An Open-label Study Comparing Lutetium (177Lu) Vipivotide Tetraxetan Versus Observation in PSMA Positive OMPC.

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of lutetium (177Lu) vipivotide tetraxetan (AAA617) in participants with oligometastatic prostate cancer (OMPC) progressing after definitive therapy to their primary tumor. The data generated from this study will provide evidence for the treatment of AAA617 in early-stage prostate cancer patients to control recurrent tumor from progressing to fatal metastatic disease while preserving quality of life by delaying treatment with androgen deprivation therapy (ADT).

Detailed Description
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All participants will be assessed for eligibility and will undergo baseline disease assessments including a mandatory gallium (68Ga) gozetotide (also known as [68Ga]Ga-PSMA-11) or piflufolastat (18F) (also known as[18F]DCFPyL) PET/CT scan and conventional imaging (i.e., CT/MRI and bone scans). Piflufolastat (18F) PET/CT scan will be performed in countries where it is approved. Stereotactic Body Radiation Therapy (SBRT) will be administered to all metastatic Prostate Cancer (PC) lesions after randomization and before the start of treatment with AAA617 or observation. The duration of SBRT procedures is approximately 3 weeks. For participants randomized to the investigational arm (AAA617), the treatment duration will be up to 4 cycles of AAA617. For participants randomized to the control arm (observation) the treatment duration will end at the last fraction of SBRT administration. The visit frequency will be every week 1 and 3 of each of the 4 cycles and every 16 weeks thereafter (for both arms) until first event of disease progression (RECIST 1.1) The study duration is approximately 6.5 years. Cross-over to AAA617 for participants in the observation arm with distant metastatic radiographic progression (MFS event) by conventional imaging, confirmed by BIRC is allowed after initiation of ADT. After the end of treatment, participants randomized to the investigational arm or crossed over from control arm will be followed for long term safety assessments every 32 weeks, until the end of this study, and after completion of this study will be enrolled into a rollover study for a total period of 10 years from first dose of AAA617. All participants will be followed for survival.

Official Title
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An International, Prospective, Open-label, Multi-center, Randomized Phase III Study Comparing Lutetium (177Lu) Vipivotide Tetraxetan (AAA617) Versus Observation to Delay Castration or Disease Recurrence in Adult Male Patients With Prostate-specific Membrane Antigen (PSMA) Positive Oligometastatic Prostate Cancer (OMPC)

Conditions
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Oligometastatic Prostate Cancer (OMPC)

Intervention / Treatment
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* Drug: AAA617


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent must be obtained prior to participation in the study Participants must be adults ≥18 years of age at the time of informed consent ECOG performance status of 0 or 1 at screening Participants must have a life expectancy ≥24 months as determined by the Investigator at screening Histologically confirmed prostate cancer prior to randomization Participants must have biochemically recurrent disease after definitive treatment to prostate by RP, (alone or with post-operative radiation to prostate bed/pelvic nodes) or XRT, (prostate alone or prostate with seminal vesicle and/or pelvic nodes) and/or brachytherapy prior to randomization. Biochemical recurrence is defined as: nadir PSA + 2 ng/mL post XRT (if participant received-radiation therapy to intact prostate) and PSA > 0.2 ng/mL and rising post RP (with or without post-operation RT) Participants must have OMPC with ≤5 PSMA-positive metastatic lesions on screening PSMA PET/CT scan (with either gallium (68Ga) gozetotide or piflufolastat (18F)) as visually assessed by BIRC based on the methodology proposed in the Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) (Eiber et al 2018); for further details, please refer to Section 8.1 and Imaging Manual. Metastatic lesions may include regional/pelvic lymph nodes (N1), distant lymph nodes (M1a), bone (M1b), lung and others visceral (M1c) except liver and brain classified using AJCC 8. When counting the number of oligometastatic lesions, each lesion is counted as distinct metastasis irrespective of its anatomical location (e.g., one pelvic and one extra-pelvic lymph node will be counted as two metastatic lesions) At least 1 PSMA-positive lesion should be a distant metastasis (M1) per AJCC8 classification at screening. For AJCC M staging, PSMA PET information should be used Participants must have a negative conventional imaging for M1 disease at screening. Note: For a participant not to be eligible, CI positive M1 lesions should be unequivocal in CI scans, i.e., potentially not attributable to findings thought to represent something other than tumor (e.g., degenerative, or post-traumatic changes or Paget's disease in bone lesions). Prior knowledge of PSMA PET positivity should not influence the radiologist (reader) in determination of CI positivity. Two different readers will be involved, one reader for PSMA PET scan and one reader for CI: Reader will be blinded to PSMA PET scan results while reading CI scans. Readers should not modify their assessment of CI scans (e.g. changing a lesion previously identified as equivocal in CI to unequivocal) after reading the PSMA PET scan. Similarly, biopsy positivity should not influence the reader in the assessment of CI positivity. More details on the reading paradigm will be provided in the imaging charter. MRI for radiation treatment planning may show M1 disease but this will not exclude the participant from the study if the lesion is deemed negative per baseline CT or bone scans. Participants with pelvic disease (N1) seen in conventional imaging are allowed if the local spread is below common iliac bifurcation (per AJCC 8 definition of local disease). Distant lymph node disease (M1a) that is visible per CI and less than 10mm in the short axis are not exclusionary irrespective of PSMA PET positivity. All metastatic lesions detected at screening should be amenable to SBRT If participants previously received SBRT for OMPC, progressive disease must be demonstrated prior to randomization (e.g., a new PSMA PET lesion). Previously treated lesions must be stable in baseline imaging scans and will not be counted towards 1-5 lesions required in this study. If a previously treated lesion was unequivocal for M1 by bone scan or CT before the previous SBRT, the participant is not eligible. Confirmation of Controlled primary tumor at screening: If local recurrence is suspected, MRI is required to rule out local relapse. Participants with MRI or PET positive local lesions require biopsy to rule out local progression. These locally recurrent participants (with biopsy proven local disease or with MRI or PET positive local lesions without biopsy) may be eligible for the study after salvage therapy to local disease. Note: Participants who previously undergone pelvic RT (salvage pelvic RT) at local recurrence after RP are allowed in the study. PSADT <10 months at screening [PSADT will be calculated using a linear regression model of the normal logarithm of PSA and time (Pound et al 1999)] Non-castration testosterone level >100 ng/dL at screening Human immunodeficiency virus (HIV)-infected participants at screening and during the study who are healthy and have a low risk of acquired immune deficiency syndrome (AIDS)-related outcomes can participate in this trial Participants must have adequate organ functions including the following laboratory values at the screening visit: Bone marrow reserve ANC ≥1.5 x 109/L Platelets ≥100 x 109/L Hemoglobin ≥9 g/dL Hepatic Total bilirubin (TBIL) ≤2 x the institutional upper limit of normal (ULN). For participants with known Gilbert's Syndrome ≤3 x ULN is permitted Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3.0 x ULN. Albumin ≥2.5 g/dL Renal eGFR ≥ 60mL/min/1.73m2 using the Modification of Diet in Renal Disease (MDRD) equation Exclusion Criteria: Participants with de novo OMPC at screening Unmanageable concurrent bladder outflow obstruction or urinary incontinence at screening. Note: participants with bladder outflow obstruction or urinary incontinence, which is manageable and controlled with best available standard of care (incl. pads, drainage) are allowed Prior therapy with: ADT including bilateral orchiectomy Participants who had XRT or RP and completed adjuvant ADT (or ADT+ Androgen Receptor Pathway Inhibitor (ARPI)) prior to recurrence are eligible to participate if the last dose of ADT (or ADT+ARPI) was before 12 months from randomization Participants who discontinued ADT due to disease progression are not allowed (i.e., CRPC participants) Other hormonal therapy. e.g., Use of estrogens, 5-α reductase inhibitors (finasteride, dutasteride), other steroidogenesis inhibitors (aminoglutethamide) First-generation anti-androgens (bicalutamide, flutamide, nilutamide, cyproterone). Second generation anti-androgens (e.g., enzalutamide, apalutamide and darolutamide) CYP17 inhibitors (e.g., abiraterone acetate, orteronel, galeterone, ketoconazole). Short term ketoconazole treatment (<28 days) is permitted. Radiopharmaceutical agents (e.g., Strontium-89, PSMA-targeted radioligand therapy) Immunotherapy (e.g., sipuleucel-T) Chemotherapy, except if administered in the adjuvant/neoadjuvant setting completed > 12 months before randomization Any other investigational or systemic agents for metastatic disease Herbal and non-herbal products that may decrease PSA levels (i.e., saw palmetto, pomegranate juice) within 28 days before randomization Use of other investigational drugs within 28 days prior to day of randomization Radiation therapy, external beam radiation therapy (EBRT), and brachytherapy within 28 days before randomization Systemic (oral/i.v./Intramuscular (IM)) corticosteroids within 28 days before randomization. Note: Short term use (≤ 4 weeks) of corticosteroids during the study is allowed if clinically indicated Concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, hormonal therapy (see ADT initiation guidance in Section 6.8.2), PARP inhibitor, biological therapy, or investigational therapy Known hypersensitivity to any of the study treatments or its excipients or to drugs of similar chemical classes Transfusion during screening procedures for the sole purpose of making a participant eligible for study inclusion Diagnosed at screening with other malignancies that are expected to alter life expectancy or may interfere with disease assessment. However, participants with a prior history of malignancy that has been adequately treated and who have been disease/treatment free for more than 3 years are eligible, as are participants with adequately treated non-melanoma skin cancer and superficial bladder cancer Concurrent serious (as determined by the Investigator) medical conditions, including, but not limited to, uncontrolled infection, known active hepatitis B or C, or other significant co-morbid conditions that in the opinion of the Investigator would impair study participation or cooperation. Participants with an active documented COVID-19 infection (any grade of disease severity) at time of informed consent may be included only when completely recovered (in accordance with local guidance) History or current diagnosis of ECG abnormalities indicating significant risk of safety for participants participating in the study such as: Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular tachycardia, and clinically significant second- or third-degree AV block without a pacemaker History of familial long QT syndrome or known family history of Torsades de Pointe Resting heart rate (physical exam or 12 lead ECG) <60 bpm History of somatic or psychiatric disease/condition that may interfere with the objectives and assessments of the study Any condition that precludes raised arms position Sexually active males unwilling to use a condom during intercourse

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Investigational arm<br>All participants will be treated with Stereotactic Body Radiation Therapy (SBRT) to all metastatic lesions followed by a dose of 7.4 GBq (200 mCi) +/- 10% of AAA617 which will be administered once every 6 weeks (1 cycle) for a planned 4 cycles. | Drug: AAA617<br>* Stereotactic Body Radiation Therapy (SBRT) followed by AAA617 will be administered once every 6 weeks (1 cycle) for a planned 4 cycles to participants randomized to the Investigational arm<br>* Other names: (177Lu) vipivotide tetraxetan;|
| No Intervention: Observational arm<br>All participants will be treated with Stereotactic Body Radiation Therapy (SBRT) to all metastatic lesions followed by observation only. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blinded Independent Review Committee (BIRC) assessed Metastasis Free Survival (MFS) | Blinded Independent Review Committee (BIRC) assessed Metastasis Free Survival (MFS) is defined as the time from randomization to first evidence of radiographically detectable bone or soft tissue distant metastasis by conventional imaging (i.e., CT/MRI and bone scans) as assessed by BIRC using RECIST 1.1 or death due to any cause, whichever occurs first. Participants who are alive without distant metastasis at the analysis data cut-off or are lost to follow-up at the time of analysis will be censored for MFS at the time of their last adequate radiographic assessment. Clinical deterioration without objective radiographic evidence will not be considered as documented distant metastasis. | From date of randomization until first evidence of radiographically detectable bone or soft tissue distant metastasis or death due to any cause, whichever occurs first, assessed up to approximately 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Key secondary endpoint: Time to Hormonal Therapy (TTHT) | Time to Hormonal Therapy (TTHT) is defined as the time from randomization to the time to Androgen Deprivation Therapy (ADT). The type of hormonal therapy will be at the discretion of the Investigator. | From date of randomization until date of Androgen Deprivation Therapy (ADT), assessed up to approximately 74 months | 
| Investigator assessed Metastasis Free Survival (MFS) | Investigator assessed Metastasis Free Survival (MFS) is defined as the time from randomization to the first evidence of radiographically detectable bone or soft tissue distant metastasis by conventional imaging (i.e., CT/MRI and bone scans) as assessed by Investigator using RECIST 1.1 or death from any cause, whichever occurs first | From date of randomization until first evidence of radiographically detectable bone or soft tissue distant metastasis or death from any cause, whichever occurs first, assessed up to approximately 74 months | 
| Time to prostate specific antigen (PSA) progression (TTPSAP) | Time to prostate specific antigen (PSA) progression (TTPSAP) is defined as time from randomization to first PSA progression 1. First PSA progression 1 is defined as a rising PSA confirmed on repeated measurement at least 3 weeks later, and at least greater than 25% and ≥2 ng/mL above nadir or baseline, whichever is lower. | From date of randomization until date of first PSA progression, assessed up to approximately 74 months | 
| Radiographic Progression Free Survival (rPFS) | Radiographic progression free survival (rPFS) is defined as the time from randomization to first documentation of confirmed radiographic progressive disease or death due to any cause (whichever occurs first) by conventional imaging (i.e., CT/MRI and bone scans) using RECIST 1.1. The rPFS will be analyzed based on BIRC and Investigator assessments respectively. | From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 74 months | 
| Time to next therapy (local or systemic) | Time to next therapy (local or systemic) is defined as the time from randomization to initiation of the next line of therapy (local or systemic). Next-line therapy is defined as the first new (local or systemic) anti-neoplastic therapy initiated after discontinuation of study treatment regardless of end of treatment (EOT) reason. | From date of randomization until initiation of the next line of therapy (local or systemic), assessed up to approximately 74 months | 
| 24-month PSA PFS | 24-month PSA PFS (>= 0.5 ng/mL) is defined as PSA PFS at 24 months. PSA PFS is defined as the time from date of randomization to the date of first documented PSA progression 2 or death from any cause, whichever occurs first. PSA progression 2 is defined as a PSA concentration above the nadir (or baseline if lower) of >= 0.5 ng/mL, confirmed by repeated measurement at least 3 weeks later | From date of randomization until date of first documented PSA progression 2 or death from any cause, whichever occurs first, assessed up to approximately 74 months | 
| Time to symptomatic progression | Time to symptomatic progression is defined as time from randomization to deterioration in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) assessed by the Investigator as clinical progression, escalation in cancer-related pain and worsening of disease-related symptoms both leading to the initiation of a new systemic anticancer therapy or the time to the development of clinically significant symptoms due to local or regional tumor progression leading to surgery or radiation therapy. | From date of randomization until deterioration in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS), assessed up to approximately 74 months | 
| Functional Assessment of Cancer Therapy - Prostate (FACT-P) Questionnaire | FACT-P assesses symptoms/problems related to prostate carcinoma and its treatment. It is a combination of the FACT- General + the Prostate Cancer Subscale (PCS). The FACTGeneral (FACT-G) is a 27 item Quality of Life (QoL) measure that provides a total score as well as subscale scores: Physical (0-28), Functional (0-28), Social (0-28), and Emotional Well-being (0-24). The total score range is between 1-108, higher scores indicates better for total score and subscale scores. PCS is a 12-item prostate cancer subscale that asks about symptoms and problems specific to prostate cancer (Range 0-48, higher scores better). The FACT-P total score is the sum of all 5 subscale scores of the FACT-P questionnaire and ranges from 0-156. Higher scores indicate higher degree of functioning and better quality of life. | From date of randomization up till 42 day safety Follow-up, assessed up to approximately 74 months | 
| Brief Pain Inventory - Short Form (BPI-SF) Questionnaire | The BPI-SF is a publicly available instrument to assess the pain and includes severity and interference scores. BPI-SF is an 11-item selfreport questionnaire that is designed to assess the severity and impact of pain on daily functions of a participant. Pain severity score is a mean value for BPI-SF questions 3, 4, 5 and 6 (questions inquiring about the extent of pain, where the extent is ranked from 0 [no pain] to 10 [pain as bad as you can imagine]). Pain severity progression is defined as an increase in score of 30% or greater from baseline without decrease in analgesic use. | From date of randomization up till 42 day safety Follow-up, assessed up to approximately 74 months | 
| European Quality of Life (EuroQol) - 5 Domain 5 Level scale (EQ-5D- 5L) | EQ-5D-5L is a standardized participant completed questionnaire that measures health-related quality of life and translates that score into an index value or utility score. EQ-5D-5L consists of two components: a health state profile and an optional visual analogue scale (VAS). EQ-5D health state profile is comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1= no problems, 2= slight problems, 3= moderate problems, 4= severe problems, and 5= extreme problems. Higher scores indicated greater levels of problems across each of the five dimensions. | From date of randomization up till 42 day safety Follow-up, assessed up to approximately 74 months | 
| Time to First Symptomatic Skeletal Event (TTSE) | Time to SSE (TTSSE) defined as date of randomization to the date of first new symptomatic pathological bone fracture, spinal cord compression, tumor-related orthopedic surgical intervention, requirement for radiation therapy to relieve bone pain or death from any cause, whichever occurs first | From date of randomization till end of treatment (EOT) or death, whichever happens first, assessed up to approximately 74 months | 
| Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) | The distribution of adverse events will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters. | From date of randomization up till 42 day safety Follow-up, assessed up to approximately 74 months | 
| Dose modifications and intensity for AAA617 | Dose modifications (dose interruptions and reductions) and dose intensity for AAA617 will be assessed and summarized using descriptive statistics. | From date of randomization until end of treatment (EOT), assessed up to approximately 30 months | 
| Overall survival (OS) | Overall Survival (OS) is defined as the time from the date of randomization to the date of death due to any cause. OS time for participants who are alive at the end of the study or are lost to follow-up will be censored at the date of last contact. | From date of randomization until date of death from any cause, assessed up to approximately 74 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lutetium (177Lu) vipivotide tetraxetan, Oligometastatic Prostate Cancer (OMPC), Metastasis Free Survival (MFS), gallium (68Ga) gozetotide, piflufolastat (18F), prostate-specific membrane antigen (PSMA), Delay Castration