An Open-label, Randomized, Phase III Study Comparing 177Lu-PSMA-617 in Combination With Standard of Care, Versus Standard of Care Alone, in Adult Male Patients With Metastatic Hormone Sensitive Prostate Cancer (mHSPC)
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 1,140
- 试验地点
- 210
- 主要终点
- Radiographic Progression Free Survival (rPFS)
研究概览
简要总结
The purpose of this study is to evaluate the efficacy and safety of 177Lu-PSMA-617 in combination with Standard of Care (SOC), versus Standard of Care alone, in adult male patients with Metastatic hormone sensitive prostate cancer (mHSPC). In this study, the SoC is defined as a combination of Androgen Receptor Directed Therapy + Androgen Deprivation Therapy. Approximately 1126 patients will be randomized in this study. As of 31-Jan-2024, 1144 participants were enrolled in 20 countries.
详细描述
In this international, open-label, prospective, phase III study, where approximately 1126 patients with treatment naïve or minimally treated PSMA-positive mHSPC were to be randomized in a 1:1 ratio to receive Standard of Care (SoC) with or without the radioligand 177Lu-PSMA-617.
The primary objective of the study was to determine whether the combination of 177Lu-PSMA-617 + SoC improved radiographic progression free survival (rPFS) over that obtained by administration of SoC alone in mHSPC patients.
The randomization was stratified according to the following three factors: disease volume (high v low), age >= 70 years (yes/no), and on Previous or planned treatment (prostatectomy or radiation) to primary (prostate) tumor (yes/no).
Study duration: approximately 50 months. screening period: after signing ICF, patients were assessed for eligibility and were scanned with 68Ga PSMA-11 to identify PSMA expression status. Following completion of all required screening procedures and verifying participant eligibility, the participant was randomized via the interactive response technology (IRT) system.
Amended protocol v02 included an option for participants to be enrolled into a separate long-term safety follow-up study, and China extension cohort (40 to 60 participants). Amended protocol v03 excluded China extension cohort and added a second 68Ga-PSMA-11 PET/CT scan at rPD.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Participants eligible for inclusion in this study must meet all of the following criteria:
- •Signed informed consent must be obtained prior to participation in the study
- •Patients must be adults ≥18 years of age
- •Patients must have an ECOG performance status of 0 to 2
- •Patients must have a life expectancy >9 months as determined by the study investigator
- •Patients must have metastatic prostate cancer with histologically or cytologically confirmed adenocarcinoma (current or prior biopsy of the prostate and/or metastatic site)
- •Patients must have evidence of PSMA-positive disease as seen on a 68Ga-PSMA-11 PET/CT scan, and eligible as determined by the sponsor's central reader
- •Patients must have at least one documented metastatic bone and/or soft tissue/visceral lesion documented in the following manners within 28 days prior randomization:
- •Metastatic disease to the bone (in any distribution) visible on 99Tc-MDP bone scintigraphy on either pre-ADT scans or baseline scans AND/OR
- •Lymph node metastases of any size or distribution. If lymph nodes are the only site of metastasis, then at least one must be at least 1.5 cm in short axis AND outside of the pelvis AND/OR
- •Visceral metastases of any size or distribution. If a participant has a history of visceral metastases at any time prior to randomization, he should be coded as having visceral metastases at baseline (i.e., patients with visceral metastases prior to ADT that disappear at baseline will be counted as having visceral metastases and would therefore have high volume disease for stratification purposes).
- •Patients must have adequate organ function:
- •Bone marrow reserve ANC ≥1.5 x 109/L Platelets ≥100 x 109/L Hemoglobin ≥9 g/dL
- •Hepatic Total bilirubin ≤2 x the institutional upper limit of normal (ULN). For patients with known Gilbert's Syndrome ≤3 x ULN is permitted Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3.0 x ULN OR ≤5.0 x ULN for patients with liver metastases
- •Renal eGFR ≥ 50 mL/min/1.73m2 using the Modification of Diet in Renal Disease (MDRD) equation
- •Albumin ≥2.5 g/dL
- •Human immunodeficiency virus (HIV)-infected patients who are healthy and have a low risk of acquired immune deficiency syndrome (AIDS)-related outcomes can participate in this trial
- •Patients must be:
- •Treatment naïve OR minimally treated with:
- •Up to 45 days of luteinizing hormone-releasing hormone (LHRH) agonist /antagonists or bilateral orchiectomy with or without first generation anti-androgen (e.g. bicalutamide, flutamide) for metastatic prostate cancer is allowed prior to ICF signature. If given, first generation anti-androgen must be discontinued prior to start of study therapy or after 45 days whatever happens first.
- •If received, prior LHRH agonist/antagonist with or without first generation anti-androgen use in the adjuvant/neo-adjuvant setting must have been discontinued > 12 months prior to ICF signature AND must not have exceeded 24 months of therapy AND must not have shown disease progression within 12 months of completing adjuvant/neo-adjuvant therapy.
- •Up to 45 days of CYP17 inhibitor or ARDT exposure for metastatic prostate cancer is allowed prior to ICF signature. No CYP17 inhibitor or ARDT exposure for earlier stages of prostate cancer is allowed.
排除标准
- •Participants meeting any of the following criteria are not eligible for inclusion in this study.
- •Participants with rapidly progressing tumor that requires urgent exposure to taxane-based chemotherapy
- •Any prior systemic anti-prostate cancer therapy (with the exception of the drugs listed on inclusion criteria 11), including chemotherapy, Poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors, immunotherapy or biological therapy (including monoclonal antibodies).
- •Concurrent cytotoxicity chemotherapy, immunotherapy, radioligand therapy, PARP inhibitor, biological therapy or investigational therapy
- •Previous treatment with any of the following within 6 months of randomization: Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223, hemi-body irradiation. Previous PSMA-targeted radioligand therapy is not allowed
- •Ongoing participation in any other clinical trial
- •Use of other investigational drugs within 30 days prior to day of randomization
- •Known hypersensitivity to any of the study treatments or its excipients or to drugs of similar chemical classes
- •Transfusion for the sole purpose of making a participant eligible for study inclusion
- •Participants with CNS metastases that are neurologically unstable, symptomatic, or receiving corticosteroids for the purpose of maintaining neurologic integrity. Participants with epidural disease, canal disease and prior cord involvement are allowed if those areas have been treated, are stable, and not neurologically impaired. Participants with parenchymal CNS metastasis (or a history of CNS metastasis), that have received prior therapy and are neurologically stable, asymptomatic and not receiving steroids for CNS metastases, are allowed, baseline and subsequent radiological imaging must include evaluation of the brain (magnetic resonance imaging (MRI) preferred or CT with contrast).
- •Diagnosed with other malignancies that are expected to alter life expectancy or may interfere with disease assessment. However, participants with a prior history of malignancy that has been adequately treated and who have been disease free, treatment free for more than 3 years prior to randomization, or participants with adequately treated non-melanoma skin cancer, superficial bladder cancer are eligible.
- •Concurrent serious (as determined by the Principal Investigator) medical conditions, including, but not limited to, uncontrolled infection, known active hepatitis B or C, or other significant co-morbid conditions that in the opinion of the investigator would impair study participation or cooperation. Participants with an active documented COVID-19 infection (any grade of disease severity) at time of informed consent may be included only when completely recovered (in accordance with local guidance).
- •Active clinically significant cardiac disease defined as any of the following:
- •NYHA class 3/4 congestive heart failure within 6 months prior to ICF signature unless treated with improvement and echocardiogram or MUGA demonstrates EF > 45% with improvement in symptoms to class <
- •History or current diagnosis of ECG abnormalities indicating significant risk of safety for participants in the study such as: Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular tachycardia, complete left bundle branch block, high-grade atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II and third degree AV block)
- •History of familial long QT syndrome or known family history of Torsades de Pointes
- •Cardiac or cardiac repolarization abnormality, including any of the following: History of myocardial infarction (MI), angina pectoris, or coronary artery bypass graft (CABG) within 6 months prior to ICF signature
- •History of somatic or psychiatric disease/condition that may interfere with the objectives and assessments of the study
- •Symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression
- •Any condition that precludes raised arms position
- •Unmanageable concurrent bladder outflow obstruction or urinary incontinence. Note: participants with bladder outflow obstruction or urinary incontinence, which is manageable and controlled with best available standard of care (incl. pads, drainage) are allowed.
- •Sexually active males unwilling to use a condom during intercourse while taking study treatment and for 14 weeks after stopping study treatment. A condom is required for all sexually active male participants to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, male participants must not donate sperm for the time period specified above. If local regulations deviate from the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the ICF
研究组 & 干预措施
Standard of Care
For participants randomized to Standard of Care arm, ARDT +ADT is considered as SOC and treatment will be administered per the physician's order
干预措施: ARDT (Drug)
177Lu-PSMA-617
Participant will receive 7.4 GBq (+/- 10%) 177Lu-PSMA-617, once every 6 weeks (+/- 1 week) for a planned 6 cycles, in addition to the Standard of Care (SOC); Androgen receptor-directed therapy (ARDT) + Androgen deprivation therapy (ADT) is considered as SOC and treatment will be administered per the physician's order
干预措施: ARDT (Drug)
177Lu-PSMA-617
Participant will receive 7.4 GBq (+/- 10%) 177Lu-PSMA-617, once every 6 weeks (+/- 1 week) for a planned 6 cycles, in addition to the Standard of Care (SOC); Androgen receptor-directed therapy (ARDT) + Androgen deprivation therapy (ADT) is considered as SOC and treatment will be administered per the physician's order
干预措施: ADT (Drug)
Standard of Care
For participants randomized to Standard of Care arm, ARDT +ADT is considered as SOC and treatment will be administered per the physician's order
干预措施: ADT (Drug)
177Lu-PSMA-617
Participant will receive 7.4 GBq (+/- 10%) 177Lu-PSMA-617, once every 6 weeks (+/- 1 week) for a planned 6 cycles, in addition to the Standard of Care (SOC); Androgen receptor-directed therapy (ARDT) + Androgen deprivation therapy (ADT) is considered as SOC and treatment will be administered per the physician's order
干预措施: 68Ga-PSMA-11 (Drug)
177Lu-PSMA-617
Participant will receive 7.4 GBq (+/- 10%) 177Lu-PSMA-617, once every 6 weeks (+/- 1 week) for a planned 6 cycles, in addition to the Standard of Care (SOC); Androgen receptor-directed therapy (ARDT) + Androgen deprivation therapy (ADT) is considered as SOC and treatment will be administered per the physician's order
干预措施: 177Lu-PSMA-617 (Drug)
Standard of Care
For participants randomized to Standard of Care arm, ARDT +ADT is considered as SOC and treatment will be administered per the physician's order
干预措施: 68Ga-PSMA-11 (Drug)
结局指标
主要结局
Radiographic Progression Free Survival (rPFS)
时间窗: From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 50 months (estimated final OS analysis)
rPFS is defined as the time of radiographic progression by Prostate Cancer Working Group 3 (PCWG3)-modified RECIST V1.1 as assessed by blinded independent central review, or death
次要结局
- Overall Survival (OS) (Key Secondary Endpoint)(From date of randomization until date of death from any cause, assessed up to 50 months (estimated final OS analysis))
- Overall Response Rate (ORR)(From date of randomization till 30 days safety fup, assessed up to 50 months (estimated final OS analysis))
- Duration of Response (DOR)(From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to 50 months (estimated final OS analysis))
- Time to Response (TTR)(From date of randomization till 30 days safety fup, assessed up to 50 months (estimated final OS analysis))
- Number of participants with Treatment Emergent Adverse Events(From randomization till 30 days safety follow-up, assessed up to 50 months (estimated final OS analysis))
- time to development of mCRPC(From date of randomization till End Of Treatment (EOT) or death, which ever happen first, assessed up to 50 months (estimated final OS analysis))
- Progression Free Survival (PFS)(From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to 50 months (estimated final OS analysis))
- second Progression Free Survival (PFS2)(From date of randomization until date of second progression or date of death from any cause, whichever comes first, assessed up to 50 months (estimated final OS analysis))
- Change in nadir level of PSA lower than 0.2 ng/ml(From date of randomization till 30 days safety fup, whichever occur first, assessed up to 50 months (estimated final OS analysis))
- Time to radiographic soft tissue progression (TTSTP)(From date of randomization until date of soft tissue radiographic progression or date of death from any cause, whichever comes first, assessed up to 50 months (estimated final OS analysis))
- Time to first symptomatic skeletal event (SSE).(From date of randomization till EOT or death, whichever happens first, assessed up to 50 months (estimated final OS analysis))
- Prostate-specific antigen 90 (PSA90) response(From date of randomization till 30 days safety fup, assessed up to 50 months (estimated final OS analysis))
- Disease Control Rate (DCR)(From date of randomization till 30 days safety fup, assessed up to 50 months (estimated final OS analysis))
- European Quality of Life ( EuroQoL) -5 Domain 5 Level Scale (EQ-5D-5L)(From screening up till 30 day safety follow-up or week 48 of long term follow up for patient prematurely discontinued, assessed up to 50 months (estimated final OS analysis))
- Functional Assessment of Cancer Therapy - Prostate (FACT-P) Questionnaire(From randomization up till 30 day safety Follow-up or week 48 of long term Follow-up for patients prematurely discontinued, assessed up to 50 months (estimated final OS analysis))
- Brief Pain Inventory-short Form (PBI-SF)(From screening up till 30 day safety follow-up or week 48 of long term follow up for patient prematurely discontinued, assessed up to 50 months (estimated final OS analysis))