A Phase I/II, Open-Label, Multicentre 2-Part Study to Assess the Safety, Tolerability, Pharmacokinetics, and Efficacy of AZD2811 as Monotherapy or in Combination in Treatment-Naïve or Relapsed/Refractory Acute Myeloid Leukaemia Patients Not Eligible for Intensive Induction Therapy.
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- AstraZeneca
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
研究概览
简要总结
This is a Phase I/II clinical study to determine the maximum tolerated dose (MTD), and schedule, safety, tolerability, pharmacokinetics, and pharmacodynamics of AZD2811 monotherapy or with combination agent(s) in relapsed/refractory acute myeloid leukaemia (AML) participants or treatment-naïve AML participants not eligible for intensive induction therapy. In addition, the study will explore the potential clinical activity by assessing anti-tumour activity in participants. The study was terminated early as a result of AstraZeneca's strategic review across the AZD2811 programme. Part A data were collected for initial cohorts; the MTD/recommended Phase 2 dose (RP2D) dose and schedule of AZD2811 monotherapy or with combination agents were not determined. Part B of the study was not initiated
详细描述
This is a Phase I/II clinical study to determine the MTD and schedule, safety, tolerability, pharmacokinetics, and pharmacodynamics of AZD2811 monotherapy or with combination agent(s) in relapsed/refractory AML participants or treatment-naïve AML participants not eligible for intensive induction therapy. The study will also explore the potential clinical activity by assessing anti-tumour activity in participants. The study will be conducted in two parts, designated Part A, dose escalation, and Part B, dose expansion. Participants will be enrolled in either Part A or Part B according to the Investigator's judgment of the most appropriate treatment for the individual participant and slot availability.
Part A - Dose Escalation
Approximately 48 evaluable treatment-naïve AML participants not eligible for intensive induction therapy or relapsed/refractory AML participants will be enrolled in Arm 1 and Arm 2 of the monotherapy escalation in Part A of this study.
The dose escalation and de-escalation plan for evaluating AZD2811 will follow the Bayesian Adaptive Design scheme which combines prior expectations about the dose toxicity relationship and applies the data at the end of each cohort to recommend a dose and schedule for the next cohort. The total number of participants will depend upon the number of dose escalations, de-escalations, and schedule changes necessary. At least 3 and up to 6 evaluable participants will be required for each dose cohort.
Part A Group 1, Arm A - Day 1 and 4 Monotherapy Dose Escalation:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 130 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Group 1 Arm A (AZD2811 Dose 1)
Participants with AML will receive intevenous (IV) infusion of AZD2811 Dose 1 on Days 1 and 4 of each 28-day cycle until disease progression, unacceptable toxicity, or the decision to discontinue treatment by the participant or the study physician, whichever occurs first.
干预措施: AZD2811 (Drug)
Group 1 Arm A (AZD2811 Dose 2)
Participants with AML and myelodysplastic syndrome (MDS) will receive IV infusion of AZD2811 Dose 2 on Days 1 and 4 of each 28-day cycle until disease progression, unacceptable toxicity, or the decision to discontinue treatment by the participant or the study physician, whichever occurs first.
干预措施: AZD2811 (Drug)
Group 1 Arm A (AZD2811 Dose 3)
Participants with AML and MDS will receive IV infusion of AZD2811 Dose 3 on Days 1 and 4 of each 28-day cycle until disease progression, unacceptable toxicity, or the decision to discontinue treatment by the participant or the study physician, whichever occurs first.
干预措施: AZD2811 (Drug)
Group 1 Arm A (AZD2811 Dose 4)
Participants with AML and MDS will receive IV infusion of AZD2811 Dose 4 on Days 1 and 4 of each 28-day cycle until disease progression, unacceptable toxicity, or the decision to discontinue treatment by the participant or the study physician, whichever occurs first.
干预措施: AZD2811 (Drug)
Group 1 Arm A (AZD2811 Dose 5)
Participants with AML will receive IV infusion of AZD2811 Dose 5 on Days 1 and 4 of each 28-day cycle until disease progression, unacceptable toxicity, or the decision to discontinue treatment by the participant or the study physician, whichever occurs first.
干预措施: AZD2811 (Drug)
Group 1 Arm B (AZD2811 Dose 2)
Participants with AML will receive IV infusion of AZD2811 Dose 2 on Days 1, 4, 15, and 18 of each 28-day cycle until disease progression, unacceptable toxicity, or the decision to discontinue treatment by the participant or the study physician, whichever occurs first.
干预措施: AZD2811 (Drug)
Group 1 Arm B (AZD2811 Dose 6)
Participants with AML will receive IV infusion of AZD2811 Dose 6 on Days 1, 4, 15, and 18 of each 28-day cycle until disease progression, unacceptable toxicity, or the decision to discontinue treatment by the participant or the study physician, whichever occurs first.
干预措施: AZD2811 (Drug)
Group 2 Arm A (AZD2811 Dose 3 + Azacitidine 75 mg/m^2)
Participants with AML and MDS will receive Azacitidine 75 mg/m^2 of body surface area (BSA) by subcutaneous (SC) injection or IV infusion prior to the start of AZD2811 infusion on Days 1 through 7 or for 5 consecutive weekdays (Days 1 through 5) with treatment holidays on the 2 weekend days (Days 6 and 7), and the remaining azacitidine dosing will be administered on the first 2 weekdays of the 2nd week (Days 8 and 9) of each 28-day cycle. Participants will receive IV infusion of AZD2811 Dose 3 on Days 1 and 4 of each 28-day cycle. Participants will receive the study treatment until disease progression, unacceptable toxicity, or the decision to discontinue treatment by the participant or the study physician, whichever occurs first.
干预措施: AZD2811 (Drug)
Group 2 Arm A (AZD2811 Dose 3 + Azacitidine 75 mg/m^2)
Participants with AML and MDS will receive Azacitidine 75 mg/m^2 of body surface area (BSA) by subcutaneous (SC) injection or IV infusion prior to the start of AZD2811 infusion on Days 1 through 7 or for 5 consecutive weekdays (Days 1 through 5) with treatment holidays on the 2 weekend days (Days 6 and 7), and the remaining azacitidine dosing will be administered on the first 2 weekdays of the 2nd week (Days 8 and 9) of each 28-day cycle. Participants will receive IV infusion of AZD2811 Dose 3 on Days 1 and 4 of each 28-day cycle. Participants will receive the study treatment until disease progression, unacceptable toxicity, or the decision to discontinue treatment by the participant or the study physician, whichever occurs first.
干预措施: Azacitidine (Drug)
Group 2 Arm A (AZD2811 Dose 4 + Azacitidine 75 mg/m^2)
Participants with AML will receive Azacitidine 75 mg/m^2 of BSA by SC injection or IV infusion prior to the start of AZD2811 infusion on Days 1 through 7 or for 5 consecutive weekdays (Days 1 through 5) with treatment holidays on the 2 weekend days (Days 6 and 7), and the remaining azacitidine dosing will be administered on the first 2 weekdays of the 2nd week (Days 8 and 9) of each 28-day cycle. Participants will receive IV infusion of AZD2811 Dose 4 on Days 1 and 4 of each 28-day cycle. Participants will receive the treatment until disease progression, unacceptable toxicity, or the decision to discontinue treatment by the participant or the study physician, whichever occurs first.
干预措施: AZD2811 (Drug)
Group 2 Arm A (AZD2811 Dose 4 + Azacitidine 75 mg/m^2)
Participants with AML will receive Azacitidine 75 mg/m^2 of BSA by SC injection or IV infusion prior to the start of AZD2811 infusion on Days 1 through 7 or for 5 consecutive weekdays (Days 1 through 5) with treatment holidays on the 2 weekend days (Days 6 and 7), and the remaining azacitidine dosing will be administered on the first 2 weekdays of the 2nd week (Days 8 and 9) of each 28-day cycle. Participants will receive IV infusion of AZD2811 Dose 4 on Days 1 and 4 of each 28-day cycle. Participants will receive the treatment until disease progression, unacceptable toxicity, or the decision to discontinue treatment by the participant or the study physician, whichever occurs first.
干预措施: Azacitidine (Drug)
Group 2 Arm B (AZD2811 Dose 2 + Azacitidine 75 mg/m^2)
Participants with AML will receive Azacitidine 75 mg/m^2 of BSA by SC injection or IV infusion prior to the start of AZD2811 infusion on Days 1 through 7 or for 5 consecutive weekdays (Days 1 through 5) with treatment holidays on the 2 weekend days (Days 6 and 7), and the remaining azacitidine dosing will be administered on the first 2 weekdays of the 2nd week (Days 8 and 9) of each 28-day cycle. Participants will receive IV infusion of AZD2811 Dose 2 on Days 1, 4, 15, and 18 of each 28-day cycle. Participants will receive the treatment until disease progression, unacceptable toxicity, or the decision to discontinue treatment by the participant or the study physician, whichever occurs first.
干预措施: AZD2811 (Drug)
Group 2 Arm B (AZD2811 Dose 2 + Azacitidine 75 mg/m^2)
Participants with AML will receive Azacitidine 75 mg/m^2 of BSA by SC injection or IV infusion prior to the start of AZD2811 infusion on Days 1 through 7 or for 5 consecutive weekdays (Days 1 through 5) with treatment holidays on the 2 weekend days (Days 6 and 7), and the remaining azacitidine dosing will be administered on the first 2 weekdays of the 2nd week (Days 8 and 9) of each 28-day cycle. Participants will receive IV infusion of AZD2811 Dose 2 on Days 1, 4, 15, and 18 of each 28-day cycle. Participants will receive the treatment until disease progression, unacceptable toxicity, or the decision to discontinue treatment by the participant or the study physician, whichever occurs first.
干预措施: Azacitidine (Drug)
Group 2 Arm B (AZD2811 Dose 6 + Azacitidine 75 mg/m^2)
Participants with AML will receive Azacitidine 75 mg/m^2 of BSA by SC injection or IV infusion prior to the start of AZD2811 infusion on Days 1 through 7 or for 5 consecutive weekdays (Days 1 through 5) with treatment holidays on the 2 weekend days (Days 6 and 7), and the remaining azacitidine dosing will be administered on the first 2 weekdays of the 2nd week (Days 8 and 9) of each 28-day cycle. Participants will receive IV infusion of AZD2811 Dose 6 on Days 1, 4, 15, and 18 of each 28-day cycle. Participants will receive the treatment until disease progression, unacceptable toxicity, or the decision to discontinue treatment by the participant or the study physician, whichever occurs first.
干预措施: AZD2811 (Drug)
Group 2 Arm B (AZD2811 Dose 6 + Azacitidine 75 mg/m^2)
Participants with AML will receive Azacitidine 75 mg/m^2 of BSA by SC injection or IV infusion prior to the start of AZD2811 infusion on Days 1 through 7 or for 5 consecutive weekdays (Days 1 through 5) with treatment holidays on the 2 weekend days (Days 6 and 7), and the remaining azacitidine dosing will be administered on the first 2 weekdays of the 2nd week (Days 8 and 9) of each 28-day cycle. Participants will receive IV infusion of AZD2811 Dose 6 on Days 1, 4, 15, and 18 of each 28-day cycle. Participants will receive the treatment until disease progression, unacceptable toxicity, or the decision to discontinue treatment by the participant or the study physician, whichever occurs first.
干预措施: Azacitidine (Drug)
Group 3 Arm A (AZD2811 Dose 2 + Venetoclax 200 mg)
Participants with AML will receive IV infusion of AZD2811 Dose 2 on Days 1 and 4 of each 28-day cycle and venetoclax 100 mg orally (PO) on Day 1 and 200 mg PO from Days 2 to 28 of each 28-day cycle until disease progression, unacceptable toxicity, or the decision to discontinue treatment by the participant or the study physician, whichever occurs first.
干预措施: AZD2811 (Drug)
Group 3 Arm A (AZD2811 Dose 2 + Venetoclax 200 mg)
Participants with AML will receive IV infusion of AZD2811 Dose 2 on Days 1 and 4 of each 28-day cycle and venetoclax 100 mg orally (PO) on Day 1 and 200 mg PO from Days 2 to 28 of each 28-day cycle until disease progression, unacceptable toxicity, or the decision to discontinue treatment by the participant or the study physician, whichever occurs first.
干预措施: Venetoclax (Drug)
Group 3 Arm A (AZD2811 Dose 2 + Venetoclax 400 mg)
Participants with AML will receive IV infusion of AZD2811 Dose 2 on Days 1 and 4 of each 28-day cycle and venetoclax 100 mg orally (PO) on Day 1, 200 mg PO on Day 2, and 400 mg PO from Days 3 to 28 of each 28-day cycle until disease progression, unacceptable toxicity, or the decision to discontinue treatment by the participant or the study physician, whichever occurs first.
干预措施: AZD2811 (Drug)
Group 3 Arm A (AZD2811 Dose 2 + Venetoclax 400 mg)
Participants with AML will receive IV infusion of AZD2811 Dose 2 on Days 1 and 4 of each 28-day cycle and venetoclax 100 mg orally (PO) on Day 1, 200 mg PO on Day 2, and 400 mg PO from Days 3 to 28 of each 28-day cycle until disease progression, unacceptable toxicity, or the decision to discontinue treatment by the participant or the study physician, whichever occurs first.
干预措施: Venetoclax (Drug)
结局指标
主要结局
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
时间窗: Day 1 through early termination of the study (approximately 42 months)
An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. There will be no updated results for this outcome measures at the time of end of study.
Number of Participants With Dose-limiting Toxicities (DLTs)
时间窗: Day 1 to Day 28 of first cycle
A DLT was defined as any adverse event (AE) not related to the underlying leukaemia requiring treatment interruption for \> 21 days, any Grade 5 AE, Grade 4 neutropenia or thrombocytopenia lasting \>= 42 days from start of cycle in absence of evidence of active leukaemia, any \>= Grade 3 non-haematological AE (except Grade 3 nausea, vomiting, mucositis, stomatitis or diarrhoea that was controlled within 4 days and Grade 3 elevations in alanine aminotransferase/ aspartate aminotransferase that return to meet initial eligibility criteria within 7 days of study drug interruption), or any other clinically significant and/or unacceptable AE that does not respond to supportive care, results in a disruption of dosing schedule for \> 7 days, or was judged as a DLT by Investigator in collaboration with the Medical Monitor. An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship.
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as Grade 4 TEAEs
时间窗: Day 1 through early termination of the study (approximately 42 months)
Participants with abnormal clinical laboratory parameters reported as Grade 4 TEAEs are reported. Laboratory analysis included hematology, clinical chemistry, and urinalysis. hematology, coagulation, chemistry, and urinalysis parameters over time are reported.
次要结局
- Number of Participants With >50% Change in Bone Marrow Blasts from Baseline in Participants With AML(Baseline (Day 1), Cycle 1 Day 22, Cycle 2 Day 22, Cycle 4 Day 22, and end of treatment (approximately 42 months))
- Number of Participants With Total Complete Remission (CR)(Day 1 through early termination of the study (approximately 42 months))
- Number of Participants With Partial Remission (PR)(Day 1 through early termination of the study (approximately 42 months))
- Number of Participants With Overall Response Rate (ORR)(Day 1 through early termination of the study (approximately 42 months))