Study of 177Lu-PSMA-617 In Metastatic Castrate-Resistant Prostate Cancer

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 survival and treatment updates,
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 the the overall censoring rate for survival reduces to a level
identified in the SAP.

An End of Treatment visit should occur once a patient is to enter the long term follow up.
This visit should occur approximately 30 days from the last dose of 177Lu-PSMA-617 or best
supportive/best standard of care, but before the initiation of subsequent anti-cancer
treatment, outside of what is allowed on study.

The planned enrollment for this study is 750 patients.

Inclusion Criteria:

- To qualify for enrollment, patients must meet the following 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 positive 68Ga-PSMA-11 PET/CT scan, as determined by the
sponsor's central reader.

8. Patients must have prior orchiectomy and/or ongoing androgen-deprivation therapy
and a castrate level of serum 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:

1. The patient is not willing to receive a second taxane regimen, or

2. The patient's physician deems him unsuitable to receive a second taxane
regimen (e.g. frailty assessed by geriatric or health status evaluation or
intolerance).

11. Patients must have progressive mCRPC. Documented progressive mCRPC will be based
on at least 1 of the following criteria:

1. 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.

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:

1. Bone marrow reserve:

- White blood cell (WBC) count ≥2.5 x 109/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)

2. 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

3. 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.

Exclusion Criteria:

- Patients who meet any of the following criteria will be excluded from the study:

1. Previous treatment with Strontium-89, Samarium-153, Rhenium-186, Rhenium-188,
Radium-223 or hemi-body irradiation within 6 months prior to randomization.
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 within 30 days of randomization.

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. Patients with adequately treated
non-melanoma skin cancer, superficial bladder cancer and patients with prior
history of malignancy who have been disease free for more than 3 years are
eligible.