A Phase 2, Open Label, Ascending Dose Study of ACE-536 for the Treatment of Anemia in Patients With Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 116
- 试验地点
- 1
- 主要终点
- Percentage of High Transfusion Burden (HTB) Participants With mHI-E
研究概览
简要总结
The purpose of this study is to evaluate the effects of luspatercept (MK-6143, formerly called ACE-536) on anemia in patients with low or intermediate-1 risk myelodysplastic syndrome (MDS). There is no primary hypothesis in this study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
- •Documented diagnosis of idiopathic/de novo myelodysplastic syndrome (MDS) or non-proliferative chronic myelomonocytic leukemia (CMML), according to WHO criteria (white blood count, 13,000/uL), that meets International Prognostic Scoring System (IPSS) classification of low or intermediate-1 risk disease as determined by microscopic and standard cytogenetic analyses of the bone marrow and peripheral complete blood count (CBC) obtained during screening
- •Anemia defined as:
- •Mean hemoglobin concentration <10.0 g/dL of 2 measurements (one performed within one day prior to Cycle 1 Day 1 and the other performed 7-28 days prior to Cycle 1 Day 1, not influenced by red blood cell (RBC) transfusion within 7 days of measurement for non-transfusion dependent patients (defined as having received <4 units of RBCs within 8 weeks prior to Cycle 1 Day 1), or Transfusion dependent, defined as having received ≥4 units of RBCs within 8 weeks prior to Cycle 1 Day 1
- •Serum erythropoietin levels and prior erythropoiesis-stimulating agent (ESA) treatment:
- •Dose escalation cohorts and expansion cohort 1 patients: Serum erythropoietin level >500 U/L, OR, if ≤500 U/L, patient is non-responsive, refractory, or intolerant to erythropoiesis-stimulating agents (ESAs), or ESAs are contraindicated or unavailable
- •Expansion cohort 2 patients: If patient is RS+ (defined as having ≥15% ring sideroblasts in the bone marrow), no prior ESA treatment and serum erythropoietin level ≤ 200 U/L. If a patient is RS- (defined as having <15% ring sideroblasts in the bone marrow), prior ESA treatment and any serum erythropoietin level is allowed
- •No alternative treatment options, per applicable MDS guidelines, are available and/or appropriate for the patient, at the discretion of the investigator
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (if related to anemia).
- •Adequate renal (creatinine ≤2 x upper limit of normal [ULN]) and hepatic (total bilirubin <2 x ULN and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <3 x ULN) function
- •Adequate transferrin saturation (≥15%), ferritin (≥ 50 µg/L), folate (≥4.5 nmol/L [≥2.0 µg/L]) and vitamin B12 (≥148 pmol/L [≥ 200 pg/mL]) during screening (supplementation and retest during screening is acceptable)
- •Females of child bearing potential (defined as sexually mature women who have not undergone hysterectomy or bilateral oophorectomy, or are not naturally postmenopausal ≥24 consecutive months) must have negative urine or blood pregnancy test prior to enrollment and use adequate birth control methods (abstinence, oral contraceptives, barrier method with spermicide, or surgical sterilization) during study participation and for 12 weeks following the last dose of luspatercept. Males must agree to use a latex condom during any sexual contact with females of child-bearing potential while participating in the study and for 12 weeks following the last dose of luspatercept, even if he has undergone a successful vasectomy. Patients must be counseled concerning measures to be used to prevent pregnancy and potential toxicities prior to the first dose of luspatercept
- •Patients are able to adhere to the study visit schedule, understand and comply with all protocol requirements
- •Patients understand and are able to provide written informed consent
排除标准
- •Prior treatment with azacitidine or decitabine
- •Treatment within 28 days prior to Cycle 1 Day 1 with:
- •Erythropoiesis stimulating agent (ESA)
- •Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF)
- •Lenalidomide
- •Iron chelation therapy if initiated within 56 days prior to Cycle 1 Day 1
- •Treatment with another investigational drug or device, or approved therapy for investigational use ≤28 days prior to Cycle 1 Day 1, or if the half-life of the previous product is known, within 5 times the half-life prior to Cycle 1 Day 1, whichever is longer
- •Major surgery within 28 days prior to Cycle 1 Day
- •Patients must have completely recovered from any previous surgery prior to Cycle 1 Day 1
- •Platelet count <30 x 109/L.
- •Any active infection requiring parenteral antibiotic therapy within 28 days prior to Cycle 1 Day 1 or oral antibiotics within 14 days of Cycle 1 Day 1
- •History of stroke, deep venous thrombosis (DVT) or arterial embolism within 6 months prior to Cycle 1 Day 1
- •Known positive for human immunodeficiency virus (HIV), active infectious hepatitis B (HBV) or active infectious hepatitis C (HCV)
- •Any malignancy other than MDS which has not been in remission and/or has required systemic therapy including radiation, chemotherapy, hormonal therapy or surgery, within the last year prior to Cycle 1 Day 1
- •Uncontrolled hypertension, defined as systolic blood pressure (BP) ≥ 150 mm Hg or diastolic BP ≥ 100 mm Hg
- •Pregnant or lactating females
- •History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational drug
- •Any other condition not specifically noted above which, in the judgment of the investigator, would preclude the patient from participating in the study
- •Transfusion event within 7 days prior to Cycle 1 Day 1
- •Prior treatment with sotatercept (MK-7962, formerly called ACE-011) or luspatercept.
- •Secondary MDS
研究组 & 干预措施
Luspatercept 0.125mg/kg (Cohort 1)
Participants receive luspatercept 0.125mg/kg as a subcutaneous (SC) injection every 3 weeks (Q3W) on Day 1 of each cycle for up to 5 cycles (each cycle length = 21 days).
干预措施: Luspatercept (Drug)
Luspatercept 0.25mg/kg (Cohort 2)
Participants receive luspatercept titrated up to 0.25mg/kg via Fibonacci scheme, SC injection Q3W on Day 1 of each cycle for up to 5 cycles (each cycle length = 21 days).
干预措施: Luspatercept (Drug)
Luspatercept 0.50mg/kg (Cohort 3)
Participants receive luspatercept titrated up to 0.50mg/kg via Fibonacci scheme, SC injection Q3W on Day 1 of each cycle for up to 5 cycles (each cycle length = 21 days).
干预措施: Luspatercept (Drug)
Luspatercept 0.75mg/kg (Cohort 4)
Participants receive luspatercept titrated up to 0.75mg/kg via Fibonacci scheme, SC injection Q3W on Day 1 of each cycle for up to 5 cycles (each cycle length = 21 days).
干预措施: Luspatercept (Drug)
Luspatercept 1.00mg/kg (Cohort 5)
Participants receive luspatercept titrated up to 1.00mg/kg via Fibonacci scheme, SC injection Q3W on Day 1 of each cycle for up to 5 cycles (each cycle length = 21 days).
干预措施: Luspatercept (Drug)
Luspatercept 1.33mg/kg (Cohort 6)
Participants receive luspatercept titrated up to 1.33mg/kg via Fibonacci scheme, SC injection Q3W on Day 1 of each cycle for up to 5 cycles (each cycle length = 21 days).
干预措施: Luspatercept (Drug)
Luspatercept 1.75mg/kg (Cohort 7)
Participants receive luspatercept titrated up to 1.75mg/kg via Fibonacci scheme, SC injection Q3W on Day 1 of each cycle for up to 5 cycles (each cycle length = 21 days).
干预措施: Luspatercept (Drug)
Expansion Cohort
Participants receive an initial dose of luspatercept 1.0mg/kg SC on Day 1 of the Cycle 1 (Cycle length = 21 days). For each subsequent cycle (up to 5 cycles), the dose was titrated via Fibonacci scheme up to a maximum dose of 1.75mg/kg based on the safety review team (SRT) recommendations
干预措施: Luspatercept (Drug)
结局指标
主要结局
Percentage of High Transfusion Burden (HTB) Participants With mHI-E
时间窗: Any consecutive 8 weeks during the study (up to approximately 75 weeks)
The mHI-E for HTB participants was defined as a ≥4 units or ≥50% reduction in RBC transfusion burden during any rolling 8-week window compared to baseline. HTB participants were those who required ≥4 units of RBC transfusions within 8 weeks prior to baseline. Rolling 8 weeks was defined as any consecutive 8 weeks during the study. The percentage of HTB participants with mHI-E were reported.
Percentage of Low Transfusion Burden (LTB) Participants With Modified Erythroid Response (mHI-E)
时间窗: Any consecutive 2 weeks during the study (up to approximately 75 weeks)
The mHI-E for LTB participants was defined as a hemoglobin increase of ≥1.5 g/dL from baseline for ≥14 days or rolling 2 weeks (in the absence of red blood cell \[RBC\] transfusions). Hemoglobin measurements within 7 days following RBC transfusion were excluded from analysis. LTB participants were those who received \<4 units of RBCs within 8 weeks prior to baseline. Rolling 2 weeks was defined as any consecutive 2 weeks during the study. The percentage of LTB participants with mHI-E were reported.
次要结局
- Number of Participants Who Discontinued Study Treatment Due To an AE(Up to approximately 12 weeks)
- Rate of Erythroid Response (HI-E) Per International Working Group (IWG) 2006 Response Criteria(Any consecutive 8 Weeks during the study treatment (up to approximately 75 weeks))
- Number of Participants Who Experienced an Adverse Event (AE)(Up to approximately 24 weeks)
- Rate of Platelet Response (HI-P) Per IWG 2006 Criteria(Any consecutive 8 Weeks during the study treatment (up to approximately 75 weeks))
- Time to Maximum Concentration (Tmax) of Luspatercept(Cycle 1 Day 1: Predose, Cycle 1: Days 8, 11, 15: Postdose; Cycle 2 Day 1, Cycle 2 Day 8, Cycle 4 Day 1, Cycle 5 Day 1, and Cycle 5 Days 8, 15: Postdose (each cycle length = 21 days))
- Percent Change From Baseline to Day 113 in Concentration of Serum Iron(Baseline (prior to first dose of luspatercept) and Day 113)
- Percent Change From Baseline to Day 113 in Concentration of Serum Hepcidin(Baseline (prior to first dose of luspatercept) and Day 113)
- Percent Change From Baseline to Day 113 in Total Bilirubin Level(Baseline (prior to first dose of luspatercept) and Day 113)
- Rate of Neutrophil Response (HI-N) Per IWG 2006 Criteria(Any consecutive 8 Weeks during the study treatment (up to approximately 75 weeks))
- Area Under the Concentration-Time Curve of Luspatercept From Time 0 to Day 21 (AUC0-21)(Cycle 1 Day 1: Predose, Cycle 1 Days 8, 11, 15 and Cycle 2 Day 1: Postdose (each cycle length = 21 days))
- Percent Change From Baseline to Day 113 in Reticulocyte Count(Baseline (prior to first dose of luspatercept) and Day 113)
- Percent Change From Baseline to Day 113 in Direct Bilirubin Level(Baseline (prior to first dose of luspatercept) and Day 113)
- Duration of HI-E Per IWG 2006 Response Criteria(up to approximately 75 weeks)
- Rate of RBC Transfusion Independence (RBC-TI)(Up to approximately 16 weeks)
- Percent Change From Baseline to Day 113 in Concentration of Transferrin(Baseline (prior to first dose of luspatercept) and Day 113)
- Percent Change From Baseline to Day 113 in Concentration of Soluble Transferrin Receptor(Baseline (prior to first dose of luspatercept) and Day 113)
- Percent Change From Baseline to Day 113 in Concentration of Serum Erythropoietin(Baseline (prior to first dose of luspatercept) and Day 113)
- Percent Change From Baseline to Day 113 in Concentration of Serum Cross-Linked C-Telopeptide of Type I Collagen (CTX)(Baseline (prior to first dose of luspatercept) and Day 113)
- Time to HI-E Per IWG 2006 Response Criteria(Any consecutive 8 weeks during the study (up to approximately 75 weeks))
- Mean Change From Baseline to Day 113 in Frequency of RBC Transfusions(Baseline (prior to first dose of luspatercept) and Day 113)
- Terminal Half-Life (t ½) of Luspatercept(Cycle 1 Day 1: Predose, Cycle 1: Days 8, 11, 15: Postdose; Cycle 2 Day 1, Cycle 2 Day 8, Cycle 4 Day 1, Cycle 5 Day 1, and Cycle 5 Days 8, 15: Postdose (each cycle length = 21 days))
- Maximum Concentration (Cmax) of Luspatercept(Cycle 1 Day 1: Predose, Cycle 1: Days 8, 11, 15: Postdose; Cycle 2 Day 1, Cycle 2 Day 8, Cycle 4 Day 1, Cycle 5 Day 1, and Cycle 5 Days 8, 15: Postdose (each cycle length = 21 days))
- Percent Change From Baseline to Day 113 in Total Iron Binding Capacity (TIBC)(Baseline (prior to first dose of luspatercept) and Day 113)
- Percent Change From Baseline to Day 113 in Concentration of Serum Ferritin(Baseline (prior to first dose of luspatercept) and Day 113)
- Percent Change From Baseline to Day 113 in Lactate Dehydrogenase Level(Baseline (prior to first dose of luspatercept) and Day 113)
- Percent Change From Baseline to Day 113 in Concentration of Serum Bone-Specific Alkaline Phosphatase (BSAP)(Baseline (prior to first dose of luspatercept) and Day 113)
- Percent Change From Baseline to Day 113 in Concentration of Non-Transferrin Bound Iron (NTBI)(Baseline (prior to first dose of luspatercept) and Day 113)
- Percent Change From Baseline to Day 113 in Nucleated RBC (nRBC)(Baseline (prior to first dose of luspatercept) and Day 113)