177Lu-DOTA-rosopatamab With Best Standard of Care (SoC) for the Second Line of Treatment for Metastatic Castrate-resistant Prostate Cancer, Which Expresses PSMA (PROSTACT)

177Lu-DOTA-rosopatamab With Best Standard of Care (SoC) for the Second Line of Treatment for Metastatic Castrate-resistant Prostate Cancer, Which Expresses PSMA

A Multinational, Multicenter, Prospective, Randomized, Controlled, Open Label Phase 3 Study With Best Standard of Care With and Without 177Lu-DOTA-rosopatamab for Patients With PSMA Expressing Metastatic Castration-resistant Prostate Cancer Progressing Despite Prior Treatment With a Novel Androgen Axis Drug

This multinational, multicenter, prospective, randomized, controlled, open label Phase 3 study is designed to investigate and confirm the benefits and risks associated with the PSMA-targeted antibody, 177Lu DOTA rosopatamab administered together with Standard of Care (SoC), as compared to the best SoC alone. The phase 3 will be conducted in patients with metastatic castration-resistant PC (mCRPC) that expresses PSMA and has progressed despite prior treatment with a novel androgen axis drug (NAAD).

This multinational, multicenter, prospective, randomized, controlled, open label Phase 3 study is designed to investigate and confirm the benefits and risks associated with 177Lu DOTA rosopatamab administered together with SoC, as compared to the best SoC alone, in patients with PSMA-positive, metastatic castration-resistant PC (mCRPC) that has progressed despite prior treatment with a novel androgen axis drug (NAAD). PSMA positivity will be defined by gallium-68 labeled PSMA-11 (68Ga-PSMA-11) positron emission tomography/computerized tomography (PET/CT) as at least one site of metastatic disease with intensity significantly greater than normal liver (i.e., standardized uptake value [SUV] max at least 1.5 times SUV of normal liver. Approximately 387 eligible patients will be randomized to one of two groups in a 2:1 ratio to receive one of the following treatments: Group A: Two single intravenous (IV) injections of 76 mCi each (equivalent to a 45 mCi/m2 dose in a standard 1.7m2 individual) of 177Lu-DOTA- rosopatamab, given 14 days apart, plus best SoC Group B: Best SoC. Randomization of patients to each group will be stratified by the following clinical factors: Prior taxane therapy (yes/no) Prior NAAD in non-metastatic (nm) and/or castration-sensitive (cs) setting (yes/no) Disease burden (defined as: number of bone metastases on 68Ga-PSMA scan < or ≥ 10). Visceral disease (yes/no) Collection of information on prior and concomitant medications and adverse events (AEs), as well as the review of temporary contra-indications and conditions for withdrawal, will occur at every interaction with the patients. Screening (Day -28 to Day -1, Visit 1) Screening procedures will take place from 28 days (Day -28 to Day -1) prior to enrollment and randomization (on Day 0). Potential participants who provide voluntary written informed consent will undergo Screening evaluations at the clinical site, including a review of the study inclusion/exclusion criteria, full physical examination, safety assessments including safety laboratory investigations (hematology, biochemistry, coagulation, and urinalysis), measurement of vital signs (systolic and diastolic blood pressures, respiratory rate, pulse rate, and body temperature), ECG, imaging (68Ga-PSMA-11 PET/CT scan, Technetium-99m [99mTc] bone scan - if not available from previous records within the last 4 weeks), and CT or MRI (magnetic resonance imaging ) scan (if not available from previous records within the last 4 weeks) as outlined in the Schedule of Assessments. Demographics, height and body weight, medical history, concomitant medication information, performance status assessment using Eastern Cooperative Oncology Group (ECOG), and health-related quality of life (HRQoL) assessment will be undertaken and blood samples for biomarker and CD4/CD8 subset analyses will be collected. Treatment Period (Day 1 [Visit 2] to Day 15 ± 1 [Visit 3]) Patients will return to the clinical site as outpatients on Day 1 (Visit 2) and their eligibility for study participation will be confirmed. Patients meeting all inclusion and no exclusion criteria will be enrolled and randomized. Safety parameters will be assessed, including collection of clinical laboratory samples, measurement of vital signs, ECG, symptom-directed physical examination, collection of ADA samples, and assessment of performance status using ECOG. Patients in Group A will be administered 177Lu-DOTA-rosopatamab on Day 1 (Visit 2). Administration of 177Lu-DOTA-rosopatamab will be performed under the supervision of a nuclear medicine or radiotherapy physician. Patient follow-up and management will be conducted by urologic or oncologic specialists skilled in the management of PC clinical trials. For all patients, the best SoC will be determined by the Principal Investigator (PI). Note: Investigational agents, any form of anti-neoplastic regimens including chemotherapy, platinum based anti-neoplastic drugs, poly adenosine diphosphate ribose polymerase (PARP) inhibitors, other systemic radioisotopes, and hemi-body radiotherapy are excluded from use as best SoC. Use of NAADs, such as abiraterone or enzalutamide, is permitted. Prophylactic use of antihistaminic and/or paracetamol/acetaminophen prior to dosing of the investigational medicinal product (IMP; first and/or second dose) will be allowed at PI(s)'s discretion. All patients will return to the clinical site on Day 15 (Visit 3) for safety monitoring, collection of clinical laboratory samples, collection of samples for urinalysis, collection of samples for biomarker analyses, measurement of vital signs, ECG, symptom-directed physical examination, and assessment of performance status using ECOG. Patients in Group A who do not meet any of the activity reduction criteria (see section below) will also be administered 177Lu-DOTA-rosopatamab on Day 15 (Visit 3). Before administration of the second dose of 177Lu-DOTA-rosopatamab, patients will be assessed and if the hematological toxicity is noted , the patient will undergo a reduction in the administered activity of 177Lu but the rosopatamab total dose will remain at 20mg. Screening (Day -28 to Day -1, Visit 1) Screening procedures will take place from 28 days (Day -28 to Day -1) prior to enrollment and randomization (on Day 0). Potential participants who provide voluntary written informed consent will undergo Screening evaluations at the clinical site, including a review of the study inclusion/exclusion criteria, full physical examination, safety assessments including safety laboratory investigations (hematology, biochemistry, coagulation, and urinalysis), measurement of vital signs (systolic and diastolic blood pressures, respiratory rate, pulse rate, and body temperature), ECG, imaging (68Ga-PSMA-11 PET/CT scan, Technetium-99m [99mTc] bone scan - if not available from previous records within the last 4 weeks), and CT or MRI (magnetic resonance imaging ) scan (if not available from previous records within the last 4 weeks) as outlined in the Schedule of Assessments. Demographics, height and body weight, medical history, concomitant medication information, performance status assessment using Eastern Cooperative Oncology Group (ECOG), and health-related quality of life (HRQoL) assessment will be undertaken and blood samples for biomarker and CD4/CD8 subset analyses will be collected. Treatment Period (Day 1 [Visit 2] to Day 15 ± 1 [Visit 3]) Patients will return to the clinical site as outpatients on Day 1 (Visit 2) and their eligibility for study participation will be confirmed. Patients meeting all inclusion and no exclusion criteria will be enrolled and randomized. Safety parameters will be assessed, including collection of clinical laboratory samples, measurement of vital signs, ECG, symptom-directed physical examination, collection of ADA samples, and assessment of performance status using ECOG. Patients in Group A will be administered 177Lu-DOTA-rosopatamab on Day 1 (Visit 2). Administration of 177Lu-DOTA-rosopatamab will be performed under the supervision of a nuclear medicine or radiotherapy physician. Patient follow-up and management will be conducted by urologic or oncologic specialists skilled in the management of PC clinical trials. For all patients, the best SoC will be determined by the Principal Investigator (PI). Note: Investigational agents, any form of anti-neoplastic regimens including chemotherapy, platinum based anti-neoplastic drugs, poly adenosine diphosphate ribose polymerase (PARP) inhibitors, other systemic radioisotopes, and hemi-body radiotherapy are excluded from use as best SoC. Use of NAADs, such as abiraterone or enzalutamide, is permitted. Prophylactic use of antihistaminic and/or paracetamol/acetaminophen prior to dosing of the investigational medicinal product (IMP; first and/or second dose) will be allowed at PI(s)'s discretion. All patients will return to the clinical site on Day 15 (Visit 3) for safety monitoring, collection of clinical laboratory samples, collection of samples for urinalysis, collection of samples for biomarker analyses, measurement of vital signs, ECG, symptom-directed physical examination, and assessment of performance status using ECOG. Patients in Group A who do not meet any of the activity reduction criteria (see section below) will also be administered 177Lu-DOTA-rosopatamab on Day 15 (Visit 3). Before administration of the second dose of 177Lu-DOTA-rosopatamab, patients will be assessed and if the hematological toxicity is noted as per the below table, the patient will undergo a reduction in the administered activity of 177Lu but the rosopatamab total dose will remain at 20mg. Short-Term Follow-up Visits (Day 22 ± 3 [Visit 4] to Day 113 ± 7 [Visit 9]) All patients will return to the clinical site on Day 22 (Visit 4) for safety monitoring, collection of clinical laboratory samples, collection of samples for urinalysis, measurement of vital signs, symptom-directed physical examination, and assessment of performance status using ECOG. All patients will return to the clinical site on Day 29 (Visit 5) for safety monitoring, collection of clinical laboratory samples, collection of samples for urinalysis, collection of samples for biomarkers and CD4/CD8 subset analysis, measurement of vital signs, symptom-directed physical examination, collection of ADA samples, and assessment of performance status using ECOG and HRQoL. Patients will return to the clinical site on Day 36, 43*, 57, and 113 (Visits 7, 8, 9, and 10) for collection of hematology, biochemistry and coagulation samples, measurement of vital signs, symptom-directed physical examination, and assessment of performance status using ECOG. On Day 57 (Visit 8) and Day 113 (Visit 9) only, assessment of HRQoL and collection of samples for urinalysis will also be conducted. Collection of samples for biomarker and CD4/CD8 subset analysis, 68Ga-PSMA-11 PET/CT and 99mTc bone scans, and CT or MRI scans will occur on Day 57 (Visit 8) only. *Note patients with hematological toxicity will be followed closely until hematological recovery. Complete blood count (CBC) should be collected at least weekly for patients who have not had count recovery by Day 43 until recovery to Grade 2 or higher. Hematology, biochemistry, coagulation and urinalysis testing will only be performed on Day 113 as clinically indicated. Hematology, biochemistry, coagulation and urinalysis testing will only be performed on Day 113 as clinically indicated. Long-Term Follow-up Visits (Day 169 ± 7 [Visit 10] up to 5 years after enrollment in the study) Patients will return to site on Day 169 (Visit 10), Day 253 (Visit 11), Day 337 (Visit 12) and once a year thereafter from time of enrollment (at Years 1, 2, 3, 4, and 5) for collection of samples for biomarker analyses, measurement of vital signs, symptom-directed physical examination, collection of ADA samples (Day 169, Years 1 and 5 only), and assessment of performance status using ECOG and HRQoL, hematology, biochemistry and urinalysis. 99mTc bone scans and CT or MRI scans will also be conducted at all timepoints and 68Ga-PSMA-11 PET/CT will be conducted on Day 169 (Visit 10), Day 253 (Visit 11), and Day 337 (Visit 12).

prostate cancer, 177Lu-DOTA-TLX591, progression free survival, overall survival, safety, gallium-68 labeled PSMA-11 (68Ga-PSMA-11) PET/CT Scan, novel androgen axis drug

Approximately 387 eligible patients will be randomized to one of two groups in a 2:1 ratio to receive one of the following treatments: Group A: Two single intravenous (IV) injections of 76 mCi each (equivalent to a 45 mCi/m2 dose in a standard 1.7m2 individual) of 177Lu-DOTA- rosopatamab, given 14 days apart, plus best SoC Group B: Best SoC.

Two single intravenous (IV) injections of 76 mCi each (equivalent to a 45 mCi/m2 dose in a standard 1.7m2 individual) of 177Lu-DOTA- rosopatamab, given 14 days apart, plus best Standard of Care

Two single intravenous (IV) injections of 76 mCi each (equivalent to a 45 mCi/m2 dose in a standard 1.7m2 individual) of 177Lu-DOTA- rosopatamab, given 14 days apart, plus best SoC

Radiographic progression-free survival (rPFS) defined as the time from randomization to disease progression confirmed by central independent radiology review according to RECIST 1.1 (for soft tissue disease) and/or PCWG3 criteria (for bone disease), or death (whichever occurs first).

Tumor response in terms of objective response rate (ORR) (malignant soft tissue response and overall radiological response [malignant soft tissue response by RECIST 1.1 and overall radiological response by RECIST 1.1 and PCWG3]).

Time to a first SSE, defined as the use of external beam radiation to relieve bone pain, or occurrence of a new symptomatic pathological fracture (vertebral or non-vertebral), or occurrence of spinal cord compression, or tumor-related orthopedic surgical intervention

PFS defined as the time from randomization to disease progression confirmed by radiology, clinical or PSA progression, or death (whichever occurs first).

Assessment of AEs graded by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0, vital signs (systolic and diastolic blood pressures, respiratory rate, pulse rate, and body temperature), ECGs, and evaluation of laboratory parameters (biochemistry, hematology, coagulation, and urinalysis).

Quality of Life is to be evaluated using the ECOG Performance Scale, Functional Assessment of Cancer Therapy-Prostate (FACT-P), and Brief Pain Inventory - Short Form (BPI-SF) questionnaires

Inclusion Criteria: Be a male, at least 18 years old, with metastatic adenocarcinoma of the prostate defined by histological / pathological confirmation of PC. Be of ECOG Performance Status 0, 1, or 2 and have an estimated life expectancy of ≥6 months. Have metastatic disease (≥1 metastatic lesions present on baseline CT, MRI, or bone scan imaging). Have castration-resistant PC (defined as disease progressing despite castration by orchiectomy or ongoing use of luteinizing hormone-releasing hormone [LHRH]) and must have a castrate level of serum/plasma testosterone (<50 ng/dL or <1.7 nmol/L). In the mCRPC setting, must have received a minimum of 12 weeks of prior therapy with a NAAD, either enzalutamide or abiraterone plus prednisone. Should have received one line of prior taxane therapy or have refused or be ineligible for taxanes Have a disease that is progressing at study entry, despite a castrate testosterone level (<50 ng/dL or <1.7 nmol/L), by the demonstration of at least one of the following: Rising PSA values done in sequence at least 1 week apart and with a minimal starting value of 2.0 ng/mL. Progressive disease or new lesion(s) in the viscera or lymph nodes as per RECIST1.1 or in bone as per Prostate Cancer Working Group 3 [PCWG3; Scher et al., 2016]). Any ambiguous results are to be confirmed by other imaging modality (e.g., CT or MRI scan). Have disease that is PSMA positive, as demonstrated by a 68Ga-PSMA11 PET/CT scan and confirmed as eligible by the Sponsor's central reader (patient must have at least one site of metastatic disease with SUVmax ≥1.5 times the SUV of normal liver). If the disease meets the criteria for PSMA positivity, but there is one or more soft tissue lesion of ≥ 2 cm that is not PSMA positive, then the patient is to be excluded on the grounds that there is substantial disease which might not respond to the therapy. Must have recovered to ≤ Grade 2 from all clinically significant toxicities related to prior therapies (i.e., surgery, local radiotherapy, NAAD, chemotherapy, etc.). Can be receiving a bisphosphonate or denosumab regimen provided that the patient has been receiving and tolerating this treatment for ≥30 days prior to randomization. Have adequate organ function at Screening: a. Bone marrow: i. Platelets ≥150×109/L. ii. Absolute neutrophil count >1.5×109/L. iii. Hemoglobin ≥10g/dL (no red blood cell transfusion in the previous 4 weeks). b. Liver function: i. Total bilirubin < 1.5×the upper limit of normal (ULN). For patients with known Gilbert's Syndrome <3×ULN is permitted. ii. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) <3×ULN OR <5×ULN for patients with liver metastases. c. Renal function: i. Serum/plasma creatinine <1.5×ULN or creatinine clearance ≥50 mL/min determined using the Cockcroft & Gault formula. Have the capacity to understand the study and be able and willing to comply with all protocol requirements. Patients must comply with the radiation protection rules (including hospital admissions and isolation) that are used by the treating institution in order to protect their contacts and the general public, especially if a female partner of the patient is or could be pregnant. Must agree to practice adequate precautions to prevent pregnancy in a partner and to avoid potential problems associated with radiation exposure to the unborn child (Refer to Clinical Trials Facilitation Group, 2020: Recommendations related to contraception and pregnancy testing in clinical trials Version 1.1, CTFG, 2020). Exclusion Criteria: Are unable to understand or are unwilling to sign a written informed consent document or to follow investigational procedures in the opinion of the Investigator. Have PC associated with pathological findings consistent with small cell or any histology other than adenocarcinoma of the prostate. If there are minor elements of neuroendocrine histology, this is acceptable. Uncontrolled pain. Diagnosed with other malignancies that are expected to alter life expectancy or may interfere with disease assessment. However, patients with a prior history of malignancy that has been adequately treated and who have been disease-free for more than 3 years are eligible, as are patients with adequately treated non-melanoma skin cancer, and superficial bladder cancer. Are at increased risk of hemorrhage or bleeding, or with a recent history of a thrombolytic event (e.g., deep vein thrombosis [DVT]/ pulmonary embolism [PE]) and have been administered long-term anti-coagulant or anti-platelet agents. Have received prior treatment with monoclonal antibody (mAb) J591 or HuJ591 or any other PSMA targeted therapy. Have known allergies, hypersensitivity, or intolerance to the investigational drug or its excipients. Have received prior systemic anti-cancer therapy (e.g., chemotherapy, immunotherapy, or biological therapy) and/or radiation therapy within 4 weeks of randomization OR if any significant AEs have not resolved to National Cancer Institute (NCI) AE Criteria ≤2; OR are receiving other concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, or investigational therapy. Have received prior treatment with radioisotopes, including but not limited to: 89Strontium, 153Samarium, 186Rhenium, 188Rhenium, 223Radium, or hemi-body irradiation within 6 months prior to randomization. Have received other investigational therapy within 4 weeks of randomization. Have known brain metastases or hepatic metastases. Have a history of seizure and/or stroke within past 6 months. Have clinical or radiologic findings indicative of impending cord compression or experience symptomatic cord compression. Have a serious active or sub-clinical infection or angina pectoris (New York Heart Association [NYHA] Class III or IV), significantly prolonged QT interval or other serious illness(es) involving the cardiac, respiratory, central nervous system, renal, hepatic or hematological organ systems, which might impair the ability to complete this study or could interfere with determination of causality of any adverse effects experienced in this study, or which require treatment that could interact with study treatment, particularly with enzalutamide. Have received treatment with any PARP inhibitors (i.e., Olaparib) or with any platinum based anti-neoplastic drugs. Have a known alteration in breast cancer genes (BRCA) BRCA1, BRCA2, or Ataxia Telangiectasia Mutated Gene (ATM) gene and are eligible to receive Olaparib therapy according to their institution's SoC