| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | LLT |
| E.1.2 | Classification code | 10076506 |
| E.1.2 | Term | Castration-resistant prostate cancer |
| E.1.2 | System Organ Class | 100000004864 |
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| 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 primary objective of this study is to compare the two alternate primary endpoints of radiographic progression-free survival (rPFS) and overall survival (OS) in patients with progressive PSMA-positive mCRPC who receive 177Lu-PSMA-617 in addition to best supportive/standard of care versus patients treated by best supportive/best standard of care alone. |
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| E.2.2 | Secondary objectives of the trial |
Key secondary objectives are an arm-to-arm comparison of the following:
1. RECIST response to include:
a. Overall Response Rate (ORR) as measured by RECIST v1.1 criteria
b. Disease control rate (DCR) as measured by RECIST v1.1 criteria
2. Time to a first symptomatic skeletal event (SSE)
Additional secondary objectives
1. Safety and tolerability of 177Lu-PSMA-617
2. Periodic assessment of health-related quality of life to evaluate impact of intervention on patient well-being (HRQoL; EuroQol 5-dimensions 5-level [EQ-5D-5L] questionnaire, Functional Assessment of Cancer Therapy – Prostate [FACT-P] questionnaire and Brief Pain Inventory – Short Form [BPI-SF])
3. Health Economics
4. Progression-free survival (PFS) (radiographic, clinical, or PSA progression-free survival)
5. Biochemical response as measured by PSA. Alkaline phosphatase [ALP] and lactate dehydrogenase [LDH] levels will also be collected.
6. Dosimetry, PK, and ECG in a sub-study of approximately 30 patients |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| A dosimetry, PK and ECG sub-study will be conducted in a non-randomized cohort (177Lu PSMA-617 plus best supportive/best standard of care) of approximately 30 patients at sites in Germany to provide a more complete assessment of the safety aspects of 177Lu PSMA-617. |
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| E.3 | Principal inclusion criteria |
1. Patients must have the ability to understand and sign an approved ICF.
2. Patients must have the ability to understand and comply with all protocol requirements.
3. Patients must be ≥18 years of age.
4. Patients must have an ECOG performance status of 0 to 2.
5. Patients must have a life expectancy >6 months.
6. Patients must have histological, pathological, and/or cytological confirmation of prostate cancer.
7. Patients must have a poitive 68Ga-PSMA-11 PET/CT scan as determined by the sponsor’s central reader.
8. Patients must have a castrate level of serum/plasma testosterone (<50 ng/dL or <1.7 nmol/L).
9. Patients must have received at least one NAAD (such as enzalutamide and/or abiraterone).
10. Patients must have been previously treated with at least 1, but no more than 2 previous taxane regimens. A taxane regimen is defined as a minimum exposure of 2 cycles of a taxane. If a patient has received only 1 taxane regimen, the patient is eligible if:
a. The patient’s physician deems him unsuitable to receive a second taxane regimen (e.g. frailty assessed by geriatric or health status evaluation, intolerance, etc.).
11. Patients must have progressive mCRPC. Documented progressive mCRPC will be based on at least 1 of the following criteria:
a. Serum PSA progression defined as 2 consecutive increases in PSA over a previous reference value measured at least 1 week prior. The minimal start value is 2.0 ng/mL.
b. Soft-tissue progression defined as an increase ≥20% in the sum of the diameter (SOD) (short axis for nodal lesions and long axis for non-nodal lesions) of all target lesions based on the smallest SOD since treatment started or the appearance of one or more new lesions.
c. Progression of bone disease: evaluable disease or new bone lesions(s) by bone scan.
12. Patients must have ≥1 metastatic lesion that is present on baseline CT, MRI, or bone scan imaging obtained ≤28 days prior to beginning study therapy.
13. Patients must have recovered to ≤ Grade 2 from all clinically significant toxicities related to prior therapies (i.e. prior chemotherapy, radiation, immunotherapy).
14. Patients must have adequate organ function:
a. Bone marrow reserve:
• White blood cell (WBC) count ≥2.5 × 109/L (2.5 × 109/L is equivalent to 2.5 × 103/μL and 2.5 × K/μL and 2.5 × 103/cumm and 2500/μL) OR absolute neutrophil count (ANC) ≥1.5 × 109/L (1.5 × 109/L is equivalent to 1.5 × 103/μL and 1.5 × K/μL and 1.5 × 103/cumm and 1500/μL)
• Platelets ≥100 × 109/L (100 × 109/L is equivalent to 100 × 103/μL and 100 × K/μL and 100 × 103/cumm and 100,000/μL)
• Hemoglobin ≥9 g/dL (9 g/dL is equivalent to 90 g/L and 5.59 mmol/L)
b. Hepatic:
• Total bilirubin ≤1.5 x the institutional upper limit of normal (ULN). For patients with known Gilbert’s Syndrome ≤3 × ULN is permitted
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3.0 × ULN OR ≤5.0 × ULN for patients with liver metastases
c. Renal:
• Serum creatinine ≤1.5 x ULN or creatinine clearance ≥50 mL/min
15. Albumin >3.0 g/dL (3.0 g/dL is equivalent to 30 g/L)
16. Patients on a stable bisphosphonate or denosumab regimen for ≥30 days prior to randomization are eligible.
17. HIV-infected patients who are healthy and have a low risk of AIDS-related outcomes are included in this trial.
For patients who have partners of childbearing potential:
18. Partner and/or patient must use a method of birth control with adequate barrier protection, deemed acceptable by the principle investigator during the study and for 3 months after last study drug administration.
19. The best standard of care/ best supportive care options planned for this patient:
a. Are allowed by the protocol
b. Have been agreed to by the treating investigator and patient
c. Allow for the management of the patient without 177Lu-PSMA-617
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|
| E.4 | Principal exclusion criteria |
1. 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.
2. Any systemic anti-cancer therapy (e.g. chemotherapy, immunotherapy or biological therapy [including monoclonal antibodies]) within 28 days prior to day of randomization.
3. Any investigational agents within 28 days prior to day of randomization.
4. Known hypersensitivity to the components of the study therapy or its analogs.
5. Other concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, or investigational therapy.
6. Transfusion for the sole purpose of making a subject eligible for study inclusion.
7. Patients with a history of CNS metastases must have received therapy (surgery, radiotherapy, gamma knife) and be neurologically stable, asymptomatic, and not receiving corticosteroids for the purposes of maintaining neurologic integrity. Patients with epidural disease, canal disease and prior cord involvement are eligible if those areas have been treated, are stable, and not neurologically impaired. For patients with parenchymal CNS metastasis (or a history of CNS metastasis), baseline and subsequent radiological imaging must include evaluation of the brain (MRI preferred or CT with contrast).
8. A superscan as seen in the baseline bone scan.
9. Symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression.
10. Concurrent serious (as determined by the Principal Investigator) medical conditions, including, but not limited to, New York Heart Association class III or IV congestive heart failure, history of congenital prolonged QT syndrome, uncontrolled infection, active hepatitis B or C, or other significant co-morbid conditions that in the opinion of the investigator would impair study participation or cooperation.
11. Diagnosed with other malignancies that are expected to alter life expectancy or may interfere with disease assessment. However, patients with a prior history of malignancy that has been adequately treated and who have been disease free for more than 3 years are eligible, as are patients with adequately treated non-melanoma skin cancer, superficial bladder cancer. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| rPFS and OS are designated as alternate primary endpoints. rPFS is defined as the time from the date of randomization to the date of radiographic disease progression as outlined in Prostate Cancer Working Group 3 (PCWG3) Guidelines (Scher et al 2016) or death from any cause. OS is defined as the time from randomization to the date of death from any cause. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
for rPFS: Every 8 weeks (± 4 days) after first dose of 177Lu-PSMA-617 for the first 24 weeks (independent of dose delays), then every 12 weeks (± 4 days)
For OS: Continuously during study treatment and long term follow-up |
|
| E.5.2 | Secondary end point(s) |
The key secondary endpoints include the following:
1. RECIST response to include:
a. Objective response rate (ORR) (CR + PR) as measured by RECIST v1.1 response in soft tissue, lymph node and visceral lesions. Duration of Response will also be measured in patients with a CR or PR from date of first response to the date of RECIST progression or death.
b. Disease Control Rate (DCR) (CR + PR + stable disease [SD]) as measured by RECIST v1.1 response in soft tissue, lymph node and visceral lesions.
2. The time to a first SSE 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.
Additional Secondary endpoints
1. To evaluate the safety and tolerability of 177Lu-PSMA-617
2. Aspects of HRQoL will be reported using the EuroQol 5-dimensions 5-level [EQ-5D-5L] questionnaire, Functional Assessment of Cancer Therapy – Prostate [FACT-P] questionnaire and Brief Pain Inventory – Short Form [BPI-SF]
3. Health economics
4. Progression-free survival is defined as the date of randomization to the date of first evidence of radiographic progression, clinical progression, PSA progression, or death from any cause, whichever occurs first.
a. Radiographic progression is defined as the date of radiographic disease progression as outlined in the Prostate Cancer Working Group 3 (PCWG3) Guidelines.
b. Unequivocal clinical progression. Unequivocal evidence of clinical progression is defined as:
• Marked escalation in cancer related pain that is assessed by the investigator to indicate the need for other systemic chemotherapy
• Immediate need for initiation of new anticancer treatment, surgical or radiological intervention for complications due to tumor progression even in the absence of radiological progression
• Marked deterioration in ECOG performance status to ≥ Grade 3 and/or in the opinion of the investigator ECOG deterioration indicates clinical progression
• In the opinion of the investigator, it is in the best interest of the patient to discontinue treatment due to clinical progression
c. PSA progression is defined as the date that a ≥ 25% increase in PSA and an absolute increase of 2 ng/mL or more from the nadir is documented and confirmed by a second consecutive value obtained 3 or more weeks later. Rises in PSA within the first 12 weeks will be ignored in the absence of other evidence of disease progression (PCWG3 Guidance). Where no decline from baseline is documented, PSA progression is defined as a 25% increase from the baseline value along with an increase in absolute value of 2 ng/mL or more after 12 weeks of treatment.
5. Biochemical response endpoints:
a. Proportion of subjects who are PSA responders, defined as a patient who has achieved a ≥50% decrease from baseline that is confirmed by a second PSA measurement ≥4 weeks.
b. Alkaline phosphatase [ALP] and lactate dehydrogenase [LDH] levels will also be collected.
6. Dosimetry, PK, and ECG in a sub-study of approximately 30 patients |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Continuously during study, except ORR and PSA response, which are evaluated per Prostate Cancer Working Group 3 criteria. ORR and PSA response evaluated every 3 months during long term follow-up.
Dosimetry will be collected during every Cycle, PK and ECG will be collected during the first week of Cycle 1
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| 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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| 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 | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Quality of life, dosimetry and ECG |
|
| 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 | No |
| 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 |
| Best Supportive/Standard of Care |
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| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 43 |
| 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 |
| United States |
| France |
| Sweden |
| Netherlands |
| Germany |
| Belgium |
| Denmark |
| United Kingdom |
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| 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
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| The trial and long-term follow-up procedures are expected to continue at least until 508 deaths have occurred. Long-term follow-up for safety and survival will continue until a separate long-term safety follow-up study is available. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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