A Phase Ib/II, Open-label, Multi-centre, Platform Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of Multiple Anti-Cancer Agents in Metastatic Prostate Cancer
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- AstraZeneca
- 入组人数
- 152
- 试验地点
- 38
- 主要终点
- Part A: Number of participants with treatment-emergent adverse events (TEAEs)including serious adverse events (SAEs), treatment-related AEs (TRAEs) and adverse events of special interests (AESIs)
研究概览
简要总结
The purpose of the study is to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of multiple anti-cancer agents in participants with metastatic prostate cancer.
详细描述
This is a multicentre, open-label and platform study to evaluate multiple anti-cancer agents in participants with metastatic prostate cancer. This platform study will comprise a series of substudies. Each substudy will follow a 2-part structure (unless otherwise stated in the individual substudy):
- Part A: A dose escalation (DE) phase to identify dose limiting toxicities (DLTs), characterise safety, PK, pharmacodynamics, preliminary efficacy, and determine biologically and clinically suitable dose levels to proceed into the dose optimisation/expansion.
- Part B: A dose optimisation/expansion phase to inform recommended Phase 3 dose (RP3D), explore efficacy with Prostate-specific antigen (PSA) decrease ≥ 50% (PSA50) rate as primary endpoints, alongside continued safety monitoring.
Sub-study 1 focuses on a specific combination regimen and it will assess the safety, tolerability, PK, pharmacodynamics, and preliminary anti-tumour activity of AZD2265 (FPI-2265) actinium (225Ac) zadavotide guraxetan [hereafter referred to as AZD2265 (FPI-2265)] in combination with palacaparib (AZD9574) compared with AZD2265 (FPI-2265) monotherapy and with standard-of-care (SoC) docetaxel chemotherapy in participants with metastatic castration resistant prostate cancer (mCRPC).
研究设计
- 研究类型
- Interventional
- 分配方式
- 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 99 Years（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Participants with a diagnosis of histologically confirmed adenocarcinoma of the prostate (no small cell, neuroendocrine, sarcomatoid, spindle or signet cell).
- •Minimum life expectancy of 3 months or more.
- •Eastern Cooperative Oncology Group (ECOG) performance status of O or 1 at screening, with no deterioration.
- •PCWG3 (Prostate Cancer Working Group 3) modified RECIST Version 1.1 evaluable disease.
- •Must have received at least one novel androgen receptor pathway inhibitor (ARPI), such as enzalutamide or darolutamide or apalutamide or abiraterone acetate.
- •Must have one or more unresectable metastatic lesions.
- •Must have had prior orchiectomy and/or ongoing androgen deprivation therapy, and a castrate level of serum testosterone (<50ng/dL or <l.7nmol/L).
- •Progressive metastatic castration-resistant prostate cancer (mCRPC) following the most recent treatment at time of study entry.
- •Adequate organ and marrow function.
- •Non sterilised participants who are sexually active with a partner of childbearing potential must use a condom (plus spermicide, if available), must refrain from fathering a child, freezing or donating sperm, and it is recommended for the partner to also use a highly effective contraceptive method.
- •Inclusion Criteria for Sub study 1:
- •Must have received a single line of ARPI, such as enzalutamide, darolutamide, apalutamide or abiraterone acetate. Participants who were exposed to more than one ARPI due to toxicity or intolerance (not due to disease progression) are eligible.
- •PSMA positive mCRPC by computed tomography positron emission tomography, obtained with PSMA ligand defined as at least 1 PSMA positive metastatic lesion with tracer uptake greater than liver, and no PSMA negative lesions. All measurable or intraprostatic lesions must be PSMA positive.
- •Capable of self-administering oral formulations.
排除标准
- •Any evidence of non adenocarcinomatous forms of prostate cancer (including small cell, spindle cell, signet cell, neuroendocrine, sarcomatous).
- •Known, unresolved urinary tract obstruction.
- •Participants with a history of central nervous system metastases.
- •Symptomatic malignant spinal cord compression or findings indicative of impending cord compression.
- •Participants with a history of leptomeningeal carcinomatosis.
- •Previous or concurrent cancer distinct from the cancer under investigation in primary site or histology .
- •Concurrent serious medical conditions.
- •Previous history of interstitial lung disease or non-infectious pneumonitis.
- •Participants with a history or clinical/laboratory features suggestive of myelodysplastic syndrome or acute myeloid leukaemia.
- •Persistent toxicities caused by previous therapy.
- •Participants unable to swallow orally administered medications or with gastrointestinal disorders likely to interfere with absorption.
- •Active infection, including tuberculosis, hepatitis C virus, and hepatitis B virus infection.
- •Known hypersensitivity to study intervention or any of their excipients.
- •Exclusion Criteria for Sub study 1:
- •History of uncontrolled seizures or requirement for >2 antiepileptic drugs.
- •History of severe brain injury or stroke.
- •Skeletal metastases demonstrating a superscan appearance on bone scan.
- •Participants have received prior therapy with palacaparib (AZD9574) or more than 1 prior line of any other Poly-ADP-ribose polymerase inhibitor (PARPi)-based regimen (either as a treatment or as maintenance).
研究组 & 干预措施
Sub study 1 Part A (SS1A): escalating dose levels of AZD9574 in combination with AZD2265 (FPI-2265)
Participants will receive escalating dose levels of AZD9574 once daily in combination with AZD2265 (FPI-2265) once every 6 weeks (Q6W).
干预措施: AZD9574 (Drug)
Sub study 1 Part B (SS1B): selected dose of AZD9574 in combination with AZD2265 (FPI-2265)
Participants will receive AZD9574 chosen from the DE phase once daily in combination with AZD2265 (FPI-2265) Q6W.
干预措施: AZD9574 (Drug)
SS1B: Docetaxel
Participants will receive docetaxel as a standard of care (SoC) once every 3 weeks (Q3W).
干预措施: Docetaxel (Drug)
Sub study 1 Part A (SS1A): escalating dose levels of AZD9574 in combination with AZD2265 (FPI-2265)
Participants will receive escalating dose levels of AZD9574 once daily in combination with AZD2265 (FPI-2265) once every 6 weeks (Q6W).
干预措施: AZD2265 (FPI-2265) (Drug)
Sub study 1 Part A (SS1A): escalating dose levels of AZD9574 in combination with AZD2265 (FPI-2265)
Participants will receive escalating dose levels of AZD9574 once daily in combination with AZD2265 (FPI-2265) once every 6 weeks (Q6W).
干预措施: AZD2287 (Imaging agent) (Drug)
Sub study 1 Part B (SS1B): selected dose of AZD9574 in combination with AZD2265 (FPI-2265)
Participants will receive AZD9574 chosen from the DE phase once daily in combination with AZD2265 (FPI-2265) Q6W.
干预措施: AZD2265 (FPI-2265) (Drug)
Sub study 1 Part B (SS1B): selected dose of AZD9574 in combination with AZD2265 (FPI-2265)
Participants will receive AZD9574 chosen from the DE phase once daily in combination with AZD2265 (FPI-2265) Q6W.
干预措施: AZD2287 (Imaging agent) (Drug)
SS1B: AZD2265 (FPI-2265) monotherapy
Participants will receive AZD2265 (FPI-2265) monotherapy Q6W.
干预措施: AZD2265 (FPI-2265) (Drug)
SS1B: Docetaxel
Participants will receive docetaxel as a standard of care (SoC) once every 3 weeks (Q3W).
干预措施: AZD2287 (Imaging agent) (Drug)
SS1B: AZD2265 (FPI-2265) monotherapy
Participants will receive AZD2265 (FPI-2265) monotherapy Q6W.
干预措施: AZD2287 (Imaging agent) (Drug)
结局指标
主要结局
Part A: Number of participants with treatment-emergent adverse events (TEAEs)including serious adverse events (SAEs), treatment-related AEs (TRAEs) and adverse events of special interests (AESIs)
时间窗: Up to approximately 1 year after last dose
To assess the safety and tolerability of palacaparib (AZD9574) in combination with AZD2265 (FPI-2265).
Part A: Number of participants with dose limiting toxicities (DLTs)
时间窗: From date of first dose up to approximately 2 cycles (up to 3 months)
To assess the safety and tolerability, and characterise the DLTs of palacaparib (AZD9574) in combination with AZD2265 (FPI-2265).
Part B: Number of participants with TEAEs
时间窗: Up to approximately 1 year after last dose
To further assess the safety and tolerability, and determine the recommended Phase 3 dose (RP3D) of palacaparib (AZD9574) in combination with AZD2265 (FPI-2265).
Part B: Prostate Specific Antigen 50 (PSA50) response rate
时间窗: Up to 3 years 4 months
PSA50 response rate is defined as proportion of participants achieving a ≥ 50% decrease in PSA from baseline to the lowest post-baseline PSA result, confirmed by a second consecutive PSA assessment at least 3 weeks later, and occurring prior to confirmed PSA progression. PSA50 will be assessed to check the anti-tumour activity of palacaparib (AZD9574) in combination with AZD2265 (FPI-2265).
次要结局
- Part A and Part B: Plasma concentration of AZD9574(From Cycle 1 Day 1 to Cycle 2 Day 15 (each cycle will be 42 days))
- Part A and Part B: Change from baseline in study-specific biomarker XYZ in response to treatment(Up to 3 years 4 months)
- Part A and Part B: PSA50 response rate(Up to 3 years 4 months)
- Part A and Part B: Prostate Specific Antigen 90 (PSA90) response rate(Up to 3 years 4 months)
- Part A and Part B: Plasma concentration of AZD2265 (FPI-2265)(From Cycle 1 Day 1 to Cycle 2 Day 1 (each cycle will be 42 days))
- Part A and Part B: Time to PSA50 (TTPSA50) response(Up to 3 years 4 months)
- Part A and Part B: Time to PSA90 (TTPSA90) response(Up to 3 years 4 months)
- Part A and Part B: Duration of PSA50 (DoPSA50) response(Up to 3 years 4 months)
- Part A and Part B: Duration of PSA90 (DoPSA90) response(Up to 3 years 4 months)
- Part A: Disease control rate (DCR)(From Day 1 to 3 years 4 months)
- Part A and Part B: Time to PSA progression(Up to 3 years 4 months)
- Part A and Part B: PSA over time(Up to 3 years 4 months)
- Part A and Part B: Radiographic Progression-free survival (rPFS)(From Day 1 to 3 years 4 months)
- Part A and Part B: Overall Response Rate (ORR)(From Day 1 to 3 years 4 months)
- Part A and Part B: Best Overall Response (BOR)(From Day 1 to 3 years 4 months)
- Part A and Part B: Duration of response (DoR)(From Day 1 to 3 years 4 months)
- Part A and Part B: Time to Response (TTR)(From Day 1 to 3 years 4 months)
- Part A and Part B: Percentage change in tumour size(From Day 1 to 3 years 4 months)
- Part A and Part B: Area under the concentration time curve (AUC)(From Cycle 1 Day 1 to Cycle 2 Day 15 (each cycle will be 42 days))
- Part A and Part B: Maximum observed drug concentration (Cmax)(From Cycle 1 Day 1 to Cycle 2 Day 15 (each cycle will be 42 days))
- Part A and Part B: Time to reach Cmax (tmax)(From Cycle 1 Day 1 to Cycle 2 Day 15 (each cycle will be 42 days))
- Part A and Part B: Terminal elimination half-life (t½λz)(From Cycle 1 Day 1 to Cycle 2 Day 15 (each cycle will be 42 days))
- Part A and Part B: Change from baseline in study-specific biomarker ABC in response to treatment(Up to 3 years 4 months)
- Part A and Part B: Plasma concentration of palacaparib (AZD9574)(From Cycle 1 Day 1 to Cycle 2 Day 15 (each cycle will be 42 days))