Anti-tumour Activity of (177Lu) rhPSMA-10.1 Injection

This is an interventional, open-label, integrated Phase 1 & 2 study to assess the safety, tolerability, radiation dosing regimen and anti-tumour activity of Lutetium (177Lu) rhPSMA-10.1 (IMP) in men with metastatic castrate-resistant prostate cancer (mCRPC). The study will consist of 2 parts: a non-randomised Phase 1 part, with safety, dose-finding, and dosimetry components, and a randomised Phase 2 part, with efficacy and safety assessments, and testing dosing regimens selected following analysis of the safety and dosimetry data in Phase 1. Both phases will include subjects with prostate-specific membrane antigen (PSMA)-positive mCRPC, which has progressed following prior therapy. Phase 1 will include a post-chemotherapy mCRPC cohort of subjects who have experienced disease progression on or after at least 1 novel androgen axis drug (NAAD) (e.g. abiraterone, enzalutamide) and at least 1 course (but no more than 2 courses) of taxane-based chemotherapy. Phase 2 will include subjects who have experienced disease progression on or after at least 1 NAAD (e.g. abiraterone, enzalutamide, apalutamide, darolutamide) but have not received previous taxane-based chemotherapy for the treatment of mCRPC.

Inclusion criteria

• Male subjects, 18 years of age or older with histologically confirmed adenocarcinoma of the prostate.
• Serum testosterone levels <50 ng/dL (1.73 nmol/L) after surgical or continued chemical castration.
• Presence of disease target or non target lesions (per RECIST v1.1) on CT/MRI and/or presence of disease on full body 99mTc bone scan performed within 28 days of screening.
• Positive disease expression of PSMA as confirmed on PSMA PET/CT scan.
• At least 4 weeks 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).
• 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 blood count, and serum biochemistry at baseline.
• Adequate contraception for patients and their partners.
• For Phase 1 mCRPC only: 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. For Phase 2 mCRPC only: Subjects who have experienced disease progression on or after at least 1 NAAD (e.g. abiraterone, enzalutamide, apalutamide, darolutamide), but have not received previous taxane-based chemotherapy for the treatment of mCRPC.

Exclusion criteria

• Known hypersensitivity to the therapeutic or diagnostic IMP or any of its constituents.
• Presence of significant PSMA-negative disease on ceCT/MRI scan
• Diffuse marrow infiltration of disease ('superscan' appearance on full body 99mTc bone scan).
• Symptomatic spinal cord compression, or clinical or radiological findings that are indicative of impending spinal cord compression.
• Known history of haematological malignancy.
• Known history of central nervous system (CNS) metastases.
• Histological findings consistent with neuroendocrine phenotype of prostate cancer.
• Known history of other solid malignancy that may reduce life expectancy and/or may interfere with disease assessment.
• Unresolved urinary tract obstruction defined as radiographic evidence of hydronephrosis with or without ureteric stent/nephrostomy.
• 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.
• Ongoing treatment with bisphosphonates for bone-targeted therapy.
• Severe urinary incontinence that would preclude safe disposal of radioactive urine.
• 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.
• Clinically significant abnormalities on a single 12 lead electrocardiogram (ECG) at screening.
• Previously received external beam irradiation to a field that includes more than 30% of the bone marrow or kidneys.
• Previous treatment with any of the following: PSMA targeted radionuclide therapy, Strontium-89, Samarium-153, Rhenium 186, Rhenium-188, Radium-223, hemi-body irradiation.
• Subjects with bilateral hip replacements or any significant metallic implants or objects, that may affect image quality and/or dosimetry calculations.
• Transfusion of blood products for the sole purpose of meeting the eligibility criteria for this clinical study.
• 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.
• Any history of clinically significant parenchymal lung disease e.g. interstitial lung disease or bullous emphysema.
• Any history of prior thoracic external beam radiotherapy.
• Presence of abnormal PSMA PET uptake in the lung parenchyma above expected physiological levels, as determined by local assessment.