9/L
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 ;
- •Adequate organ function, defined as:
- •Serum bilirubin ≤ 1.5 times the upper limit of normal (ULN);
- •Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.0 times the ULN;
- •Serum Creatinine ≤ 1.5 times the ULN;
- •Females of childbearing potential (FCBP) must:
- •Agree to the use of a physician-approved contraceptive method (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) while on azacitidine; and
- •for 3 months following the last dose of azacitidine; and have a negative serum pregnancy test within 72 hours prior to starting Investigational Product (IP).
- •Male subjects with a female partner of childbearing potential must agree to the use of a physician-approved contraceptive method throughout the course of the study and avoid fathering a child during the course of the study and for 3 months following the last dose of azacitidine;
- •Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures are conducted;
- •Able to adhere to the study visit schedule and other protocol requirements.
排除标准
- •The presence of any of the following will exclude a subject from enrollment:
- •Previous treatment with azacitidine or decitabine;
- •Diagnosis of malignant disease within the previous 12 months (excluding basal cell carcinoma of the skin without complications, "in-situ" carcinoma of the cervix or breast, or other local malignancy excised or irradiated with a high probability of cure);
- •Uncorrected red cell folate deficiency or vitamin B12 deficiency;
- •Diagnosis of metastatic disease;
- •Malignant hepatic tumors;
- •Known or suspected hypersensitivity to azacitidine or mannitol;
- •Candidate to proceed to bone marrow or stem cell transplant during the study;
- •Prior transplantation or cytotoxic therapy, including azacitidine and chemotherapy, administered to treat MDS;
- •Treatment with erythropoietin or myeloid growth factors (granulocyte colony-stimulating factor [G-CSF] or granulocyte-macrophage colony-stimulating factor [GM-CSF]) during the 21 days prior to Day 1 of Cycle 1;
- •Treatment with androgenic hormones during the 14 days prior to Day 1 of Cycle 1;
- •Active viral infection with known human immunodeficiency virus (HIV) or viral hepatitis type B or C;
- •Treatment with other investigational drugs, including thalidomide and arsenic trioxide, within the previous 30 days prior to Day 1 of Cycle 1, or ongoing adverse events from previous treatment with investigational drugs, regardless of the time period; and
- •Pregnant or lactating females;
- •Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study;
- •Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study;
- •Any condition that confounds the ability to interpret data from the study.
研究组 & 干预措施
Azacitidine
Azacitidine 75 mg/m^2/day subcutaneously (SC) for 7 days every 28 days until disease progression (DP), adverse events (AE), withdrawal of consent from further treatment, withdrawal of consent, death, lost to follow-up, or protocol violation.
干预措施: Azacitidine (Drug)
结局指标
主要结局
Percentage of Participants Achieving a Hematologic Improvement (HI) Based on 2000 IWG Response Criteria for MDS and Programmatically Assessed by the Sponsor Using Clinically Relevant Data.
时间窗: Up to 29 January 2015; 894 days
Hematologic improvements (HI) have 4 categories: 1. Erythroid response (HI-E): Major \>20g/L increase or transfusion independent. Minor: 10-20g/L increase or ≥50% decrease in transfusion requirements. 2. Platelet response (HI-P): Major absolute increase of ≥30x10\^9/L or platelet transfusion independence. Minor: ≥50% increase. 3. Neutrophil response (HI-N): Major 100% increase or an absolute increase of \>0.5x10\^9/L. Minor: ≥100% increase and absolute increase of \<0.5x10\^9/L 4. Progression or relapse after HI Hematological improvement (HI) was defined as any type (major or minor) of improvement of HI-E, HI-P, or HI-N. Criteria: Pretreatment=hemoglobin \<100g/L or RBC transfusion-dependent, platelet count \<100x10\^9/L or platelet transfusion dependent, absolute neutrophil count \<1.5x10\^9/L. Sponsor's determination was derived using clinically relevant data. Denominator for progression/relapse after HI included participants who had achieved HI.
Percentage of Participants With a Hematologic Response Based on the International Working Group (IWG) Criteria for Myelodysplastic Syndrome (MDS) and Programmatically Assessed by the Sponsor Using Clinically Relevant Data.
时间窗: Response initially assessed at end of cycle 6, then every 4 cycles; Up to 29 January 2015; 894 days
Hematologic Response is defined by those participants who experienced a Complete Response, Partial Response and Stable Disease (SD) based on IWG 2000 response criteria for MDS. CR = repeat bone marrow (BM) shows \<5% myeloblasts, and peripheral blood values lasting ≥ 2 months of hemoglobin (hgb) (\>110 g/L), neutrophils (≥1.5x10\^9/L), platelets (≥100x10\^9/L), blasts (0%) and no dysplasia • PR = same as CR for peripheral blood: BM shows blasts decrease by ≥ 50% or a less advanced FAB classification from pretreatment • Stable disease (SD): failure to achieve a PR, no evidence of progression for at least 2 months. • Failure: death during treatment or disease progression • Relapse After CR or PR: return to pretreatment BM blast percent or decrement of ≥ 50% from remission/response levels in granulocytes or platelets; or reduction in hgb by ≥20 g/L or transfusion dependence • Disease Progression: change in blast levels • Disease Transformation to Acute Myelogenous Leukemia.
Percentage of Participants With a Hematologic Response Using IWG Criteria for MDS and Assessed by the Investigator
时间窗: Response initially assessed at end of cycle 6, then every 4 cycles; Up to 29 January 2015; 894 days
Hematologic Response is defined by those participants who experienced a Complete Response, Partial Response and Stable Disease (SD) based on IWG 2000 response criteria for MDS. CR = repeat bone marrow (BM) shows \<5% myeloblasts, and peripheral blood values lasting ≥ 2 months of hemoglobin (hgb) (\>110 g/L), neutrophils (≥1.5x10\^9/L), platelets (≥100x10\^9/L), blasts (0%) and no dysplasia • PR = same as CR for peripheral blood: BM shows blasts decrease by ≥ 50% or a less advanced FAB classification from pretreatment • Stable disease (SD): failure to achieve a PR, no evidence of progression for at least 2 months. • Failure: death during treatment or disease progression • Relapse After CR or PR: return to pretreatment BM blast percent or decrement of ≥ 50% from remission/response levels in granulocytes or platelets; or reduction in hgb by ≥20 g/L or transfusion dependence • Disease Progression: change in blast levels • Disease Transformation to Acute Myelogenous Leukemia.
次要结局
- The Number of Units of Platelet Transfusions by Cycle(Up to cycle 27; The on-treatment period was considered the period from the date of first dose to the last treatment study visit; Up to 29 January 2015; 894 days)
- The Number of RBC Transfusions by Cycle(Up to cycle 27; The on-treatment period was considered the period from the date of first dose to the last treatment study visit; Up to 29 January 2015; 894 days)
- The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle(Up to cycle 27; The on-treatment period was considered the period from the date of first dose to the last treatment study visit; Up to 29 January 2015; 894 days)
- Kaplan Meier Estimates for Overall Survival (OS)(Until the end of the survival follow-up period; Up to data cut-off of 29 January 2015; 894 days)
- Maximum Observed Plasma Concentration (Cmax) of Azacitidine(PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7)
- The Number of Platelet Transfusions by Cycle(Up to cycle 27; The on-treatment period was considered the period from the date of first dose to the last treatment study visit; Up to 29 January 2015; 894 days)
- The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle(Up to cycle 27; The on-treatment period was considered the period from the date of first dose to the last treatment study visit; Up to 29 January 2015; 894 days)
- Time to Maximum Plasma Concentration (Tmax) of Azacitidine(PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7)
- Apparent Total Plasma Clearance (CL/F) of Azacitidine(PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7)
- Apparent Volume of Distribution (Vd/F) of Azacitidine(PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7)
- Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Extension Phase(Up to final data cut off date of 25 April 2018; from the first dose of study drug extesnion of 29 December 2014 to 28 days after the date of the last dose of study drug; median duration of any dose of study drug was 169 days)
- Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Parent Phase(Up to 29 January 2015; from the first dose of study drug to 28 days after the date of the last dose of study drug (maximum time on study was 244 days))
- Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC∞) of Azacitidine(PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7)
- Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUCt) of Azacitidine(PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7)
- Terminal Phase of Half-life (T1/2) of Azacitidine(PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7)