A Phase 1, Open-Label, Multi-Centre Study to Assess the Safety, Pharmacokinetics, and Preliminary Efficacy of AMX-883 Monotherapy in Participants With Acute Myeloid Leukaemia and High-Risk Myelodysplastic Syndrome and in Combination With Anticancer Agents in Participants With Acute Myeloid Leukaemia
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 54
- 试验地点
- 1
- 主要终点
- Number of participants with adverse events (AEs), treatment-emergent adverse events (TEAEs), adverse events of special interests (AESIs) and serious adverse events (SAEs)
研究概览
简要总结
The purpose of the study is to assess the safety, pharmacokinetics, and preliminary efficacy of AMX-883 monotherapy in participants with acute myeloid leukaemia (AML) and high-risk myelodysplastic syndrome (MDS) and in combination with anticancer agents in participants with AML.
详细描述
This is a modular, Phase 1, open-label, multi-centre dose-escalation study investigating AMX-883 in participants with relapsed/refractory AML and high-risk MDS. The study comprises Module 1, which will evaluate AMX-883 as monotherapy and in combination with posaconazole.
Module 1 consists of three parts:
- Part A consists of the monotherapy dose escalation cohorts and investigation of the food-effect at selected dose(s).
- Part B consists of AMX-883 in combination with posaconazole dose escalation cohorts.
Other modules may be added by protocol amendment. The study aims to establish optimal dosing and preliminary efficacy data to support further clinical development of AMX-883.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 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
- •Participants with relapsed or refractory AML who have failed all available standard therapies or relapsed or refractory high-risk MDS with BM blasts 10-19%
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
- •Adequate washout from prior therapies
- •Adequate kidney and liver function
- •Female participants of childbearing potential must use highly effective contraception, and male participants must agree to use barrier contraception and avoid sperm donation for at least 120 days after last dose
- •If enrolled in M1B: Participant must have no documented contraindication to treatment with posaconazole before start of treatment
排除标准
- •Diagnosis of acute promyelocytic leukaemia or chronic myelogenous leukaemia in blast crisis
- •Clinically active central nervous system (CNS) leukaemia
- •Receiving immunosuppressive therapy post HSCT
- •History of another malignancy that is active, progressing, or has required systemic treatment within the past 2 years
- •Presence of >Grade 1 active graft versus host disease within 4 weeks prior to C1D1
- •Significant cardiovascular disease
- •Family history of sudden cardiac death before 40 years of age or a family history of long QT syndrome
- •Clinically significant electrolyte imbalances (e.g., hypokalaemia, hypomagnesaemia, hypocalcaemia) that may contribute to QT interval prolongation
- •Clinically significant bradycardia (<50 beats per minute) that is symptomatic or causes haemodynamic instability
- •Major surgery within 4 weeks prior to C1D1 or inadequate recovery from prior surgery
- •Uncontrolled intercurrent illness
- •Inability to fast, swallow, ingest, or absorb oral medication due to a pre-existing condition
- •History of interstitial lung disease or pneumonitis requiring systemic corticosteroid treatment
- •Requirement for medications with a known risk of Torsades de Pointes that cannot be discontinued prior to study treatment
- •Detectable human immunodeficiency virus (HIV) viral load
- •Known serologic status reflecting active hepatitis B or C infection
- •Active uncontrolled systemic fungal, bacterial, viral, or other infection or a condition predisposing to severe infection
研究组 & 干预措施
Module 1 Part A (M1A): AMX-883 monotherapy dose escalation cohort
Participants will receive escalating dose levels of AMX-883 administered as monotherapy.
干预措施: AMX-883 (Drug)
Module 1 Part A (M1A): AMX-883 monotherapy food effect cohort
Participants will receive a selected dose of AMX-883 from the M1A dose escalation cohort, administered as monotherapy, under fed and fasted conditions.
干预措施: AMX-883 (Drug)
Module 1 Part B (M1B): AMX-883 + posaconazole
Participants will receive a selected dose level for at least two escalating dose levels of AMX-883 selected from the M1A dose escalation cohort, administered in combination with posaconazole.
干预措施: AMX-883 (Drug)
Module 1 Part B (M1B): AMX-883 + posaconazole
Participants will receive a selected dose level for at least two escalating dose levels of AMX-883 selected from the M1A dose escalation cohort, administered in combination with posaconazole.
干预措施: Posaconazole (Drug)
结局指标
主要结局
Number of participants with adverse events (AEs), treatment-emergent adverse events (TEAEs), adverse events of special interests (AESIs) and serious adverse events (SAEs)
时间窗: Until 30 days after last dose (Approximately 2 years 8 months)
To determine the safety and tolerability of AMX-883 in participants with relapsed or refractory AML and high-risk MDS when administered as monotherapy and in combination with posaconazole.
Number of participants with dose limiting toxicities (DLTs)
时间窗: During Cycle 1 (each cycle will be 28 days)
To determine the maximum tolerated dose (MTD)/optimal biological dose (OBD) and the recommended dose for expansion (RDE) of AMX-883 in participants with relapsed or refractory AML and high-risk MDS when administered as monotherapy and in combination with posaconazole.
次要结局
- Maximum plasma concentration (Cmax)(At predefined intervals from Cycle 1 Day 1 (C1D1) until completion of treatment period (Approximately 2 years 8 months))
- Minimum plasma concentration (Cmin)(At predefined intervals from Cycle 1 Day 1 (C1D1) until completion of treatment period (Approximately 2 years 8 months))
- Time to Cmax (Tmax)(At predefined intervals from Cycle 1 Day 1 (C1D1) until completion of treatment period (Approximately 2 years 8 months))
- Terminal plasma half-life (t½λz)(At predefined intervals from Cycle 1 Day 1 (C1D1) until completion of treatment period (Approximately 2 years 8 months))
- Area under the plasma concentration-time curve from zero to infinity (AUCinf)(At predefined intervals from Cycle 1 Day 1 (C1D1) until completion of treatment period (Approximately 2 years 8 months))
- Oral plasma clearance (CL/F)(At predefined intervals from Cycle 1 Day 1 (C1D1) until completion of treatment period (Approximately 2 years 8 months))
- Oral volume of distribution during terminal phase (Vz/F)(At predefined intervals from Cycle 1 Day 1 (C1D1) until completion of treatment period (Approximately 2 years 8 months))
- Mean residence time (MRT)(At predefined intervals from Cycle 1 Day 1 (C1D1) until completion of treatment period (Approximately 2 years 8 months))
- Area under the plasma concentration-time curve from zero to tau (AUC0-tau) where tau=12(At predefined intervals from Cycle 1 Day 1 (C1D1) until completion of treatment period (Approximately 2 years 8 months))
- Relapse-free survival (RFS) (AML)(Approximately 2 years 8 months)
- Composite complete remission (CRc) (AML)(Approximately 2 years 8 months)
- Morphologic leukaemia-free state (MLFS) (AML)(Approximately 2 years 8 months)
- Overall Response rate (ORR) (AML)(Approximately 2 years 8 months)
- Duration of remission (DOR) (AML)(Approximately 2 years 8 months)
- Transfusion independence (TI) (AML)(Approximately 2 years 8 months)
- Progression-free survival (PFS) (AML)(Approximately 2 years 8 months)
- Event-free survival (EFS) (AML)(Approximately 2 years 8 months)
- Time to response (TTR) (AML)(Approximately 2 years 8 months)
- Overall survival (OS) (AML)(Approximately 2 years 8 months)
- Treatment failure (AML)(Approximately 2 years 8 months)
- 30-day and 60-day mortality rate (Extramedullary Disease- 30 [ED-30] and ED-60) (AML)(Approximately 2 years 8 months)
- CR (high-risk MDS)(Approximately 2 years 8 months)
- CR equivalent (high-risk MDS)(Approximately 2 years 8 months)
- Partial remission (PR) (high-risk MDS)(Approximately 2 years 8 months)
- Complete remission with limited count recovery (CRL) (high-risk MDS)(Approximately 2 years 8 months)
- CRh (high-risk MDS)(Approximately 2 years 8 months)
- Haematologic improvement (HI) (high-risk MDS)(Approximately 2 years 8 months)
- ORR (high-risk MDS)(Approximately 2 years 8 months)
- DOR (high-risk MDS)(Approximately 2 years 8 months)
- TTR (high-risk MDS)(Approximately 2 years 8 months)
- PFS (high-risk MDS)(Approximately 2 years 8 months)
- EFS (high-risk MDS)(Approximately 2 years 8 months)
- OS (high-risk MDS)(Approximately 2 years 8 months)
- Change from baseline in BRD9 expression levels in peripheral blood mononuclear cells (PBMCs)(At predefined intervals from Cycle 1 Day 1 (C1D1) until completion of treatment period (Approximately 2 years 8 months))