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/best standard of care versus patients treated with best supportive/best standard
of care alone.
Patients with PSMA positive scans will be randomized in a 2:1 ratio to receive either
177Lu-PSMA-617 plus best supportive/best standard of care or to receive best supportive/best
standard of care only. Best supportive/best standard of care will be determined by the
treating physician/investigator but will exclude investigational agents, cytotoxic
chemotherapy, other systemic radioisotopes, and hemi-body radiotherapy. Novel androgen axis
drugs [NAADs] (such as abiraterone or enzalutamide) are allowed.
The study is open-label and patients will be monitored throughout the 6 to 10-month treatment
period for survival, disease progression, and adverse events.
A long-term follow-up period will include the collection of rPFS survival and information
about new treatments, responses to new treatments, adverse events assessment, as well as
blood for hematology and chemistry testing. During follow-up, patients will be contacted
every 3 months (+/- 1 month) via phone, email, or letter for 24 months or until 508 deaths
An End of Treatment visit should occur once a patient discontinues the treatment part of the
study for any reason (patient or investigator decision, going on to long term follow up,
etc.). This visit should occur approximately 30 days from the last dose of 177Lu-PSMA-617 or
the date of the best supportive/best standard of care end of treatment decision (whichever
occurs later), but before the initiation of subsequent anti-cancer treatment, outside of what
is allowed on study.
The planned enrollment for this study is 814 patients.
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. In order to not bias the results obtained from randomized patients in the
main study, the data of the sub-study patients will be analyzed descriptively and not
considered in the primary and secondary analysis of the main study.
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
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
7. Patients must be 68Ga-PSMA-11 PET/CT scan positive, and eligible 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
9. Patients must have received at least one NAAD (such as enzalutamide and/or
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,
11. Patients must have progressive mCRPC. Documented progressive mCRPC will be based on at
least 1 of the following criteria:
1. Serum/plasma 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.
2. 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.
3. Progression of bone disease: evaluable disease or new bone lesions(s) by bone
scan (2+2 PCWG3 criteria, Scher et al 2016).
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, etc.).
14. Patients must have adequate organ function:
a. Bone marrow reserve:
- White blood cell (WBC) count ≥2.5 x 10^9/L (2.5 x 10^9/L is equivalent to 2.5 x
10^3/μL and 2.5 x K/μL and 2.5 x 10^3/cumm and 2500/μL) OR absolute neutrophil
count (ANC) ≥1.5 x 10^9/L (1.5 x 10^9/L is equivalent to 1.5 x 10^3/μL and 1.5 x
K/μL and 1.5 x 10^3/cumm and 1500/μL)
- Platelets ≥100 x 10^9/L (100 x 10^9/L is equivalent to 100 x 10^3/μL and 100 x
K/μL and 100 x 10^3/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 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 c. Renal:
- Serum/plasma 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) [Inclusion #16 has been removed]
17. HIV-infected patients who are healthy and have a low risk of AIDS-related outcomes are
included in this trial.
18. For patients who have partners of childbearing potential: 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 6 months after last study drug
19. The best standard of care/ best supportive care options planned for this patient:
1. Are allowed by the protocol
2. Have been agreed to by the treating investigator and patient
3. Allow for the management of the patient without 177Lu-PSMA-617
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
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
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,
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.
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.