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

Study Overview
=================
Brief Summary
-----------------
To determine the dose, safety, radiation dosimetry and efficacy of 177Lu-rhPSMA-10.1 in participants with PSMA-expressing metastatic castrate resistant prostate cancer.

Detailed Description
-----------------
This is an interventional, non-randomised, open-label, integrated Phase 1 & 2 study to assess the safety, radiation dosing regimen and anti-tumour activity of Lutetium (177Lu) rhPSMA-10.1 (Tx IMP) in men with metastatic castrate-resistant prostate cancer (mCRPC). The study will consist of 2 parts: a Phase 1, with safety, dose-finding, and dosimetry components, and a Phase 2, with assessment of efficacy and safety utilising the dose selected from Phase 1. Both phases will include subjects with prostate-specific membrane antigen (PSMA)-positive mCRPC as detected using 18F-rhPSMA-7.3 diagnostic IMP.

Official Title
-----------------
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

Conditions
-----------------
Prostate Cancer, Metastatic Castration-resistant Prostate Cancer, mCRPC, Urogenital Neoplasms, Prostatic Neoplasms, Prostatic Diseases

Intervention / Treatment
-----------------
* Drug: 177Lu-rhPSMA-10.1 injection
* Diagnostic Test: 18F-rhPSMA-7.3 injection


Participation Criteria
=================
Eligibility Criteria
-----------------
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 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. Cohorts: Phase 1 and Phase 2 post-chemotherapy mCRPC Phase 2 taxane-naïve 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1, Cohort A<br>Subjects with PSMA positive disease will receive 5.55GBq of 177Lu-rhPSMA-10.1 (maximum of 3 cycles). | Drug: 177Lu-rhPSMA-10.1 injection<br>* Therapeutic cycles of 177Lu-rhPSMA-10.1<br>* Other names: 177Lu-rhPSMA-10.1;Diagnostic Test: 18F-rhPSMA-7.3 injection<br>* 18F-rhPSMA-7.3 at an administered activity of 296 MBq (8 mCi) for PET/CT scan to ascertain whether the subject has PSMA-positive disease.<br>* Other names: 18F-rhPSMA-7.3;|
| Experimental: Phase 1, Cohort B<br>Subjects with PSMA positive disease will receive 7.4GBq of 177Lu-rhPSMA-10.1 (maximum of 2 cycles). | Drug: 177Lu-rhPSMA-10.1 injection<br>* Therapeutic cycles of 177Lu-rhPSMA-10.1<br>* Other names: 177Lu-rhPSMA-10.1;Diagnostic Test: 18F-rhPSMA-7.3 injection<br>* 18F-rhPSMA-7.3 at an administered activity of 296 MBq (8 mCi) for PET/CT scan to ascertain whether the subject has PSMA-positive disease.<br>* Other names: 18F-rhPSMA-7.3;|
| Experimental: Phase 2, Cohort 1, post-chemotherapy mCRPC<br>Subjects with PSMA positive disease will receive up to 6 cycles of the Therapeutic IMP at the Recommended Phase 2 dose [RP2D] | Drug: 177Lu-rhPSMA-10.1 injection<br>* Therapeutic cycles of 177Lu-rhPSMA-10.1<br>* Other names: 177Lu-rhPSMA-10.1;Diagnostic Test: 18F-rhPSMA-7.3 injection<br>* 18F-rhPSMA-7.3 at an administered activity of 296 MBq (8 mCi) for PET/CT scan to ascertain whether the subject has PSMA-positive disease.<br>* Other names: 18F-rhPSMA-7.3;|
| Experimental: Phase 2, Cohort 2, Taxane-naïve mCRPC<br>Subjects with PSMA positive disease will receive up to 6 cycles of the Therapeutic IMP at the Recommended Phase 2 dose [RP2D] . | Drug: 177Lu-rhPSMA-10.1 injection<br>* Therapeutic cycles of 177Lu-rhPSMA-10.1<br>* Other names: 177Lu-rhPSMA-10.1;Diagnostic Test: 18F-rhPSMA-7.3 injection<br>* 18F-rhPSMA-7.3 at an administered activity of 296 MBq (8 mCi) for PET/CT scan to ascertain whether the subject has PSMA-positive disease.<br>* Other names: 18F-rhPSMA-7.3;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 Incidence of DLTs | Incidence of DLTs during the DLT observation period. | 6 weeks post final IMP | 
| Phase 1 Frequency and nature of TEAEs | Frequency and nature of treatment-emergent adverse events (TEAEs). | End of study | 
| Phase 2, anti-tumour response | The number of subjects with an anti-tumour response defined as ≥50% reduction in PSA level from baseline. | 12 weekly intervals | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
PSMA, mCRPC, Prostate cancer, 177Lu rhPSMA-10.1, 18F-rhPSMA-7.3, BET-PSMA-121, Blue Earth Therapeutics Limited, Radiohybrid, Radiopharmaceuticals