A Modular Phase I/II, Open-label, Multicentre Study to Evaluate the Safety, Tolerability and Preliminary Efficacy of AZD2962, an IRAK4 Inhibitor, as Monotherapy and in Combination With Other Agents, in Participants With Haematologic Neoplasms
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- AstraZeneca
- 入组人数
- 72
- 试验地点
- 21
- 主要终点
- Number of participants with dose limiting toxicity (DLT)
研究概览
简要总结
The purpose of the study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of AZD2962, an Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) inhibitor, as monotherapy and in combination with other agents in participants with haematologic neoplasms.
详细描述
This is a modular study. In Module 1, the study will begin with a dose escalation of AZD2962 monotherapy in participants with myelodysplastic syndromes (MDS) and dysplastic chronic myelomonocytic leukemia (CMML).
Module 1 of the study will comprise of:
- A Screening Period of maximum 21 days.
- Treatment period with 28-day cycles where each patient will receive an oral dose of AZD2962 once daily, starting on Day 1, and will continue treatment until disease progression, unacceptable toxicity, or withdrawal.
- Safety Follow-up period after 30 days after last dose.
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 110 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants with relapsed/refractory MDS or participants with relapsed/refractory dysplastic CMML, with peripheral blasts or bone marrow blasts < 20%, and who received one or more prior lines of therapy as per standard of care (or who exhausted locally available treatments including treatments for actionable mutations). Diagnosis must be histologically confirmed as per the WHO 2016 classification of myeloid neoplasms.
- •Eastern Cooperative Oncology Group (ECOG) performance status of ≤
- •Participants must have symptomatic disease that requires therapy and allows for objective efficacy assessments.
- •Willing to provide baseline bone marrow aspirate (or biopsy if dry-tap).
- •Contraceptive use by participants or participant partners should be consistent with local regulations and also comply with Clinical Study Protocol requirements.
- •All women of childbearing potential must have a negative serum pregnancy test result at Screening.
排除标准
- •Prior treatment with IRAK inhibitors or inhibitors of the inflammasome pathway.
- •Received any antineoplastic therapy (except hydroxyurea) within 15 days prior to first dose.
- •Received any strong or moderate Cytochrome P450 3A (CYP3A) inhibitors within 15 days prior to first dose.
- •Received major surgery within 28 days prior to first dose, or still recovering from surgery.
- •Received drugs that are known to prolong corrected QT interval (QTc) and with known risk of Torsades de Pointes, within 15 days prior to first dose.
- •Received immunosuppressive medications (including Graft-Versus-Host Disease prophylaxis) within 28 days prior to first dose, or within 15 days in the case of systemic steroids (doses exceeding 10 mg/day of prednisone or equivalent).
- •Received live attenuated vaccines within 28 days prior to first dose.
- •Active major bleeding event.
- •Any evidence of systemic disease, significant clinical disorder, or laboratory finding that make undesirable the participation in the study.
- •15. Mean resting corrected QT interval using Fridericia's formula (QTcF) > 450 ms obtained from triplicate Electrocardiograms (ECGs) and averaged, recorded within 5 minutes. In the presence of bundle branch block, QTcF > 470 ms is applicable.
- •16. History of intracranial bleeding within 6 months prior to first dose.
- •Active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism or excretion of oral therapy.
- •18. History of a prior non-haematologic neoplasm (with some exceptions).
- •Unresolved Grade > 2 toxicities from prior anticancer therapies (with some exceptions).
- •20. Concurrent enrolment in another clinical study (with some exceptions).
- •Known hypersensitivity to study intervention or its excipients.
研究组 & 干预措施
Module 1- AZD2962 (Monotherapy)
Participants with MDS and dysplastic CMML will receive AZD2962 as monotherapy in a dose escalation pattern.
干预措施: AZD2962 (Drug)
结局指标
主要结局
Number of participants with dose limiting toxicity (DLT)
时间窗: From Cycle 1 Day 1 up to end of Cycle 1 (28 Days)
A DLT is defined as an adverse event or abnormal laboratory value occurring during the DLT-evaluation period (first 28 days of treatment). This will be evaluated to assess the safety and tolerability and also to identify optimal biological dose (OBD) of AZD2962.
Number of participants with Adverse events (AEs) and serious AEs
时间窗: Cycle 1 Day 1 up to safety follow-up (30 days after last dose) (Approximately 3 years)
To assess the safety and tolerability of AZD2962 and also to identify OBD of AZD2962.
Duration of exposure
时间窗: Cycle 1 Day 1 up to safety follow-up (30 days after last dose) (Approximately 3 years)
To assess the safety and tolerability of AZD2962, and also to identify OBD of AZD2962.
Relative dose intensity
时间窗: Cycle 1 Day 1 up to safety follow-up (30 days after last dose) (Approximately 3 years)
To assess the safety and tolerability of AZD2962, and also to identify OBD of AZD2962.
次要结局
- Percentage of participants with Objective response (OR)(First dose up to progression of disease (PD) or last evaluable assessment in the absence of progression, whichever comes first (Approximately 3 Years))
- Duration of response (DoR)(First documented response, up to the date of the first documented PD or study end, which ever comes first (Approximately 3 Years))
- Time to Response (TTR)(First dose up to PD or last evaluable assessment, whichever comes first (Approximately 3 Years))
- Overall Survival (OS)(First dose up to death due to any cause (Approximately 3 Years))
- Time to Progression to Acute myeloid leukaemia (AML)(First dose up to first diagnosis of AML (Approximately 3 Years))
- Plasma concentration of AZD2962(Cycle 1 Day 1 (each cycle is 28 days) up to end of the treatment (EoT) (Approximately 3 Years))
- Area under the concentration time curve (AUC).(Cycle 1 Day 1 (each cycle is 28 days) up to EoT (Approximately 3 Years))
- Maximum plasma drug concentration (Cmax)(Cycle 1 Day 1 (each cycle is 28 days) up to EoT (Approximately 3 Years))
- Time to reach maximum concentration (tmax)(Cycle 1 Day 1 (each cycle is 28 days) up to EoT (Approximately 3 Years))