Combination of Radium-223 and Lutetium-177 PSMA-I&T in Men with Metastatic Castration-Resistant Prostate Cancer
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 36
- 试验地点
- 1
- 主要终点
- Recommended Phase 2 Dose (RP2D)
研究概览
简要总结
This clinical trial will evaluate the safety of Radium-223 in combination with 177Lu-PSMA-I&T in metastatic castration-resistant prostate cancer: Phase I/II study
详细描述
This prospective, single-centre, single-arm, open label, phase I/II trial will assess and establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and recommended phase 2 dose (RP2D) of Radium-223 in combination with 177Lu-PSMA-I&T in patients with mCRPC.
36 men with mCRPC who have progressed on second-generation AR antagonist will be enrolled in this trial in two stages: dose escalation and a dose expansion phase over a period of 24 months.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 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
- Male
- 接受健康志愿者
- 否
入选标准
- •Patient must be ≥ 18 years of age and must have provided written informed consent.
- •Histologically or cytologically confirmed adenocarcinoma of the prostate, OR unequivocal diagnosis of metastatic prostate cancer. (i.e. involving bone or pelvic lymph nodes or para-aortic lymph nodes) with an elevated serum PSA.
- •Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
- •Patients must have progressed on ≥ 1 second-generation AR-targeted agent (e.g., enzalutamide, abiraterone, apalutamide, or darolutamide).
- •Patients must have progressive disease for study entry. PCWG3 defines this as any one of the following:
- •PSA progression: minimum of two rising PSA values from a baseline measurement with an interval of ≥ 1 week between each measurement.
- •Soft tissue progression as per RECIST 1.1 criteria
- •Bone progression: ≥ 2 new lesions on bone scan
- •Symptomatic progression eg. Bone pain
- •At least three weeks since receiving anti-cancer treatment (other than ADT), the completion of surgery or radiotherapy prior to registration.
- •Prior surgical orchiectomy or chemical castration maintained on luteinizing hormone-releasing hormone (LHRH) analogue (agonist or antagonist).
- •Serum testosterone levels ≤ 1.75nmol/L (≤ 50ng/dL) within 28 days before registration.
- •Significant PSMA avidity on PSMA PET/CT, defined as a minimum uptake of SUVmax 20 at a site of disease, and SUVmax >10 at sites of measurable disease >10mm (unless subject to factors explaining a lower uptake, e.g. respiratory motion, reconstruction artefact).
- •≥ 2 bone metastases must be present on bone scintigraphy which have not been previously treated with radiotherapy.
- •No contraindication to treatment with a bone antiresorptive agent such as denosumab or zoledronic acid.
- •Patients must have adequate bone marrow, hepatic and renal function documented within 28 days prior to registration, defined as:
- •Haemoglobin ≥ 90 g/L independent of transfusions (no red blood cell transfusion in last four weeks)
- •Absolute neutrophil count ≥ 1.5x10^9/L
- •Platelets ≥ 150 x10^9/L
- •Total bilirubin ≤ 1.5 x upper limit of normal (ULN) except for patients with known Gilbert's syndrome, where this applies for the unconjugated bilirubin component.
- •Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN if there is no evidence of liver metastasis or ≤ 5 x ULN in the presence of liver metastases
- •Albumin ≥ 25 g/L
- •Adequate renal function: patients must have a creatinine clearance estimated of ≥ 40 mL/min using the Cockcroft Gault equation
- •Sexually active patients are willing to use medically acceptable forms of barrier contraception.
- •Willing to undergo biopsies, if disease is considered accessible and biopsy is feasible.
- •Willing and able to comply with all study requirements, including all treatments and the timing and nature of all required assessments.
排除标准
- •Patients who meet any of the following criteria will be excluded from study entry:
- •Superscan on Bone scan (WBBS) or diffuse marrow involvement on PSMA PET/CT
- •Prior treatment with 223Ra or 177Lu-PSMA.
- •Has received more than one previous line of chemotherapy for the treatment of metastatic prostate cancer.
- •Sites of discordant FDG-positive disease defined by minimal PSMA-expression and no uptake on WBBS (for bone metastases).
- •Other malignancies within the previous 2 years other than basal cell or squamous cell carcinomas of skin or other cancers that are unlikely to recur within 24 months.
- •Symptomatic brain metastases or leptomeningeal metastases.
- •Patients with symptomatic or impending cord compression unless appropriately treated beforehand and clinically stable for ≥ four weeks.
- •Concurrent illness, including severe infection that may jeopardise the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety.
研究组 & 干预措施
Radium-223 and Lutetium-177 PSMA-I&T
In this single-arm study, patients will receive 7.4 GBq of 177Lu-PSMA-I&T on Day 1 of every 6 week Cycle. Radium-223 will be administered concurrently every 6 weeks. The dose of Radium-223 will vary in dose-escalation. Up to 6 Cycles will be given.
干预措施: Lutetium-177 PSMA-I&T (Drug)
Radium-223 and Lutetium-177 PSMA-I&T
In this single-arm study, patients will receive 7.4 GBq of 177Lu-PSMA-I&T on Day 1 of every 6 week Cycle. Radium-223 will be administered concurrently every 6 weeks. The dose of Radium-223 will vary in dose-escalation. Up to 6 Cycles will be given.
干预措施: Radium-223 (Drug)
结局指标
主要结局
Recommended Phase 2 Dose (RP2D)
时间窗: Up to 30 months from the time the first patient is recruited.
After the MTD is established, additional patients will be treated at the MTD. Safety and efficacy data from the study will be used to define the RP2D.
Dose Limiting toxicities (DLTs)
时间窗: Dose escalation phase is expected to be completed 6 months from the time the first patient is recruited.
A DLT is defined as a toxicity that prevents further administration of the trial treatment at that dose level. Each cohort of 3 patients be assessed for DLTs in the first 6 weeks (cycle 1) of treatment and a dose for the next cohort will be determined.
Maximum Tolerated dose (MTD)
时间窗: Dose escalation phase is expected to be completed 6 months from the time the first patient is recruited.
The MTD is defined as the highest dose level at which the incidence of DLT was less than 2/6.
50% Prostate-Specific Antigen Response Rate (PSA-RR)
时间窗: Through study completion, up until 12 months after the last patient commences treatment
PSA will be assessed at baseline and every 3 weeks from cycle 1 day 1. PSA response will be defined as a 50% or greater decrease in PSA from baseline to the lowest post-baseline PSA result. A second consecutive value obtained 3 or more weeks later is required to confirm the PSA response.
次要结局
- Radiographic Progression-Free Survival (rPFS)(Through study completion, up until 12 months after the last patient commences treatment)
- Describe pain within 12 months of treatment commencement(Through completion of 12 months after treatment commencement of last patient)
- Describe health-related QoL within 12 months of treatment commencement(Through completion of 12 months after treatment commencement of last patient)
- Adverse Events and Serious Adverse Events measured using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0(Through study completion, up until 12 months after the last patient commences treatment)
- PSA progression free survival (PSA-PFS)(Through study completion, up until 12 months after the last patient commences treatment)
- Progression Free Survival (PFS)(Through study completion, up until 12 months after the last patient commences treatment)
- Overall survival (OS)(Through study completion, up until 12 months after the last patient commences treatment)
- Objective response rate (ORR) by RECIST1.1 in patients with measurable disease(Through study completion, up until 12 months after the last patient commences treatment)