A Phase I, First-in-human, Dose Escalation Study Of [225Ac]-AZD2284 in Patients With Metastatic Castration-Resistant Prostate Cancer
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- AstraZeneca
- 入组人数
- 136
- 试验地点
- 16
- 主要终点
- Number of participants with adverse event (AEs)
研究概览
简要总结
The main purpose of the study is to assess the safety and tolerability of AZD2284, AZD2287, and AZD2275.
详细描述
This is a first-in-human, Phase I, non-randomized, open-label clinical trial designed to evaluate AZD2284, AZD2287, and AZD2275.
This trial will consist of 2 Parts:
Part A (Imaging):
- Part A (Cold Antibody Exploration): aims to determine the optimal dosing regimen, with or without unconjugated antibody (AZD2275) pre-administration to improve the biodistribution of AZD2287.
Part B (Therapeutic):
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 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Main Inclusion Criteria:
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or
- •Histologically confirmed diagnosis of adenocarcinoma of the prostate without strong clinical suspicion of majority neuroendocrine differentiation.
- •Must have had prior bilateral orchiectomy and/or ongoing androgen-deprivation therapy and a castrate level of serum/plasma testosterone (< 50 ng/dL or < 1.7 nmol/L).
- •At least one metastatic lesion present on baseline Computed Tomography (CT), Magnetic Resonance Imaging (MRI), or bone scan obtained ≤ 28 days prior to the first dose of Investigational Medicinal Product (IMP). Participants may have non-measurable lesions including bone only metastases.
- •Adequate organ function
- •Part A only: Metastatic prostate cancer considered to be stable or progressing metastatic castration resistant prostate cancer (mCRPC).
- •Part B only: Progressing mCRPC defined as meeting at least one of following documented criteria -
- •Serum/plasma PSA progression
- •Soft-tissue progression
- •Progression of bone disease
- •Part B Dose Escalation: Previously treated with at least 2 prior lines of systemic anti-cancer therapy for mCRPC. Prior lines must include:
- •At least 1 androgen receptor pathway inhibitor (ARPI)
- •A poly (adp-ribose) polymerase (PARP) inhibitor for participants with known BRCA mutation
- •A checkpoint inhibitor for participants with known microsatellite instability-high (MSI-H), deficient mismatch pair (dMMR), or tumor mutational burden (TMB) ≥ 10 mut/Mb
- •Part B Dose Expansion: Previously treated with at least 1 prior line of systemic anti-cancer therapy for mCRPC. Prior lines must include:
- •At least 1 ARPI
- •A PARP inhibitor for participants with known BRCA mutation per local practice, unless ineligible per Investigator decision.
- •A checkpoint inhibitor for participants with known MSI-H, dMMR, or TMB ≥ 10 mut/Mb.
- •No previous cytotoxic chemotherapy for CRPC. Taxanes for metastatic hormone sensitive prostate cancer (mHSPC) is acceptable if the last cycle Day 1 was > 12 months before first study treatment.
- •Previous treatment with prostate specific membrane antigen radioligand therapy (PSMA-RLT) or Radium-223 is allowed but not required. Participants who have had prior radiation therapy, including therapeutic radiopharmaceuticals, external bean radiation therapy (EBRT), and/or brachytherapy are eligible, subject to satisfying all other inclusion/
排除标准
- •. Therapeutic radiopharmaceuticals will be considered a prior line of systemic therapy.
- •Main Exclusion Criteria:
- •Treatment with any radiopharmaceutical within 6 weeks of the first dose of Investigational Medicinal Product (IMP).
- •Radiation therapy (RT) or external beam radiation therapy (EBRT) within 28 days prior to the first dose and all RT-related events have not recovered to Grade ≤
- •Administration of any systemic cytotoxic or investigational therapy ≤ 28 days of the first dose of IMP or 5 half-lives, whichever is shorter.
- •All prior treatment-related adverse events must have resolved to Grade ≤
- •Concurrent severe and/or uncontrolled illness not related to cancer and/or social situation that would limit compliance with study requirements.
- •Known or suspected allergies or contraindications to any of the investigational drugs or any component of the investigational drug formulation.
- •Clinically relevant proteinuria
- •Diffuse and intense osseous radiotracer uptake on bone scintigraphy or PSMA imaging characteristic of a superscan.
- •Chronic corticosteroid use greater than 10 mg prednisone equivalent daily.
研究组 & 干预措施
Part A: Cohort A3: AZD2275 + AZD2287 (Cold +Hot)
Participants will receive DL2 of AZD2275 followed by AZD2287. If eligible for treatment, will receive DL1 of AZD2284.
干预措施: AZD2275 (Drug)
Part A: Cohort A2: AZD2275 + AZD2287 (Cold +Hot)
Participants will receive DL1 of AZD2275 followed by AZD2287. If eligible for treatment, will receive DL1 of AZD2284.
干预措施: AZD2284 (Drug)
Part A: Cohort A3: AZD2275 + AZD2287 (Cold +Hot)
Participants will receive DL2 of AZD2275 followed by AZD2287. If eligible for treatment, will receive DL1 of AZD2284.
干预措施: AZD2287 (Drug)
Part A: Cohort A3: AZD2275 + AZD2287 (Cold +Hot)
Participants will receive DL2 of AZD2275 followed by AZD2287. If eligible for treatment, will receive DL1 of AZD2284.
干预措施: AZD2284 (Drug)
Part A: Cohort A1: AZD2287 (Hot only)
Participants will receive AZD2287. If eligible for treatment, will receive dose level (DL)1 of AZD2284.
干预措施: AZD2287 (Drug)
Part A: Cohort A1: AZD2287 (Hot only)
Participants will receive AZD2287. If eligible for treatment, will receive dose level (DL)1 of AZD2284.
干预措施: AZD2284 (Drug)
Part A: Cohort A2: AZD2275 + AZD2287 (Cold +Hot)
Participants will receive DL1 of AZD2275 followed by AZD2287. If eligible for treatment, will receive DL1 of AZD2284.
干预措施: AZD2287 (Drug)
Part A: Cohort A2: AZD2275 + AZD2287 (Cold +Hot)
Participants will receive DL1 of AZD2275 followed by AZD2287. If eligible for treatment, will receive DL1 of AZD2284.
干预措施: AZD2275 (Drug)
Part B: Cohort E1
Participants will receive dose of AZD2284 determined by the earlier results. Expansion cohort may be opened to further characterize the safety and efficacy of the dose level.
干预措施: AZD2287 (Drug)
Part B: Cohort E1
Participants will receive dose of AZD2284 determined by the earlier results. Expansion cohort may be opened to further characterize the safety and efficacy of the dose level.
干预措施: AZD2275 (Drug)
Part B: Cohort E1
Participants will receive dose of AZD2284 determined by the earlier results. Expansion cohort may be opened to further characterize the safety and efficacy of the dose level.
干预措施: AZD2284 (Drug)
Part B: Cohort E2
Participants will receive dose of AZD2284 determined by the earlier results. Expansion cohort may be opened to further characterize the safety and efficacy of the dose level.
干预措施: AZD2287 (Drug)
Part B: Cohort E2
Participants will receive dose of AZD2284 determined by the earlier results. Expansion cohort may be opened to further characterize the safety and efficacy of the dose level.
干预措施: AZD2275 (Drug)
Part B: Cohort E2
Participants will receive dose of AZD2284 determined by the earlier results. Expansion cohort may be opened to further characterize the safety and efficacy of the dose level.
干预措施: AZD2284 (Drug)
结局指标
主要结局
Number of participants with adverse event (AEs)
时间窗: Part A: From Screening (Day -28) to Day 28; Part B: Screening (Day -42 to Day -14) up to 5 years
Number of participants with Dose Limiting Toxicities (DLTs)
时间窗: Part B: Screening (Day -42 to Day -14) up to 2 cycles (84 days) of AZD2284
Estimates of residence time
时间窗: Part A: Up to Day 8 after dosing with AZD2287 on Day 1
Absorbed radiation doses for AZD2287 and AZD2284
时间窗: Part A: Up to Day 8 after dosing with AZD2287 on Day 1; Part B: Up to Day 8 after dosing with AZD2287 on Day -14
Compare organ uptake of AZD2287 with and without pre-dose administration of AZD2275
时间窗: Part A: Up to Day 8 after dosing with AZD2287 on Day 1; Part B: Up to Day 8 after dosing with AZD2287 on Day -14
Tumor uptake of AZD2287 in selected regions of interest on SPECT/CT and/or planar images
时间窗: Part A: Up to Day 8 after dosing with AZD2287 on Day 1; Part B: Up to Day 8 after dosing with AZD2287 on Day -14
次要结局
- Pharmacokinetic Clearance(Part A: Up to Day 28; Part B: Up to Cycle 2 (each cycle is 42 days))
- Overall Response Rate (ORR)(Up to 12 months after the last dose of AZD2284)
- Proportion of participants with Prostate-Specific Antigen (PSA) 50(Up to 12 months after the last dose of AZD2284)
- Proportion of participants with PSA90(Up to 12 months after the last dose of AZD2284)
- Time to maximum PSA % decline(Up to 12 months after the last dose of AZD2284)
- Duration of Response (DoR)(Up to 12 months after the last dose of AZD2284)
- Radiographic Progression Free Survival (rPFS)(Up to 12 months after the last dose of AZD2284)
- Overall Survival (OS)(Part A: Up to Day 28; Part B: Up to 5 years)
- Area under concentration-curve from time 0 to the last quantifiable concentration (AUClast)(Part A: Up to Day 28; Part B: Up to Cycle 2 (each cycle is 42 days))
- Maximum observed drug concentration (Cmax)(Part A: Up to Day 28; Part B: Up to Cycle 2 (each cycle is 42 days))
- Half-life (t1/2)(Part A: Up to Day 28; Part B: Up to Cycle 2 (each cycle is 42 days))
- Changes in plasma concentrations of AZD2287 and AZD2284 following AZD2275 pre-administration compared to AZD2287 and AZD2284 alone(Part A: Up to Day 28; Part B: Up to Cycle 2 (each cycle is 42 days))
- Number of participants with positive antidrug antibodies (ADAs)(Part A dose exploration: Up to Day 28; Part B: Up to End of Trial (approximately 1 year))