A Phase II Study of AAA617 Alone and AAA617 in Combination With ARPI in Patients With PSMA PET Scan Positive CRPC

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 AAA617 alone (Lutetium [177Lu] vipivotide tetraxetan) and in combination with an Androgen Receptor Pathway Inhibitors (ARPI) in participants with PSMA-positive, castration-resistant prostate cancer and no evidence of metastasis in conventional imaging (CI) (i.e., CT/MRI and bone scans). Approximately 120 participants will be randomized.

Official Title
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An International Prospective Open-label, Multi-center, Randomized, Non-comparative Phase II Study of Lutetium [177Lu] Vipivotide Tetraxetan (AAA617) Alone and Lutetium [177Lu] Vipivotide Tetraxetan (AAA617) in Combination With Androgen Receptor Pathway Inhibitors in Patients With PSMA PET Scan Positive Castration-Resistant Prostate Cancer

Conditions
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Prostatic Neoplasm

Intervention / Treatment
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* Drug: AAA617
* Drug: AAA517
* Drug: Piflufolastat F 18
* Drug: ARPI
* Drug: ADT
* Other: Best supportive care


Participation Criteria
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Eligibility Criteria
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Key Inclusion criteria Participants must be adults ≥ 18 years of age with signed informed consent prior to participation to study Histologically or cytologically confirmed prostate cancer Participants must have ongoing androgen deprivation therapy with a GnRH agonist/antagonist or prior bilateral orchiectomy Castrate level of serum testosterone (< 1.7 nmol/l [50 ng/dl]) on GnRH agonist or antagonist therapy or after bilateral orchiectomy Participants must have evidence of PSMA-positive disease as seen on a AAA517 or piflufolastat F 18 PET/CT scan at baseline as determined by Blinded Independent Central Review (BICR) based on the methodology proposed in the Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) (Eiber et al 2018). Participants with M1 disease only on PSMA PET scan are allowed to participate Participants must have a negative conventional imaging for M1 disease. PSA Doubling Time (PSADT) of ≤ 10 months Participants must have adequate organ functions: bone marrow reserve, hepatic & renal Key Exclusion criteria Prior or present evidence of metastatic disease as assessed by CT/MRI locally for soft tissue disease and whole-body radionuclide bone scan for bone disease. Exception: Participants with soft tissue pelvic disease may be eligible (e.g., participants with enlarged lymph nodes below the aortic bifurcation (N1) are eligible if the short axis of the largest lymph node is <20 mm) Unmanageable concurrent bladder outflow obstruction or urinary incontinence. Note: participants with bladder outflow obstruction or urinary incontinence, which is manageable with best available standard of care (incl. pads, drainage) are allowed Active clinically significant cardiac disease; history of seizure or condition that may pre-dispose to seizure which may require treatment with surgery or radiation therapy Prior therapy with: second generation anti-androgens (e.g., enzalutamide, apalutamide and darolutamide); CYP17 inhibitors (e.g., abiraterone acetate, orteronel, galeterone, ketoconazole; 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 > 2 years before randomization; any other investigational agents for CRPC; use of estrogens, 5-α reductase inhibitors (finasteride, dutasteride), other steroidogenesis inhibitors (aminoglutethimide) or first-generation anti-androgens (bicalutamide, flutamide, nilutamide, cyproterone) within 28 days before randomization; radiation therapy (external beam radiation therapy [EBRT] and brachytherapy within 28 days before randomization Other concurrent cytotoxicity chemotherapy, immunotherapy, radioligand therapy, poly adenosine diphosphate-ribose polymerase (PARP) inhibitor, biological therapy or investigational therapy Other protocol-defined inclusion/exclusion criteria may apply.

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
Interventional Model Description: No cross-over allowed
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Participants will receive 7.4 GBq (+/- 10%) of AAA617 (Lutetium [177Lu] vipivotide tetraxetan) once every 6 weeks for 6 cycles. ADT must be ongoing; Best supportive care is allowed. | Drug: AAA617<br>* Administration intravenously once every 6 weeks (1 cycle) for 6 cycles<br>* Other names: 177Lu-PSMA-617;Drug: AAA517<br>* Single intravenous dose of approx. 150 Megabecquerel (MBq) prior PSMA-PET scans<br>* Other names: 68Ga-PSMA-11;Drug: Piflufolastat F 18<br>* Single intravenous dose of approx. 333 Megabecquerel (MBq) prior PSMA-PET scans<br>Drug: ADT<br>* as prescribed by the local investigator<br>Other: Best supportive care<br>* as prescribed by the local investigator<br>|
| Experimental: Arm B<br>Participants will receive 7.4 GBq (+/- 10%) of AAA617 (Lutetium [177Lu] vipivotide tetraxetan) once every 6 weeks for 6 cycles. In addition of SOC (ADT plus choice of ARPI as per physician's decision), Best supportive care is allowed. | Drug: AAA617<br>* Administration intravenously once every 6 weeks (1 cycle) for 6 cycles<br>* Other names: 177Lu-PSMA-617;Drug: AAA517<br>* Single intravenous dose of approx. 150 Megabecquerel (MBq) prior PSMA-PET scans<br>* Other names: 68Ga-PSMA-11;Drug: Piflufolastat F 18<br>* Single intravenous dose of approx. 333 Megabecquerel (MBq) prior PSMA-PET scans<br>Drug: ARPI<br>* Enzalutamide, Darolutamide, Apalutamide as prescribed by the local investigator<br>Drug: ADT<br>* as prescribed by the local investigator<br>Other: Best supportive care<br>* as prescribed by the local investigator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PSA response | PSA response is defined as the time of PSA nadir value of =< 0.2 ng/mL is confirmed by a second (the next) PSA measurement at least 4 weeks later | From randomization until PSA nadir value of =< 0.2 ng/mL that is confirmed by a second (the next) PSA measurement >= 4 weeks later, up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metastatic Free Survival (MFS) | MFS is defined as the time from date of randomization to the first evidence of radiographically detectable bone or soft tissue distant metastasis by conventional imaging using RECIST 1.1 or death. | From date of randomization until date of progression or date of death whichever occurs first, up to 5 years | 
| Radiographic Progression Free Survival (rPFS) | rPFS is defined as the time from the date of randomization to the date of first documented radiographic disease progression by conventional imaging assessed using RECIST 1.1 or death. | From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, up to 5 years | 
| Overall Survival (OS) | OS defined as date of death due to any cause | From date of randomization until date of death from any cause, up to 5 years | 
| second Progression Free Survival (PFS2) | PFS2 defined as time from the date of randomization to the date of first documented disease progression by investigator's assessment (PSA, radiographic, symptomatic, or any combination) on next line of therapy subsequent to MFS event or death due to any cause, whichever occurs first | From date of randomization until date of second progression or date of death from any cause, whichever comes first, assessed up to 5 years | 
| Time to symptomatic progression | Time to symptomatic progression will be defined as the time from the date of randomization to the date of first documented event for any of the following: Development of a symptomatic skeletal event (SSE) Pain progression or worsening of disease-related symptoms requiring initiation of a new systemic anti-cancer therapy Development of clinically significant symptoms due to loco-regional tumor progression requiring surgical intervention or radiation therapy | From date of randomization until development of a symptomatic skeletal event, new systemic anti-cancer therapy, surgical intervention or radiation therapy, whichever occurs first, up to 5 years | 
| Time to initiation of cytotoxic chemotherapy | Time to initiation of cytotoxic chemotherapy will be defined as the time from the date of randomization to the date of first documented dose of new cytotoxic chemotherapy being administered to the participant | From the date of randomization to the date of first documented dose of new cytotoxic chemotherapy administered to the participant, up to 5 years | 
| Time to first symptomatic skeletal event (TTSSE) | TTSSE is defined as the time from the date of randomization to the first new symptomatic pathological bone fracture, spinal cord compression, tumor-related orthopedic surgical intervention, requirement for radiation therapy to relieve bone pain or death due to any cause, whichever occurs first | From the date of randomization to the date of the first new symptomatic pathological bone fracture, spinal cord compression, orthopedic surgical intervention, radiation therapy or death due to any cause, whichever occurs first, up to 5 years | 
| Time to distant metastasis development | Time to distant metastasis development is defined as the time from the date of randomization to the date of first evidence of radiographically detectable bone or soft tissue distant metastasis by conventional imaging using RECIST 1.1 | From the date of randomization to the date of first evidence of radiographically detectable bone or soft tissue distant metastasis, up to 5 years | 
| Time to local radiological progression | Time to local radiological progression is defined as the time from the date of randomization to the date of first documented local radiographic disease progression by conventional imaging using RECIST 1.1 | From the date of randomization to the date of first documented local radiographic disease progression, up to 5 years | 
| Time to initiation or change in therapy | Time to initiation or change in therapy is defined as the time from the date of randomization to the date of first documented dose of a new / change in therapy being administered to the participant | From the date of randomization to the date of first dose of a new / change in therapy, up to 5 years | 
| Time to PSA response | Time to PSA response is calculated as the time from randomization to PSA response with a PSA nadir value of =< 0.2ng/mL. | From randomization to PSA response, up to 5 years | 
| PSA50 response | PSA50 response is defined as the proportion of participants who have a >= 50% decrease in PSA from baseline that is confirmed by a second (the next) PSA measurement >= 4 weeks later | From date of randomization until end of efficacy follow-up, up to 5 years | 
| PSA90 response | PSA90 response is defined as the proportion of participants who have a >= 90% decrease in PSA from baseline that is confirmed by a second (the next) PSA measurement >= 4 weeks later | From date of randomization until end of efficacy follow-up, up to 5 years | 
| Functional Assessment of Cancer Therapy - Prostate (FACT-P) | 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 until end of efficacy follow-up, up to 5 years | 
| Functional Assessment of Cancer Therapy - Radiotherapies (FACT-RNT) Questionnaire | The FACT-RNT is assessing treatment-related symptoms of special interest/associated with Radionuclides Therapies. The FACT-RNT contains 15 items assessing dry mouth, dry eyes, difficulty urinating, nausea, vomiting, diarrhea, constipation, loss of appetite, fatigue, impact of fatigue, pain, bone pain, pain interference, bothered by of side effects of treatment and isolation due to illness or treatment. | From date of randomization until end of efficacy follow-up, up to 5 years | 
| 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 until end of efficacy follow-up, up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prostate-specific membrane antigen (PSMA), Lutetium [177Lu] vipivotide tetraxetan (AAA617), Androgen Receptor Pathway Inhibitors (ARPI), Enzalutamide, Darolutamide, Apalutamide, Castration Resistant Prostate Cancer, Androgen Deprivation Therapy, gallium [68Ga] gozetotide (AAA517), piflufolastat F 18