NCT04644068进行中（未招募）1 期
A Modular Phase I/IIa, Open-label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of Ascending Doses of AZD5305 as Monotherapy and in Combination With Anti-cancer Agents in Patients With Advanced Solid Malignancies
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- AstraZeneca
- 入组人数
- 702
- 试验地点
- 68
- 主要终点
- The number of subjects with adverse events/serious adverse events
研究概览
简要总结
This research is designed to determine if experimental treatment with PARP inhibitor, AZD5305, alone, or in combination with anti-cancer agents is safe, tolerable, and has anti-cancer activity in patients with advanced solid tumors.
详细描述
This study is a Phase I/IIa modular, open-label, multi-center study of AZD5305 administered orally, either as monotherapy or in combination with other anti-cancer agents in patients with advanced solid malignancies.
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 130 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 18 at the time of screening
- •Histological or cytological confirmation of advanced malignancy considered to be suitable for study treatment and meeting module specific eligibility criteria..
- •Eastern Cooperative Oncology Group Performance status (ECOG PS: 0-2)
- •Life expectancy ≥ 12 weeks
- •Progressive cancer at the time of study entry
- •Patients must have evaluable disease as defined in module-specific criteria for Part A and Part B
- •Adequate organ and marrow function as defined by the protocol.
- •For Part B expansion cohorts: Provision of formalin-fixed and paraffin embedded (FFPE) tumour specimen is mandatory, where available, except if stated that it is optional in a specific Module.
- •For Part A:
- •- Patients may have received up to one prior line of therapy with a PARPi-based regimen (either as a treatment or as maintenance)
- •For Part B:
- •- Patients must not have received prior therapy with a PARPi-based regimen (either as a treatment or as maintenance).
排除标准
- •Treatment with any of the following:
- •Nitrosourea or mitomycin C within 6 weeks of the first dose of study treatment
- •Any investigational agents or study drugs from a previous clinical study within 5 half-lives or 3 weeks (whichever is shorter) of the first dose of study treatment
- •Any other chemotherapy, immunotherapy or anticancer agents within 3 weeks of the first dose of study treatment
- •Any live virus or bacterial vaccine within 28 days of the first dose of study treatment
- •Concomitant use of medications or herbal supplements known to be cytochrome P450 3A4 (CYP3A4) strong inhibitors or inducers.
- •Concomitant use of drugs that are known to prolong or shorten QT and have a known risk of Torsades de Pointes.
- •Receiving continuous corticosteroids at a dose of >10 mg prednisone/day or equivalent for any reason.
- •Major surgery within 4 weeks of the first dose of study treatment.
- •Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a limited field of radiation for palliation within 2 weeks of the first dose of study treatment.
- •Any history of persisting (> 2 weeks) severe pancytopenia due to any cause
- •Spinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring continuous corticosteroids at a dose of >10mg prednisone/day or equivalent for at least 4 weeks prior to start of study treatment. Patients with leptomeningeal carcinomatosis are excluded.
- •patient with known predisposition to bleeding (e.g., active peptic ulceration, recent [within 6 months] haemorrhagic stroke, proliferative diabetic retinopathy).
- •Cardiac conditions as defined by the clinical study protocol
- •Other cardiovascular diseases as defined by any of the following:
- •Symptomatic heart failure,
- •uncontrolled hypertension,
- •hypertensive heart disease with significant left ventricular hypertrophy
- •acute coronary syndrome (ACS)/acute myocardial infarction (AMI), unstable angina pectoris, coronary intervention procedure with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) within 6 months.
- •cardiomyopathy of any etiology
- •presence of clinically significant valvular heart disease
- •history of atrial or ventricular arrhythmia requiring treatment; subjects with atrial fibrillation and optimally controlled ventricular rate (< 100 beats per minute) are permitted.
- •subjects with atrial fibrillation and optimally controlled ventricular rate are permitted
- •transient ischaemic attack, or stroke within 6 months prior to screening
- •patients with symptomatic hypotension at screening
- •Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML).
- •Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD5305
- •Known allergy or hypersensitivity to investigational product(s) or any of the excipients of the investigational product(s).
- •Prior malignancy whose natural history, in the Investigator's opinion, has the potential to interfere with safety and efficacy assessments of the investigational regimen.
- •other module-specific criteria may apply
研究组 & 干预措施
Module 1: AZD5305 Monotherapy
Experimental
AZD5305 Monotherapy
干预措施: AZD5305 (Drug)
Module 5 AZD5305 + Datopotamab Deruxtecan
Experimental
AZD5305 + Dato-DXd
干预措施: Dato-DXd (Drug)
Module 6 AZD5305 + Camizestrant
Experimental
AZD5305 + Camizestrant
干预措施: AZD5305 (Drug)
Module 6 AZD5305 + Camizestrant
Experimental
AZD5305 + Camizestrant
干预措施: Camizestrant (Drug)
Module 3: AZD5305 + Carboplatin with or without Paclitaxel
Experimental
AZD5305 + Carboplatin with or without Paclitaxel
干预措施: AZD5305 (Drug)
Module 3: AZD5305 + Carboplatin with or without Paclitaxel
Experimental
AZD5305 + Carboplatin with or without Paclitaxel
干预措施: Carboplatin (Drug)
Module 2: AZD5305 + Paclitaxel
Experimental
AZD5305 + Paclitaxel
干预措施: AZD5305 (Drug)
Module 4: AZD5305 + Trastuzumab Deruxtecan
Experimental
AZD5305 + T- DXd
干预措施: T- Dxd (Drug)
Module 5 AZD5305 + Datopotamab Deruxtecan
Experimental
AZD5305 + Dato-DXd
干预措施: AZD5305 (Drug)
Module 4: AZD5305 + Trastuzumab Deruxtecan
Experimental
AZD5305 + T- DXd
干预措施: AZD5305 (Drug)
Module 2: AZD5305 + Paclitaxel
Experimental
AZD5305 + Paclitaxel
干预措施: Paclitaxel (Drug)
Module 3: AZD5305 + Carboplatin with or without Paclitaxel
Experimental
AZD5305 + Carboplatin with or without Paclitaxel
干预措施: Paclitaxel (Drug)
结局指标
主要结局
The number of subjects with adverse events/serious adverse events
时间窗: From time of Informed Consent to 28 + 7 days post last dose ( modules 1,2,3,5 and 6). 40+7 days post last dose for Module 4.
Number of patients with adverse events and with serious adverse events including abnormal clinical observations, abnormal ECG parameters, abnormal laboratory assessments and abnormal vital signs that changed from baseline
The number of subjects with dose-limiting toxicity (DLT), as defined in the protocol.
时间窗: From first dose of study treatment until the end of Cycle 1.
A DLT is defined as any toxicity that occurs from the first dose of study treatment (either AZD5305 or combination anti-cancer agent) up to and including the planned end of Cycle 1 (the DLT assessment period) that is assessed as unrelated to the disease or disease-related processes under investigation. DLTs occurring outside the DLT window (ie, late onset toxicities) may be defined as a DLT after consultation with the sponsor and investigators, based on the emerging safety profile.
次要结局
- Best percentage change in target lesion(From Screening to confirmed progressive disease (approximately 1 year))
- Objective Response Rate(From Screening to confirmed progressive disease (approximately 1 year))
- Duration of Response(From Screening to confirmed progressive disease (approximately 1 year))
- Progression Free Survival(From Screening to confirmed progressive disease (approximately 1 year))
- Time To Response(From Screening to confirmed progressive disease (approximately 1 year))
- Effects of AZD5305 on pH2AX (Ser139) PD biomarker(From Cycle 0 Day 1 to Cycle 1 Day 15 (approximately 21 days))
- CA125 response (ovarian cancer)(From Screening to confirmed progressive disease (approximately 1 year))
- Module 1: Area Under Curve (AUC)(At predefined intervals throughout the treatment period (approximately 12 weeks))
- Module 1: Maximum plasma concentration of the drug (Cmax)(At predefined intervals throughout the treatment period (approximately 12 weeks))
- Module 1: The time taken to reach the maximum concentration (Tmax)(At predefined intervals throughout the treatment period (approximately 12 weeks))
- Module 1 and Module 5: Objective Response Rate (prostate cancer)(From Screening to confirmed progressive disease (approximately 1 year))
- Module 1: Radiographic progression free survival (prostate cancer)(From Screening to confirmed progressive disease (approximately 1 year))
- Module 1: Proportion of subjects with ≥ 50% PSA decrease (prostate cancer)(From Screening to confirmed progressive disease (approximately 1 year))
- Module 1 : To investigate the effect of a high-fat meal on the PK of AZD5305(Cycle 0, Day 1 (C0D1), in either the "fasted" or "fed" state, followed by a single oral dose of AZD5305 in the other state for Cycle 1, Day 1 (C1D1) at least 72 hours later; 1 cycle is 28 days.)
- Module 2: Area Under Curve (AUC)(At predefined intervals throughout the treatment period (approximately 12 weeks))
- Module 2: Maximum plasma concentration of the drug (Cmax)(At predefined intervals throughout the treatment period (approximately 12 weeks))
- Module 2: The time taken to reach the maximum concentration (Tmax)(At predefined intervals throughout the treatment period (approximately 12 weeks))
- Module 3: Area Under Curve (AUC)(At predefined intervals throughout the treatment period (approximately 12 weeks))
- Module 3: Maximum plasma concentration of the drug (Cmax)(At predefined intervals throughout the treatment period (approximately 12 weeks))
- Module 3: The time taken to reach the maximum concentration (Tmax)(At predefined intervals throughout the treatment period (approximately 12 weeks))
- Module 4 : Area Under Curve(At predefined intervals throughout the treatment period (approximately 12 weeks))
- Module 4: Maximum plasma concentration of the drug (Cmax)(At predefined intervals throughout the treatment period (approximately 12 weeks))
- Module 4: The time taken to reach the maximum concentration (Tmax)(At predefined intervals throughout the treatment period (approximately 12 weeks))
- Module 4: Anti-Drug Antibody (ADA)(Samples will be collected within 1 hour before dose administration on Day 1 of Cycle 1, 2, and 4, then every 4 Cycles (each cycle is 21 days), EoT, and at safety follow-up (40 days after last dose) as per Schedule of Assessments)
- Module 4: To assess the preliminary anti-tumour activity of AZD5305 as monotherapy and in combination with T-DXd.(From screening to approximately 6 months)
- Module 5: Area Under Curve(At predefined intervals throughout the treatment period (approximately 12 weeks))
- Module 5: Maximum plasma concentration of the drug (Cmax)(At predefined intervals throughout the treatment period (approximately 12 weeks))
- Module 5: The time taken to reach the maximum concentration (Tmax)(At predefined intervals throughout the treatment period (approximately 12 weeks))
- Module 5: Anti-Drug Antibody (ADA)(Whole blood samples for determination of ADA for Dato-DXd in plasma will be collected in patients receiving Dato-DXd per the schedule specified in the SoA : Day 1 of Cycle 1, 2, 4, and 8 (each cycle is 21 days) , EoT, and then 28 day follow up visit.)
- Module 5: Premilinary anti tumour activity AZD5305 in combination with Dato-DXd(From screening to confirmed progresive disease ( approximately 12 weeks))
- Module 6: To characterise the PK of AZD5305 and camizestrant following a single dose and at steady state after multiple dosing, when given in combination.(At predefined interval throughout the treatment (approximately 12 weeks))
- Module 6: To evaluate the effect of camizestrant on the PK of AZD5305.(At predefined intervals throughout the treatment period (approximately 12 weeks))
- Module 6: To evaluate the effect of AZD5305 on the PK of Camizestrant.(At predefined intervals throughout the treatment period (approximately 12 weeks))
研究者
研究点 (68)
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