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/dL 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 progressive mCRPC on or after the last systemic treatment administered for
   the advanced disease including metastatic disease. Disease progression defined as
   increasing serum PSA (per PCWG3), radiological progression or ≥ 2 new bone lesions.

   - Must have received prior systemic treatment for mCRPC including CYP17 inhibitors
   and/or androgen-pathway inhibitors (i.e. abiraterone and/or enzalutamide when
   available) and one and no more than one line of chemotherapy for the advanced disease
   (unless ineligible (unfit) to receive chemotherapy).

   - 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 5.0 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 x10e9/L

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

      3. Neutrophil count > 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.

   - Diffuse 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)

   - Prior exposure to radioligand therapy radioisotope therapy (e.g. 89Sr), systemic
   radiotherapy or 223Ra-therapy.

   - 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 important 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 or low grade
   superficial bladder 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.