177Lu-PSMA-R2 in Patients With PSMA Positive Progressive, Metastatic, Castration Resistant Prostate Cancer

Inclusion Criteria:

- Male patients, 18 years of age or older

- Signed and dated written ICF by the patient or legally acceptable representative prior
to any study-specific procedures

- Histologically confirmed adenocarcinoma of the prostate

- Serum testosterone levels < 50 ng/L after surgical or continued chemical castration

- Metastatic disease documented by CT/MRI or bone scan (not older than 28 days at
enrollment) revealing at least one metastatic lymph-node, visceral metastasis and/or
bone metastasis

- Positive 68Ga-PSMA-R2 PET/CT scan for central eligibility assessment. Patients who
receive 68Ga-PSMA-R2 as part of separate clinical protocol are eligible (must meet all
study eligibility criteria)

- Documented disease progression on or after prior systemic treatment administered for
the advanced disease including CYP 17 inhibitors and/or androgen-pathway inhibitors
(i.e. abiraterone and/or enzalutamide when available) and no more than one line of
chemotherapy for the advanced disease, or patients who were ineligible (unfit) to
receive chemotherapy. Disease progression defined as increasing serum PSA (per PCWG3),
radiological progression or ≥ 2 new bone lesions. (Chemical castration is required
unless surgically orchiectomized.)

- At least 28 days elapsed between last anti-cancer treatment administration and the
initiation of study treatment (except for Luteinizing Hormone-releasing Hormone [LHRH]
or Gonadotropin-releasing Hormone [GnRH]), or resolution of all previous treatment
related toxicities to CTCAE version 4.03 grade of ≤ 1 (except for chemotherapy induced
alopecia and grade 2 peripheral neuropathy or grade 2 urinary frequency which are
allowed). Prior major surgery must be at least 12 weeks prior to study entry.

- Eastern cooperative oncology group (ECOG) performance status of 0-2 with a life
expectancy ≥ 6 months

- Adequate bone marrow reserve and organ function as demonstrated by complete blood
count, and biochemistry in blood and urine at baseline

1. Platelet count of >100 x109/L

2. White blood cell (WBC) count 3,000/mL

3. Neutrophil count of > 1,500/mL

4. Hemoglobin ≥ 10 g/dL

5. Serum creatinine < 1.5 x upper limit normal (ULN) or estimated glomerular
filtration rate (GFR) > 50 mL/min based upon Chronic Kidney Disease-Epidemiology
Collaboration (CKD-EPI) equation. Patients with estimated GFR between 50 - 60
mL/min at baseline will require a 99mTc-DTPA GFR test and only patients with
non-obstructive pathology will be included in the study.

6. Total bilirubin < 3 x ULN (except if confirmed history of Gilbert's disease)

7. Baseline serum albumin > 30 g/L

8. Aspartate aminotransferase (AST) < 3 times the ULN

- For male patients with partners of childbearing potential, agreement to use barrier
contraceptive method (condom) and to continue its use for 6 months from receiving the
last dose of IP

Exclusion Criteria:

- Pathological finding consistent with small cell, neuroendocrine carcinoma of the
prostate or any other histology different than adenocarcinoma

- Previously administered chemotherapy or 223Ra-therapy within the context of diffuse
bone or bone-marrow involvement (i.e. "superscan" defined as bone scintigraphy in
which there is excessive skeletal radioisotope uptake [>20 bone lesions] in relation
to soft tissues along with absent or faint activity in the genitourinary tract due to
diffuse bone/ bone marrow metastases)

- Current severe urinary incontinence, hydronephrosis, severe voiding dysfunction, any
level of urinary obstruction requiring indwelling/condom catheters

- Spinal cord compression or brain metastases

- Uncontrolled pain that results in patient's lack of compliance with the imaging
procedures

- Uncontrolled cardiovascular history, defined as:

- Congestive heart failure (New York Heart Association [NYHA] II, III, IV)

- Mean resting corrected QT interval (QTc) >450 millisecond (msec), obtained from 3
ECGs recordings, using the screening clinic ECG machine-derived QTc value.

- Any clinically relevant abnormalities in rhythm, conduction, or morphology of
resting ECG (e.g., complete left bundle branch block, third-degree heart block,
second-degree heart block, PR interval >250 msec).

- Any factor increasing the risk of QTc prolongation or risk of arrhythmic events
such as heart failure, hypokalemia, congenital long QT syndrome, family history
of long QT syndrome, or unexplained sudden death under 40 years of age in
first-degree relatives, or any concomitant medication known to prolong the QT
interval.

- Other known co-existing malignancies except non-melanoma skin cancer unless
definitively treated and proven no evidence of recurrence for 5 years.

- History of deep vein thrombosis and/or pulmonary embolism within 4 weeks of
enrollment.

- Known incompatibility to CT or PET scans.

- Any evidence of severe or uncontrolled systemic or psychiatric diseases, including
uncontrolled hypertension and active bleeding diatheses, which in the Investigator's
opinion makes it undesirable for the patient to participate in the trial or which
would jeopardize compliance with the protocol

- Active infection including human immunodeficiency virus (HIV) and untreated hepatitis
B, and hepatitis C. Screening for chronic conditions is not required.

- Patients who have received any investigational treatment agent within the last 28
days.

- Known allergies, hypersensitivity, or intolerance to the IP or its excipients

- Known history of myelodysplastic syndrome/leukemia at any time

- Patient is unlikely to comply with study procedures, restrictions and requirements and
judged by the Investigator that the patient is not suitable for participation in the
study.