Phase III Randomized Study of 177Lu-PSMA-617 with Standard of Care vs. Standard of Care in Metastatic Hormone-Sensitive Prostate Cancer
- Trial ID
- 2023-507970-42-00
- Protocol
- CAAA617C12301
- Sponsor
- Novartis Pharma AG
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate **radiographic progression-free survival** (rPFS) in patients with PSMA-positive metastatic hormone-sensitive prostate cancer (mHSPC) who are receiving Standard of Care in combination with 177Lu-PSMA-617, compared to those receiving Standard of Care alone. This objective is clinically relevant as it aims to determine the efficacy of adding 177Lu-PSMA-617 to the treatment regimen, potentially improving patient outcomes by delaying disease progression.
Secondary objectives include:
- Evaluating the contribution of 177Lu-PSMA-617 to Standard of Care in terms of overall survival (OS) in patients with mHSPC.
- Assessing PSA90 response at 12, 24, and 48 weeks.
- Evaluating the time to development of metastatic castration-resistant prostate cancer (mCRPC) as determined by investigators.
- Assessing Progression-Free Survival (PFS) by investigator.
- Evaluating the second Progression-Free Survival (PFS2) by investigator.
- Assessing the change in the nadir levels of PSA < 0.2 ng/mL at months 12, 24, and 48 weeks.
- Evaluating the overall response rate (ORR), disease control rate (DCR), time to response (TTR), duration of response (DOR), and time to soft tissue progression (TTSTP) based on Prostate Cancer Working Group 3 (PCWG3)-modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by Blinded Independent Review Committee (BIRC) assessment.
- Evaluating the safety and tolerability of 177Lu-PSMA-617.
- Assessing the effect of 177Lu-PSMA-617 on health-related quality of life (HRQoL).
- Evaluating the time to first symptomatic skeletal event (SSE).
Participants
The clinical trial involves a total of **699 participants** diagnosed with **PSMA-positive metastatic hormone-sensitive prostate cancer (mHSPC)**. The study population is exclusively male, with an age range of **18 years and older**. Participants were selected based on specific inclusion criteria, including a confirmed diagnosis of metastatic prostate cancer with histologically or cytologically confirmed adenocarcinoma, and evidence of PSMA-positive disease as seen on a 68Ga-PSMA-11 PET/CT scan. The trial does not include a vulnerable population. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 and a life expectancy greater than 9 months. They must also demonstrate adequate organ function, including bone marrow reserve, hepatic, and renal function. Lifestyle considerations such as diet and physical activity are not specified in the trial data. The selection criteria ensure that participants are treatment-naïve or minimally treated, with specific allowances for prior therapies under defined conditions. The trial does not include female subjects, and no information is provided regarding the general health status beyond the specified criteria.
Plans and Procedures
The clinical trial is designed as an **open-label**, randomized, Phase III study aimed at evaluating the efficacy of **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)**. The primary objective is to assess radiographic progression-free survival (rPFS) as evaluated by a Blinded Independent Review Committee (BIRC). The trial is expected to run from June 2021 to February 2026, with participant involvement lasting up to 36 months.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and evidence of PSMA-positive disease. Following randomization, participants will receive either the investigational treatment or standard care. Regular follow-up visits will be scheduled to monitor safety, efficacy, and disease progression. These visits will include assessments such as imaging studies, laboratory tests, and clinical evaluations. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.
Participants are expected to remain in the study for the full duration unless specific conditions necessitate early withdrawal. These conditions include significant adverse events, disease progression, or withdrawal of consent. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results, contributing valuable data to the understanding and treatment of mHSPC.
Treatment
The clinical trial involves the administration of **Pluvicto** (lutetium (177Lu) vipivotide tetraxetan), a radiopharmaceutical preparation provided as a solution for injection/infusion. The maximum daily dose is 7.4 GBq, with a total dose not exceeding 44.4 GBq. The treatment is administered intravenously over a maximum period of 36 weeks. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.
**Locametz** (gozetotide) is another investigational product used in this trial. It is provided as a kit for radiopharmaceutical preparation, specifically a solution for injection. The maximum daily and total dose is 150 MBq, administered intravenously. The treatment period is limited to a single day, and compliance is ensured through direct supervision during administration.
**Flutamide** is included as an auxiliary treatment in the trial. It is provided in a pharmaceutical form coded as PHF00245MIG, with an unknown route of administration. The treatment period extends up to 106 weeks, with compliance monitored through regular follow-ups and assessments.
**Apalutamide** is also used as an auxiliary treatment, provided in a pharmaceutical form coded as PHF00082MIG. The route of administration is unspecified, and the treatment period can last up to 106 weeks. Participant adherence is monitored through scheduled visits and assessments.
**Relugolix** is administered as an auxiliary treatment in a pharmaceutical form coded as PHF00082MIG. The route of administration is not specified, and the treatment period is up to 60 weeks. Compliance is monitored through regular clinical evaluations.
**Darolutamide** is included as an auxiliary treatment, provided in a pharmaceutical form coded as PHF00082MIG. The route of administration is unspecified, with a treatment period extending up to 106 weeks. Participant adherence is monitored through routine clinical assessments.
**Buserelin acetate** is administered as an auxiliary treatment in a pharmaceutical form coded as PHF00148MIG. The route of administration is not specified, and the treatment period is up to 60 weeks. Compliance is monitored through regular clinical evaluations.
**Leuprorelin acetate** is included as an auxiliary treatment, provided in a pharmaceutical form coded as PHF00231MIG. The route of administration is unspecified, with a treatment period extending up to 60 weeks. Participant adherence is monitored through routine clinical assessments.
**Triptorelin acetate** is administered as an auxiliary treatment in a pharmaceutical form coded as PHF00231MIG. The route of administration is not specified, and the treatment period is up to 60 weeks. Compliance is monitored through regular clinical evaluations.
**Enzalutamide** is included as an auxiliary treatment, provided in a pharmaceutical form coded as PHF00007MIG. The route of administration is unspecified, with a treatment period extending up to 106 weeks. Participant adherence is monitored through routine clinical assessments.
**Abiraterone** is administered as an auxiliary treatment in a pharmaceutical form coded as PHF00245MIG. The route of administration is not specified, and the treatment period is up to 60 weeks. Compliance is monitored through regular clinical evaluations.
**Goserelin acetate** is included as an auxiliary treatment, provided in a pharmaceutical form coded as PHF00104MIG. The route of administration is unspecified, with a treatment period extending up to 60 weeks. Participant adherence is monitored through routine clinical assessments.
**Degarelix** is administered as an auxiliary treatment in a pharmaceutical form coded as PHF00231MIG. The route of administration is not specified, and the treatment period is up to 60 weeks. Compliance is monitored through regular clinical evaluations.
**Bicalutamide** is included as an auxiliary treatment, provided in a pharmaceutical form coded as PHF00009MIG. The route of administration is unspecified, with a treatment period extending up to 106 weeks. Participant adherence is monitored through routine clinical assessments.
**Nilutamide** is administered as an auxiliary treatment in a pharmaceutical form coded as PHF00245MIG. The route of administration is not specified, and the treatment period is up to 106 weeks. Compliance is monitored through regular clinical evaluations.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the evaluation of **radiographic progression-free survival (rPFS)**. This parameter is defined as the time from the date of randomization to the date of first documented radiographic disease progression or death due to any cause, as assessed by a Blinded Independent Review Committee (BIRC) following the Prostate Cancer Working Group 3 (PCWG3) Guidelines. Secondary endpoints include overall survival, which measures the time from randomization to death from any cause, and PSA90 response, defined as the proportion of patients achieving a ≥90% decrease in PSA from baseline confirmed by a subsequent measurement at least four weeks later. Additional secondary endpoints include time to development of metastatic castration-resistant prostate cancer (mCRPC), progression-free survival (PFS), and PFS2, which considers progression on next-line therapy or death.
Other efficacy parameters include the proportion of patients with PSA levels below 0.2 ng/mL at specified timepoints (12, 24, and 48 weeks), and various response rates such as overall response rate (ORR), disease control rate (DCR), time to response (TTR), duration of response (DOR), and time to symptomatic skeletal events (TTSSE). Safety and tolerability will also be evaluated through the incidence and severity of adverse events (AEs) and serious adverse events (SAEs), as well as changes in laboratory values, vital signs, and ECGs. Health-related quality of life (HRQoL) will be assessed using the Functional Assessment of Cancer Therapy Prostate (FACT-P), Brief Pain Inventory Short Form (BPI-SF), and the European Quality of Life 5 Domain 5 Level scale (EQ-5D-5L).
Inclusion and Exclusion Criteria
Inclusion 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 metastatic bone and/or soft tissue/visceral lesion documented in the following manners within 28 days prior randomization: a. Metastatic disease to the bone (in any distribution) visible on 99Tc-MDP bone scintigraphy on either pre-ADT scans or baseline scans AND/ OR b. 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 c. 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 antiandrogen (e.g. bicalutamide, flutamide) for metastatic prostate cancer is allowed prior to ICF signature. If given, first generation antiandrogen 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 antiandrogen 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.
Exclusion Criteria
- Patients 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
- Participant with CNS metastases that are neurologically unstable, symptomatic, or receiving corticosteroids for the purpose of maintaining neurologic integrity. Participant with epidural disease, canal disease and prior cord involvement are allowed if those areas have been treated, are stable, and not neurologically impaired. Patients 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 for them 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 < 3. • 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 atrioventicular (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
- Inability to complete the study imaging procedures due to any reason (e.g., severe claustrophobia, inability to lie still for the entire imaging time, any condition that precludes raised arms position)
- Unmanageable concurrent bladder outflow obstruction or urinary incontinence. Note: patients 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
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 09 Jun 2021 | 43 |
 Belgium | Not Recruiting | 09 Jun 2021 | 11 |
 Czechia | Not Recruiting | 09 Jun 2021 | 18 |
 Denmark | Not Recruiting | 09 Jun 2021 | 4 |
 France | Not Recruiting | 09 Jun 2021 | 109 |
 Germany | Not Recruiting | 09 Jun 2021 | 49 |
 The Netherlands | Not Recruiting | 09 Jun 2021 | — |
 Poland | Not Recruiting | 09 Jun 2021 | 32 |
 Spain | Not Recruiting | 09 Jun 2021 | 135 |
 Sweden | Not Recruiting | 09 Jun 2021 | 17 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Locametz 25 micrograms kit for radiopharmaceutical preparation | Test | KIT FOR RADIOPHARMACEUTICAL PREPARATION | INTRAVENOUS | 150 | 1 | PRD10117083 |
ABIRATERONE | Other | PHF00245MIG | UNKNOWN USE | 0 | 60 | SCP132446 |
LEUPRORELIN | Other | PHF00231MIG | UNKNOWN USE | 0 | 60 | SCP151923 |
HISTRELIN | Other | PHF00104MIG | UNKNOWN USE | 0 | 60 | SCP245660 |
ENZALUTAMIDE | Other | PHF00007MIG | UNKNOWN USE | 0 | 106 | SCP26779505 |
TRIPTORELIN | Other | PHF00231MIG | UNKNOWN USE | 0 | 60 | SCP1035124 |
NILUTAMIDE | Other | PHF00245MIG | UNKNOWN USE | 0 | 106 | SCP188413 |
Pluvicto 1 000 MBq/mL solution for injection/infusion | Test | SOLUTION FOR INJECTION/INFUSION | INTRAVENOUS | 7.4 | 36 | PRD10117050 |
GOSERELIN | Other | PHF00104MIG | UNKNOWN USE | 0 | 60 | SCP14945975 |
DEGARELIX | Other | PHF00231MIG | UNKNOWN USE | 0 | 60 | SCP8252543 |