E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
PSMA-positive metastatic hormone-sensitive prostate cancer (mHSPC) |
|
E.1.1.1 | Medical condition in easily understood language |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10036909 |
E.1.2 | Term | Prostate cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The main objective of the trial is to evaluate radiographic progression free survival (rPFS) as assessed by Blinded Independent Review Committee (BIRC) in patients with mHSPC receiving Standard of Care and 177Lu-PSMA-617 versus patients receiving Standard of Care without 177Lu-PSMA-617. |
|
E.2.2 | Secondary objectives of the trial |
Key Secondary objective is to evaluate the contribution of 177Lu-PSMA-617 to Standard of Care in terms of overall survival (OS) in patients with mHSPC.
Secondary objectives are : - To evaluate PSA90 response at 12, 24 and 48 weeks -To evaluate the time to development of metastatic castration resistant prostate cancer (mCRPC) as determined by investigators. - To evaluate Progression Free Survival (PFS) - To evaluate the second progression Free Survival (PFS2) - To evaluate the change in the nadir levels of PSA < 0.2 ng/mL at 12, 24 and 48 months - To evaluate the overall response rate (ORR), disease control rate (DCR), time to response (TTR), duration of response (DOR) and Time to soft tissue progression (TTSTP) - To evaluate safety and tolerability of 177LuPSMA-617 - To assess the effect of 177Lu-PSMA-617 on the health-related quality of life (HRQoL) - To evaluate the time from the date of randomization to the date to first symptomatic skeletal event (SSE). |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Signed informed consent must be obtained prior to participation in the study 2. Patients must be adults ≥18 years of age 3. Patients must have an ECOG performance status of 0 to 2 4. Patients must have a life expectancy >9 months as determined by the study investigator 5. Patients must have metastatic prostate cancer with histologically or cytologically confirmed adenocarcinoma (current or prior biopsy of the prostate and/or metastatic site) 6. 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 7. 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. 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. 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). 8. 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 9. Albumin ≥2.5 g/dL 10. 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
other protocol-defined inclusion criteria may apply |
|
E.4 | Principal exclusion criteria |
1. Patients with rapidly progressing tumor that requires urgent exposure to taxane-based chemotherapy 2.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). 3. Concurrent cytotoxicity chemotherapy, immunotherapy, radioligand therapy, PARP inhibitor, biological therapy or investigational therapy 4. 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 5. Ongoing participation in any other clinical trial 6. Use of other investigational drugs within 30 days prior to day of randomization 7. Known hypersensitivity to any of the study treatments or its excipients or to drugs of similar chemical classes 8. Transfusion for the sole purpose of making a participant eligible for study inclusion 9. 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). 10. 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. .
other protocol-defined exclusion criteria may apply |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Radiographic progression-free survival (rPFS) is designated as primary endpoint. rPFS is defined as the time from the date of randomization to the date of first documented radiographic disease progression as assessed by blinded independent central review (BIRC) and as outlined in Prostate Cancer Working Group 3 (PCWG3) Guidelines (Scher et al 2016) or death due to any cause |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Radiographic progression-free survival (rPFS) will be evaluated every 12 weeks (+/-7 days) after first dose of 177Lu-PSMA-617 (investigational arm) or first dose of ARDT (Control arm) - independant of dose delays during 24 months, then every 16 weeks (+/-7days) until radiographic disease progression, death, withdraw of consent, loss to FUP, subject/guardian decision.
|
|
E.5.2 | Secondary end point(s) |
Overall survival (OS) is designated as key secondary end point. OS is defined as the time from the date of randomization to the date of death due to any cause
Secondary end points are the following: - PSA90 response is defined as the proportion of patients who have a ≥90% decrease in PSA from baseline that is confirmed by a second (the next) PSA measurement ≥4 weeks later.
- PSA90
- Time to development of mCRPC is defined as the time from date of randomization to disease progression despite androgen deprivation therapy (ADT) presenting as either a continuous rise in serum prostate-specific antigen (PSA) levels, the progression of pre-existing disease, and/or the appearance of new metastases.
- PFS is defined as the time from date of randomization to the date of first documented progression by investigator assessment (radiographic progression, clinical progression, PSA progression) or death from any cause, whichever occurs first
- PFS2 is defined as time from date of randomization to the first documented progression by investigator assessment (radiographic progression, clinical progression, PSA progression) on next-line therapy or death from any cause, whichever occurs first.
- Proportion of patients with PSA < 0.2 ng/mL
- ORR, DCR, TTR, DOR, TTSTP
- Safety: incidence and severity of AEs and serious adverse event (SAE)s, changes in laboratory values, vital signs and ECGs. Any clinically significant lab, vital signs, ECG abnormalities will be captured as an AE.
- Tolerability: dose interruptions, reductions and dose intensity
- HRQoL as assessed by Functional Assessment of Cancer Therapy Prostate (FACT-P), Brief Pain Inventory (Short Form (BPI-SF) and European
- Quality of Life (EuroQol) 5 Domain 5 Level scale (EQ-5D-5L)
- Time to SSE (TTSSE) defined as date of randomization to the date of first new symptomatic pathological bone fracture, spinal cord compression, tumor-related orthopedic surgical intervention, requirement for radiation therapy to relieve bone pain or death from any cause, whichever occurs first |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
For OS: continuously during study treatment and post-treatment follow-up
ORR, DCR, TTR, DOR, TTSTP will be evaluated based on PCWG3 modified RECIST 1.1
PSA90 and proportion of patients with PSA < 0.2 ng/mL will be evaluated at 12, 24 and 48 weeks.
Continuously during study for other secondary endpoints. |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
|
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 47 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
China |
Hong Kong |
Japan |
Korea, Republic of |
Singapore |
Taiwan |
United States |
Switzerland |
Russian Federation |
Austria |
Belgium |
Czechia |
Denmark |
France |
Germany |
Netherlands |
Poland |
Spain |
Sweden |
United Kingdom |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
Last visit of the last participant (LVLP) |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 18 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |