A Multi-Center, Open-Label, Randomized Phase 3 Trial Comparing the Safety and Efficacy of [177Lu]LU-PSMA-I&T versus Hormone Therapy in Patients with Metastatic Castration-Resistant Prostate Cancer
- Trial ID
- 2022-501493-19-00
- Protocol
- CURLu177PSM0001
- Sponsor
- Curium Pet France
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the improvement of **radiographic progression-free survival** (rPFS) in men with metastatic castration-resistant prostate cancer (mCRPC) treated with [177Lu]LU-PSMA-I&T compared to those receiving hormone therapy. This is clinically relevant as rPFS is a critical endpoint in evaluating the efficacy of treatments for mCRPC, providing insights into the potential of [177Lu]LU-PSMA-I&T to delay disease progression.
Secondary objectives include:
- Evaluating the improvement in overall survival (OS) in men with mCRPC treated with 177Lu-PSMA-I&T compared to hormone therapy.
- Assessing changes in the time to second radiographic progression for patients who crossover from the hormone therapy arm to the [177Lu]LU-PSMA-I&T treatment arm.
- Identifying changes in progression-free survival (PFS, composite) following [177Lu]LU-PSMA-I&T radioligand therapy compared to hormone therapy.
- Identifying changes in progression-free survival 2 (PFS2, composite) following [177Lu]LU-PSMA-I&T radioligand therapy compared to hormone therapy.
- Assessing changes in PSA50 response rate following [177Lu]LU-PSMA-I&T radioligand therapy compared to hormone therapy.
- Determining the impact of [177Lu]LU-PSMA-I&T compared to hormone therapy on skeletal symptoms.
- Determining the impact of [177Lu]LU-PSMA-I&T compared to hormone therapy on radiographic soft-tissue progression.
- Assessing changes in the use of chemotherapy following [177Lu]LU-PSMA-I&T compared to hormone therapy.
- Evaluating the impact on quality of life following [177Lu]LU-PSMA-I&T radioligand therapy compared to hormone therapy.
Participants
The clinical trial involves a total of **250 male participants** diagnosed with **metastatic Castration-Resistant Prostate Cancer (mCRPC)**. The study population is exclusively male, aged 18 years or older, and includes individuals who are able to understand and provide signed written informed consent. Participants were selected based on their ability to attend required study visits and return for adequate follow-up. The trial does not include a vulnerable population. Participants with well-managed HIV, HBV, or HCV are eligible, provided their symptoms are sufficiently controlled. Lifestyle considerations such as diet and physical activity are not specified. Key inclusion criteria include a life expectancy of at least six months, willingness to initiate androgen receptor axis-targeted (ARAT) therapy, and effective castration with a serum testosterone level of less than 50 ng/dL. Participants must have a histologically or pathologically confirmed diagnosis of prostate adenocarcinoma without a predominant small cell component and must have shown progressive disease as defined by specific clinical criteria. Previous treatment with next-generation androgen receptor-directed therapy is required, with progression while on such therapy. A positive PSMA-PET scan is also necessary for inclusion.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, Phase 3 study to evaluate the safety and efficacy of **177Lu-PSMA-I&T** compared to hormone therapy in patients with **metastatic castration-resistant prostate cancer (mCRPC)**. The primary objective is to assess the improvement in radiographic progression-free survival (rPFS) in men treated with 177Lu-PSMA-I&T versus those receiving hormone therapy. The trial is expected to run until February 2029, with recruitment having commenced in December 2022.
Participants will be randomly assigned to receive either 177Lu-PSMA-I&T via **intravenous infusion** or hormone therapy, which includes **enzalutamide**, **abiraterone acetate**, and **prednisone**, administered orally. The maximum treatment period for 177Lu-PSMA-I&T is 24 weeks, while hormone therapy is administered for up to 20 weeks. The study will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes.
The expected duration of participant involvement is approximately 24 weeks, with conditions for early termination including significant adverse events, disease progression, or withdrawal of consent. The primary endpoint is the time from randomization to radiographic progression as determined by the Prostate Cancer Working Group 3 (PCWG3) criteria, assessed by a blinded independent central review. Secondary endpoints include overall survival, time to second radiographic progression, and quality of life improvements.
Treatment
The clinical trial involves the administration of **177LU-PSMA-I&T**, a **solution for injection** containing the active substance **lutetium (177Lu) zadavotide guraxetan**. This experimental medication is administered via **intravenous infusion**. The maximum daily dose is 7.4 GBq, with a total maximum dose of 29.6 GBq over a treatment period of up to 24 weeks. The pharmaceutical form is a solution for injection, and the product is manufactured by Curium US LLC. Participant compliance is monitored through regular assessments of radiographic progression-free survival.
**ENZALUTAMIDE** is used as a comparator treatment in the study. It is provided in the form of **soft capsules** and is administered **orally**. The maximum daily dose is 1000 mg, with a total maximum dose of 140 g over a 20-week treatment period. Enzalutamide functions as a hormone antagonist and is classified as an anti-androgen. Compliance is monitored through regular dosing logs and patient interviews.
Another comparator treatment, **ABIRATERONE ACETATE**, is administered in **tablet** form and taken **orally**. The maximum daily dose is 160 mg, with a total maximum dose of 22,400 mg over a 20-week period. Abiraterone acetate is categorized under endocrine therapy and other hormone antagonists. Participant adherence is tracked through pill counts and patient diaries.
**PREDNISONE** is included as a supportive treatment in the trial. It is available in **tablet** form and is administered **orally**. The maximum daily dose is 10 mg, with a total maximum dose of 1400 mg over a 20-week period. Prednisone is classified as a corticosteroid. Compliance is ensured through regular follow-ups and medication adherence checks.
Additionally, **Pylclari 1 000 MBq/mL solution for injection**, containing the active substance **piflufolastat (18F)**, is used as a diagnostic agent. It is administered via **intravenous injection** with a maximum dose of 360 MBq. The administration is limited to a single day, and the product is manufactured by Curium PET France. The administration is monitored by healthcare professionals to ensure accurate dosing and patient safety.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the improvement in **radiographic progression-free survival (rPFS)** in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with [177Lu]LU-PSMA-I&T compared to those receiving hormone therapy. The primary endpoint is the time from randomization to radiographic progression, as determined by the Prostate Cancer Working Group 3 (PCWG3) criteria, assessed by a blinded independent central review. Secondary endpoints include the time from randomization to death by any cause, the second radiographic progression, progression based on PCWG3 or RECIST criteria, PSA50 response rate, time to first symptomatic skeletal event, radiographic soft tissue progression, first use of chemotherapy, and quality of life improvement based on the EORTC QLQ-C30 questionnaire.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male 18 years or older able to understand and provide signed written informed consent
- Life expectancy of at least 6 months as assessed by investigator.
- Willing to initiate ARAT therapy determined by investigator.
- For patients who have partners of childbearing potential: The patient and/or partner must use a method of birth control with adequate barrier protection, deemed acceptable by the principal investigator during the study and for 6 months after the last study drug administration.
- Histologically or pathologically confirmed prostate adenocarcinoma without predominant small cell component.
- Progressive disease by one or more of the following criteria: a. Serum/plasma PSA progression defined as 2 consecutive increases in PSA over a previous reference value measured at least 1 week apart with a minimum start value of >2 ng/mL. b. Progression of measurable disease (RECIST 1.1) or presence of at least two new bone lesions (PCWG3 criteria).
- Previous treatment with next-generation androgen receptor (AR)-directed therapy (e.g. abiraterone, enzalutamide, apalutamide, darolutamide). a. Must have received no more than one previous AR-directed therapy. b. Must have been administered ARAT (abiraterone, enzalutamide, darolutamide, or apalutamide) in the castration-sensitive or castrationresistant setting. c. Must have progressed while on ARAT.
- PSMA-PET scan (e.g. 68Ga-PSMA-11 or 18F-DCFPyL) positive as determined by central reader.
- Effective castration with serum testosterone level of <50 ng/dL and plan to continue with chronic medical or surgical castration
- Ability to attend required study visits and return for adequate follow-up, as required by this protocol.
- Patients with HIV that are healthy and with a low risk of acquired immune deficiency syndrome related outcomes may participate in the trial at the investigators' discretion.
- Patients with HBV and HCV may also participate if symptoms are sufficiently managed.
- ADDITIONAL INCLUSION CRITERIA FOR SUB STUDY: Separate informed consent for participation in the sub-study.
- ADDITIONAL INCLUSION CRITERIA FOR SUB STUDY: Willing to undergo SPECT: Willing to undergo SPECT/CT imaging at 4 hours, 24 hours, 48 hours, and 7 +/-1 days after 177Lu-PSMA-I&T treatment cycle .
- ADDITIONAL INCLUSION CRITERIA FOR SUB STUDY: Willing to undergo additional blood sampling for plasma pharmacokinetic measurements.
Exclusion Criteria
- Prior treatment with radioligand therapy including other lutetium-labeled compounds.
- Use of an investigational therapeutic drug within the last 4 weeks prior to start of study treatment or scheduled to receive one during the study period.
- Known central nervous system (CNS) metastasis unless received therapy, asymptomatic and neurologically stable.
- Patients receiving zoledronic acid for bone-targeted therapy must be on stable dose for 4 weeks prior to randomization.
- Major surgery within 30 days of randomization as determined by the Investigator.
- Patients with active significant cardiac disease defined by any of the following: a. New York Heart Association class 3 or 4 congestive heart failure within 6 months of signing the Informed Consent Form (ICF) unless treated with improvement. b. Current diagnosis of electrocardiogram abnormalities with significant cardiac arrhythmias c. History of long QT syndrome or know history of Torsades de Pointe d. History of myocardial infarction, angina pectoris, or coronary artery bypass graft within 6 months of ICF signature
- Participants with symptomatic cord compression or clinical/radiological findings indicating impending spinal cord compression
- Patients with a superscan seen on baseline bone scan as determined by investigator.
- Active malignancy other than low-grade non-muscle-invasive bladder cancer and non-melanoma skin cancer
- Previous use of G-CSF for persistent neutropenia after standard of care treatment.
- Participants with active Covid19. Recovered patients may be included when completely recovered (no symptoms at least 28 days before study medication and a negative Covid test within 72 hours).
- Prior treatment with radium-223 (Xofigo) within the past 12 weeks.
- Prior chemotherapy treatment for castration-resistant prostate cancer. Prior docetaxel use in the hormone-sensitive setting is permitted as long as no more than 6 doses were received, the last dose was administered >1 year prior to consent and disease progression did not occur during docetaxel treatment.
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥ 2
- Patients with known HRR gene-mutation (BRCA 1/2 encompassing both germline and somatic) who have not been previously treated with olaparib or rucaparib.
- Other concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, or investigational therapy.
- Inadequate organ and bone marrow function as evidenced by: a. Hemoglobin < 8 g/dL. b. Absolute neutrophil count < 1.5 x 109/L. c. Platelet count < 100 x 109/L. d. AST/SGOT and/or ALT/SGPT > 3.0 x ULN. e. Total bilirubin > 2 x ULN unless patient has known Gilbert’s syndrome and then may be 3 x ULN. f. Creatinine clearance (CrCl) < 50 mL/min based on the Cockcroft-Gault equation. g. Albumin < 2.75 g/dL
- Patients who undergo a transfusion for the sole purpose of meeting eligibility for this trial will be excluded.
- Assessment by the Investigator as unable or unwilling to comply with the requirements of the protocol.
- ADDITIONAL EXCLUSION CRITERIA FOR SUB STUDY: Unable to undergo SPECT/CT imaging as required in the sub-study protocol.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 15 Dec 2022 | 80 |
 Italy | Not Recruiting | 15 Dec 2022 | 30 |
 Spain | Not Recruiting | 15 Dec 2022 | 40 |
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 |
|---|---|---|---|---|---|---|
177LU-PSMA-I&T | Test | SOLUTION FOR INJECTION | INTRAVENOUS INFUSION | 7.4 | 24 | PRD10220377 |
ENZALUTAMIDE | Comparator | — | ORAL | 1000 | 20 | SUB77412 |
ABIRATERONE ACETATE | Comparator | — | ORAL | 160 | 20 | SUB31647 |
Pylclari 1 000 MBq/mL solution for injection | Test | SOLUTION FOR INJECTION | INTRAVENOUS INJECTION | 360 | 1 | PRD10810414 |
PREDNISONE | Other | — | ORAL | 10 | 20 | SUB10020MIG |