A Phase 1 First in Human Study Evaluating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 224 in Subjects With Relapsed or Refractory Multiple Myeloma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Amgen
- 入组人数
- 42
- 试验地点
- 1
- 主要终点
- Number of Participants With a Treatment-emergent Adverse Event (TEAE)
研究概览
简要总结
This is a first in human phase 1 multicenter open label study in subjects with relapsed or refractory multiple myeloma.
详细描述
This is a first in human phase 1 multicenter open label study to evaluate the safety and tolerability of AMG 224 in subjects with relapsed or refractory multiple myeloma. The study will be conducted in 2 parts. Part 1 is the dose-exploration and part 2 is the dose-expansion. Study medication will be administered once every 3 weeks by intravenous (IV) infusion.
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
- •Pathologically documented,multiple myeloma relapsed or refractory progressive disease after at least 3 lines of therapy for multiple myeloma.
- •Prior therapeutic treatment or regimens must include proteasome inhibitors (e.g. bortezomib) and immunomodulatory drugs (e.g. lenalidomide).
- •Willing and able to undergo bone marrow aspirate per protocol (with or without bone marrow biopsy per institutional guidelines).
- •Measurable disease per the International Myeloma Working Group (IMWG) response criteria
- •Hematological function, as follows, without transfusion support:
- •Absolute neutrophil count ≥ 1.0 X 10^9/L,
- •Platelet count ≥ 75 X 10^9/L (in patients with < 50% of bone marrow nucleated cells were plasma cells) or ≥ 50 X 10^9/L (in patients with ≥ 50% of bone marrow nucleated cells were plasma cells) without transfusion or growth factor support
- •Hemoglobin > 8 g/dL (> 80 g/L)
- •Adequate renal and hepatic function
- •Left ventricular ejection fraction (LVEF) > 50%
排除标准
- •Currently receiving treatment in another investigational device or drug study, or less than 28 days since ending treatment on another investigational device or drug study
- •Autologous stem cell transplant less than 90 days prior to study day 1
- •Multiple myeloma with IgM subtype
- •POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) syndrome, Plasma cell leukemia, Waldenstrom's macroglobulinemia or Amyloidosis
- •Glucocorticoid therapy (prednisone > 30 mg/day or equivalent) within 7 days prior to study day
- •Myocardial infarction within 6 months of study day 1, symptomatic congestive heart failure (New York Heart Association > class II)
- •A baseline ECG QTcF > 470 msec
- •Anti-tumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, or investigational agent) within 28 days prior to study day 1
研究组 & 干预措施
Dose Exploration: AMG 224 Dose A
Participants were administered AMG 224 Dose A as an intravenous (IV) infusion once every 3 weeks (Q3W) on Day 1 of each cycle, where each cycle is 3 weeks.
干预措施: AMG 224 (Drug)
Dose Exploration: AMG 224 Dose B
Participants were administered AMG 224 Dose B as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks.
干预措施: AMG 224 (Drug)
Dose Exploration: AMG 224 Dose C
Participants were administered AMG 224 Dose C as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks.
干预措施: AMG 224 (Drug)
Dose Exploration: AMG 224 Dose D
Participants were administered AMG 224 Dose D as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks.
干预措施: AMG 224 (Drug)
Dose Exploration: AMG 224 Dose E
Participants were administered AMG 224 Dose E as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks.
干预措施: AMG 224 (Drug)
Dose Exploration: AMG 224 Dose F
Participants were administered AMG 224 Dose F as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks.
干预措施: AMG 224 (Drug)
Dose Exploration: AMG 224 Dose G
Participants were administered AMG 224 Dose G as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks.
干预措施: AMG 224 (Drug)
Dose Expansion: AMG 224 Dose H + prior CD38 targeting antibody treatment
Participants who had prior treatment with CD38-targeting antibody were administered AMG 224 Dose H (the maximum tolerated dose [MTD] based on the dose exploration phase) as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks.
干预措施: AMG 224 (Drug)
Dose Expansion: AMG 224 Dose H + no prior CD38 targeting antibody treatment
Participants who had no prior treatment with CD38-targeting antibody were administered AMG 224 Dose H (the MTD based on the dose exploration phase) as an IV infusion Q3W on Day 1 of each cycle, where each cycle is 3 weeks.
干预措施: AMG 224 (Drug)
结局指标
主要结局
Number of Participants With a Treatment-emergent Adverse Event (TEAE)
时间窗: Day 1 of Cycle 1 to up to the end of Cycle 4, where each cycle is 3 weeks; up to 12 weeks.
An adverse event (AE) is defined as any untoward medical occurrence in a clinical trial participant. TEAEs were any AE that occurred after receiving at least 1 dose of treatment. Treatment-related TEAEs were those considered related to study treatment by the investigator. Any clinically significant changes in ECGs, vital signs, physical examination with a neurologic assessment and clinical laboratory tests were recorded as TEAEs.
Number of Participants Who Experienced a Dose-Limiting Toxicity (DLT)
时间窗: Day 1 to Day 28
Adverse events, including DLTs, were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. A DLT was considered as any of the below, if judged by the investigator to be possibly related to AMG 224: Hematological: * Grade 4 neutropenia lasting \> 7 days * Grade 3 or 4 neutropenia with fever \> 38.5°C * Grade 3 thrombocytopenia with ≥ Grade 2 hemorrhage * Grade 4 thrombocytopenia lasting \> 7 days * Grade 3 anemia with symptoms or required intervention * Grade 4 anemia * Lymphopenia is not considered a DLT Non-hematological: * ≥ Grade 3 nausea, vomiting or diarrhea persisting \> 3 days despite optimal medical support * Grade 3 fatigue persisting \> 7 days * ≥ Grade 3 acute kidney injury lasting \> 3 days * Elevation of aspartate aminotransferase or alanine aminotransferase \>3x to \>8x upper limit of normal (ULT) dependent on criteria * Total bilirubin \> 3x ULN Participants meeting the criteria for Hy's Law case were considered to have a DLT.
次要结局
- Area Under the Concentration-time Curve (AUC) of AMG 224 Conjugated Antibody, Total Anti-BCMA Antibody, and Total Unconjugated DM1(AMG 224 and anti-BCMA antibody: pre-dose, 0.5 hours, EOI, 4 hours, 24 hours, 96 hours, 168 hours, and 336 hours post-dose (Cycle 1 + 2); DM1: pre-dose, 0.5 hours, EOI, 4 hours, 24 hours, and 96 hours post-dose (Cycles 1 + 2))
- Best Overall Response (BOR) According to International Myeloma Working Group Uniform Response Criteria (IMWG-URC)(Day 1 of Cycle 1 to up to the end of study visit; up to approximately 6 years)
- Number of Participants With Conversion to Minimal Residual Disease (MRD)-Negativity(Day 1 of Cycle 1 to up to the end of study visit; up to approximately 6 years)
- Time To Progression (TTP) According to IMWG-URC(Day 1 of Cycle 1 to up to the end of study visit; up to approximately 6 years)
- Duration of Response (DOR) According to IMWG-URC(Day 1 of Cycle 1 to up to the end of study visit; up to approximately 6 years)
- Number of Participants With Anti-AMG 224 Antibodies(Day 1 of Cycle 1 to up to the end of study visit; up to approximately 6 years)
- Maximum Observed Concentration (Cmax) of AMG 224 Conjugated Antibody, Total Anti-B-cell Maturation Antigen (Anti-BCMA) Antibody, and Total Unconjugated DM1(AMG 224 and anti-BCMA antibody: pre-dose, 0.5 hours, end of infusion (EOI), 4 hours, 24 hours, 96 hours, 168 hours, and 336 hours post-dose (Cycles 1 + 2); DM1: pre-dose, 0.5 hours, EOI, 4 hours, 24 hours, and 96 hours post-dose (Cycles 1 + 2))
- Terminal Half-life (t1/2,z) of AMG 224 Conjugated Antibody, Total Anti-BCMA Antibody, and Total Unconjugated DM1(AMG 224 and anti-BCMA antibody: pre-dose, 0.5 hours, EOI, 4 hours, 24 hours, 96 hours, 168 hours, and 336 hours post-dose (Cycles 1 + 2); DM1: pre-dose, 0.5 hours, EOI, 4 hours, 24 hours, and 96 hours post-dose (Cycles 1 + 2))
- Minimum Observed Concentration (Cmin) of AMG 224 Conjugated Antibody, Total Anti-BCMA Antibody, and Total Unconjugated DM1(AMG 224 and anti-BCMA antibody: pre-dose, 0.5 hours, EOI, 4 hours, 24 hours, 96 hours, 168 hours, and 336 hours post-dose (Cycles 1 + 2); DM1: pre-dose, 0.5 hours, EOI, 4 hours, 24 hours, and 96 hours post-dose (Cycles 1 + 2))
- Clearance (CL) of AMG 224 Conjugated Antibody, Total Anti-BCMA Antibody, and Total Unconjugated DM1(AMG 224 and anti-BCMA antibody: pre-dose, 0.5 hours, EOI, 4 hours, 24 hours, 96 hours, 168 hours, and 336 hours post-dose (Cycles 1 + 2); DM1: pre-dose, 0.5 hours, EOI, 4 hours, 24 hours, and 96 hours post-dose (Cycles 1 + 2))