A Modular Phase I/II, Open-label, Multicentre Study to Assess AZD4573 in Novel Combinations With Anti-cancer Agents in Patients With Advanced Haematological Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- AstraZeneca
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- Module 1: Number of Participants With Adverse Events
研究概览
简要总结
This is a modular, multicentre, open-label, non-randomised, Phase I/II, dose-setting and expansion study including an intra-participants dose ramp up. AZD4573 will be administered intravenously, in novel combinations with anti-cancer agents, to participants with relapsed/refractory (r/r) haematological malignancies.
详细描述
In Module 1 Part A (dose-setting), this study module will enrol participants with r/r Diffuse large B-cell lymphoma (DLBCL) or r/r Marginal zone lymphoma (MZL) who have failed prior therapy(ies), are not eligible for curative treatment options, for whom there is no standard therapy available, and will initially explore once weekly administration of AZD4573 at up to three target dose levels in combination with oral acalabrutinib 100 mg twice daily. The primary objective of Part A will be to identify the maximum tolerated dose and/or Recommended Phase II dose (RP2D) for further evaluation in Part B. A 5-week DLT-assessment period will incorporate the whole of Cycle 1 in Part A, including the dose ramp up and the first 3 weeks at the target dose. In Module 1 Part B (expansion), separate expansion cohorts for participants with Germinal Centre B-cell (GCB) and non-GCB DLBCL subtypes will be opened at the RP2D.
In Module 2, this study module will enroll participants with r/r Mantle Cell Lymphoma (MCL) who have failed at least one line of prior therapy, are not eligible for curative treatment options. Module 2, Part A consist of AZD4573 monotherapy (Period 1) followed by AZD4573 + acalabrutinib combination treatment (Period 2). Period 1: AZD4573 will be administered weekly (12 mg, infusion). Period 2: AZD4573 (RP2D from Module 1) will be administered (weekly) in combination with oral acalabrutinib 100 mg twice daily. Cycle 1 of each dosing period has a duration of 5 weeks; subsequent cycles have a duration of 3 weeks. The AZD4573 monotherapy (Period 1) includes an intra-patient ramp up; participants will receive AZD4573 at Cycle 1 Week 1, Cycle 1 Week 2, and Cycle 1 Week 3 in 3 dose escalation manner (6, 9 and 12 mg respectively). Part A, Period 1 of Module 2 aims to confirm the AZD4573 monotherapy RP2D in MCL participants. In Period 2, the safety and tolerability of the RP2D of AZD4573 + acalabrutinib established in Module 1 will be assessed in participants with MCL. The study design of Part B of Module 2 will be determined from the data emerging from Part A.
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
- •Current refractory nausea and vomiting, malabsorption syndrome, disease significantly affecting gastrointestinal function, stomach resection, extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, bowel obstruction, or gastric restrictions and bariatric surgery.
- •Prior use of standard anti-lymphoma therapy or radiation therapy within 14 days of receiving the first dose of study treatment.
- •Requires treatment with strong CYP3A inhibitors or inducers.
- •Requires treatment with proton-pump inhibitors. Participants receiving proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrolment to this study.
- •Serologic status reflecting active hepatitis B or C infection.
- •Active Cytomegalovirus (CMV) infection.
- •Requires or receiving therapeutic anticoagulants, with the exception of short-acting heparins, within 7 days of first dose of study treatment. Novel oral anticoagulants are allowed except for the initial high dose treatment period.
- •Participants on dual antiplatelet and therapeutic anticoagulant therapy.
- •Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists.
- •History of or ongoing confirmed progressive multifocal leukoencephalopathy
- •Exclusion Criteria: Module 2
- •Current refractory nausea and vomiting, malabsorption syndrome, disease significantly affecting gastrointestinal function, stomach resection, extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery.
- •Prior use of standard anti-lymphoma therapy or radiation therapy within 14 days of receiving the first dose of study treatment.
- •Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists.
- •Requires treatment with strong CYP3A inhibitors or inducers.
- •Requires treatment with proton-pump inhibitors. Participants receiving proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrolment to this study.
- •Serologic status reflecting active hepatitis B or C infection.
- •Active CMV infection.
- •Requires or receiving therapeutic anticoagulants, with the exception of short-acting heparins, within 7 days of first dose of study treatment. Novel oral anticoagulants are allowed except for the initial high dose treatment period.
- •Participants on dual antiplatelet and therapeutic anticoagulant therapy.
- •History of or ongoing confirmed progressive multifocal leukoencephalopathy
研究组 & 干预措施
Module 1: Part A and Part B
Participants will receive intravenous ascending doses of AZD4573 once weekly with oral acalabrutinib twice daily continuously in Part A. For Part A, cohorts 1, 2, and 3 have different target dose levels respectively.
In Part B, participants will receive the RP2D of AZD4573 from Part A.
干预措施: AZD4573 (Drug)
Module 1: Part A and Part B
Participants will receive intravenous ascending doses of AZD4573 once weekly with oral acalabrutinib twice daily continuously in Part A. For Part A, cohorts 1, 2, and 3 have different target dose levels respectively.
In Part B, participants will receive the RP2D of AZD4573 from Part A.
干预措施: Acalabrutinib (Drug)
Module 2: Part A and Part B
Participants will receive AZD4573 as monotherapy for Period 1 and AZD4573 + acalabrutinib as combination therapy for Period 2.
Part B of Module 2 will be determined from the data emerging from Part A.
干预措施: AZD4573 (Drug)
Module 2: Part A and Part B
Participants will receive AZD4573 as monotherapy for Period 1 and AZD4573 + acalabrutinib as combination therapy for Period 2.
Part B of Module 2 will be determined from the data emerging from Part A.
干预措施: Acalabrutinib (Drug)
结局指标
主要结局
Module 1: Number of Participants With Adverse Events
时间窗: From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 2.5 years)
Safety and tolerability of AZD4573 in combination with acalabrutinib was assessed.
Module 2: Number of Participants With Adverse Events
时间窗: From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 2.5 years)
Assessed safety and confirmed the RP2D of AZD4573 monotherapy in MCL participants and assessed the safety and tolerability of AZD4573 in combination with acalabrutinib in participants administered AZD4573 monotherapy.
Module 1: Overall Response Rate (ORR) of AZD4573 in Combination With Acalabrutinib
时间窗: From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 2.5 years)
Overall response rate (ORR), defined as the proportion of participants who have a tumour response (complete response \[CR\] and partial response \[PR\]).
次要结局
- Module 1: Complete Response (CR) Rate(From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 2.5 years))
- Module 1: Duration of Response (DoR)(From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 2.5 years))
- Module 1: Progression Free Survival (PFS)(From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 2.5 years))
- Module 1: Overall Survival (OS)(From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 2.5 years))
- Module 1: Cmax of AZD4573(Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1)
- Module 1: Cmax of Acalabrutinib(Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1)
- Module 1: Cmax of ACP-5862(Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1)
- Module 1: AUClast of AZD4573(Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1)
- Module 1: AUClast of Acalabrutinib(Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1)
- Module 1: AUClast of ACP-5862(Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1)
- Module 1: AUCinf of AZD4573(Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1)
- Module 1: AUCinf of Acalabrutinib(Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1)
- Module 1: AUCinf of ACP-5862(Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1)
- Module 1: Tmax of AZD4573(Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1)
- Module 1: Tmax of Acalabrutinib(Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1)
- Module 1: Tmax of ACP-5862(Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1)
- Module 1: t1/2 of AZD4573(Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1)
- Module 1: t1/2 of Acalabrutinib(Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1)
- Module 1: t1/2 of ACP-5862(Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1)