An open-label, multicentre, integrated Phase 1 & 2 study to evaluate the safety, tolerability, radiation dosimetry and anti-tumour activity of Lutetium (177Lu) rhPSMA 10.1 injection in men with metastatic castrate resistant prostate cancer

1. Male subjects, 18 years of age or older.
2. Willing to provide signed and dated written informed consent form (ICF)
prior to any study-specific procedures.
3. Willing to comply with required lifestyle restrictions following
administration of the IMP per local regulations.
4. Histologically confirmed adenocarcinoma of the prostate.
5. Serum testosterone levels <50 ng/dL (1.73 nmol/L) after surgical or
continued chemical castration.
6. Meets respective cohort-specific inclusion criterion for Phase 2 only.
7. Presence of disease target or non-target lesions (per RECIST v1.1) on CT/MRI
and/or full body 99mTc bone scan performed within 28 days of screening.
8. Positive disease expression of PSMA as confirmed on 18F-rhPSMA-7.3 PET/CT
scan. Note, for phase 1 only, a LOCAMETZ® or a positive PSMA PET/CT scan which
has already been obtained within 4 weeks (28 days) prior to screening may be
used for subject selection in Phase 1
9. At least 28 days or 5 half-lives (whichever is longer) elapsed between last
anti-cancer treatment administration and the initiation of study treatment
(except for Luteinising Hormone-releasing Hormone or GnRH).
10. 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).
11. Prior major surgery must be at least 12 weeks prior to study entry.
12. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 with a
life expectancy >=6 months.
13. Adequate bone marrow reserve and organ function as demonstrated by blood
count, and serum biochemistry at baseline:
* Platelet count >= 150 × 109/L
* WBC count >= 3.0 × 109/L
* Neutrophil count of >= 1.5 × 109/L
* Haemoglobin >= 10 g/dL
* Estimated glomerular filtration rate (using Chronic Kidney Disease
Epidemiology
Collaboration Creatinine Equation [2009]) (Levey 2009) >=60 mL/min
* Total bilirubin <1.5× ULN (except if confirmed history of Gilbert's disease)
* Serum albumin >=30 g/L
* AST <2× the ULN
* ALT <2× the ULN
14. Male subjects must not father children or donate sperm during the study and
for at least 6 months after the last study treatment. In addition, they must
agree to use effective contraception for this same period to protect partners
from any exposure to the IMP. For males with partners who are of childbearing
potential, effective contraception is a combination of male condom with either
cap, diaphragm, or sponge with spermicide (double barrier methods). A man is
only considered to be infertile if he has had bilateral orchidectomy or
successful vasectomy with laboratory confirmed aspermia.
15. Cohort-specific inclusion criteria:
a) Phase 1 and Phase 2 mCRPC: Subjects who have experienced disease
progression on or after at least 1 NAAD (e.g. abiraterone, enzalutamide), and
at least 1 course (but no more than 2 courses) of taxane-based chemotherapy.
b) Phase 2 mCRPC: Subjects who have experienced disease progression on or after
at least 1 NAAD (e.g. abiraterone, enzalutamide), but have not received
previous taxane-based chemotherapy.

1. Known hypersensitivity to the therapeutic or diagnostic IMP or any of its
constituents.
2. Presence of PSMA-negative disease: PSMA-negative disease defined as any
large PSMA-negative lymph node >1 cm in the short axis and/or a PSMA-negative
bone metastasis which has a significant soft tissue component suggesting
ongoing disease activity and/or a PSMA-negative solid organ metastasis >1 cm in
the long axis. In addition, subjects with significant low PSMA-expressing
disease should be excluded.
3. Diffuse marrow infiltration of disease (*superscan* appearance on full body
99mTc bone scan). A superscan is defined as bone scintigraphy in which there is
excessive skeletal radioisotope uptake in relation to soft tissues along with
absent or faint activity in the genitourinary tract and soft tissues due to
diffuse bone/bone marrow metastases. Further details regarding this appearance
are provided in the Image Acquisition Guidelines.
4. Symptomatic spinal cord compression, or clinical or radiological findings
that are indicative of impending spinal cord compression.
5. Known history of haematological malignancy.
6. Known history of central nervous system (CNS) metastases.
7. Histological findings consistent with neuroendocrine phenotype of prostate
cancer.
8. Known history of other solid malignancy that may reduce life expectancy
and/or may interfere with disease assessment.
9. Unresolved urinary tract obstruction defined as radiographic evidence of
hydronephrosis with or without ureteric stent/nephrostomy. Where the clinical
team judges that the subject*s hydronephrosis is not obstructing, and renal
function meets the inclusion criteria, the subject may undergo 99mTc
mercaptoacetyltriglycerine scanning during the screening period and if the
result is non-obstructed, the subject can be eligible for the study.
10. Any uncontrolled significant medical, psychiatric, or surgical condition or
laboratory finding that would pose a risk to subject safety or interfere with
study participation or interpretation of individual subject results. For
cardiac conditions, this includes, but is not limited to, New York Heart
Association class III or IV congestive heart failure, history of congenital
prolonged QT syndrome, and myocardial infarction diagnosed within 6 months
prior to enrolment.
11. Ongoing treatment with bisphosphonates for bone-targeted therapy.
12. Severe urinary incontinence that would preclude safe disposal of
radioactive urine.
13. Single kidney or renal transplant or any concomitant nephrotoxic therapy
that might put the subject at high risk of renal toxicity during the study in
the judgement of the investigator.
14. Clinically significant abnormalities on a single 12-lead electrocardiogram
(ECG) at screening.
15. Previously received external beam irradiation to a field that includes more
than 30% of the bone marrow or kidneys.
16. Sponsor employees or investigator site personnel directly affiliated with
this study, and their immediate families. Immediate family is defined as a
spouse, parent, child, or sibling, whether biological or legally adopted.
17. Previous treatment with any of the following: PSMA-targeted radionuclide
therapy, Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223,
hemi-body irradiation.
18. Subjects with bilateral hip replacements or any significant metallic
implants or objects, which may in the opinion of the investigator, affect image
quality and/or dosimetry calculations.
19. Transfusion of blood products for the sole purpose of meeting the
eligibility criteria for this clinical study.
20. Participation in other studies involving IMP(s) within 28 days or 5
half-lives (whichever is longer) prior to study entry and/or during study
participation.