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

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

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Prostatic Neoplasm
• Intervention / Treatment: Drug: AAA617; Drug: AAA517; Drug: Piflufolastat F 18; Drug: ADT; Other: Best supportive care; Drug: ARPI

Detailed Description

All participants will be assessed for eligibility and will undergo baseline disease assessments including a mandatory gallium [68Ga] gozetotide (hereinafter referred to as AAA517) 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 US only.

The treatment duration will be up to 6 cycles of AAA617, treatment will be administered once every 6 weeks (duration of 1 cycle). Participants randomized to Arm B may continue to receive ARPI after second end of treatment (EOT2) outside the study protocol at the investigator's discretion and in accordance with local guidelines.

The visit frequency will be every week 1 and week 4 of each of the 6 cycles and every 16 weeks thereafter (for both arms) until the first event of disease progression (RECIST 1.1) or until global end of study (EOS), whichever comes first. After cycle 1 the safety visit at week 4 is optional onsite and could be paired with efficacy assessments or handled remotely. No biomarker collections are expected after the last end of trial (EOT) visit is completed. The study duration will be approximately 36 months.

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 2

Contacts and Locations

Study Locations

• Brazil
  • São Paulo
    • São Paulo, São Paulo, Brazil, 01308-050
      • Novartis Investigative Site
    • São Paulo, São Paulo, Brazil, 05652-000
      • Novartis Investigative Site
• Canada
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 2Y9
      • Novartis Investigative Site
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Novartis Investigative Site
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Novartis Investigative Site
    • Montreal, Quebec, Canada, H2X 1R9
      • Novartis Investigative Site
• Czechia
  • Olomouc, Czechia, 779 00
    • Novartis Investigative Site
• France
  • Angers, France, 49055
    • Novartis Investigative Site
  • Brest, France, 29609
    • Novartis Investigative Site
  • Strasbourg, France, 67000
    • Novartis Investigative Site
  • Strasbourg, France, F 67085
    • Novartis Investigative Site
• Germany
  • Berlin, Germany, 10249
    • Novartis Investigative Site
• Italy
  • Milan, Italy, 20141
    • Novartis Investigative Site
  • Naples, Italy, 80131
    • Novartis Investigative Site
  • GE
    • Genova, GE, Italy, 16132
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00128
      • Novartis Investigative Site
• Poland
  • Kielce, Poland, 25-640
    • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 169608
    • Novartis Investigative Site
• South Korea
  • Seoul, South Korea, 03080
    • Novartis Investigative Site
  • Seoul, South Korea, 05505
    • Novartis Investigative Site
• Spain
  • Barcelona, Spain, 08036
    • Novartis Investigative Site
  • Madrid, Spain, 28040
    • Novartis Investigative Site
  • Barcelona
    • L'Hospitalet de Llobregat, Barcelona, Spain, 08907
      • Novartis Investigative Site
• United States
  • Colorado
    • Denver, Colorado, United States, 80218
      • Rocky Mountain Cancer Centers
  • Georgia
    • Athens, Georgia, United States, 30607
      • University Cancer and Blood Center LLC
  • Indiana
    • Indianapolis, Indiana, United States, 46254
      • Urology of Indiana
  • Iowa
    • Des Moines, Iowa, United States, 50323
      • Unity Point Clinic
  • Nebraska
    • Omaha, Nebraska, United States, 68130
      • Urology Cancer Center PC
  • New York
    • Syracuse, New York, United States, 13210
      • Associated Med Professionals of NY
  • Oregon
    • Springfield, Oregon, United States, 97477
      • Oregon Urology Institute
  • Pennsylvania
    • York, Pennsylvania, United States, 17403
      • Wellspan York Hospital
  • South Carolina
    • Conway, South Carolina, United States, 29526
      • Coastal Cancer Center
    • Myrtle Beach, South Carolina, United States, 29572
      • Carolina Urologic Research Center
    • Myrtle Beach, South Carolina, United States, 29577
      • Carolina Regional Cancer Center
  • Texas
    • Dallas, Texas, United States, 75390-9034
      • Univ of Texas Southwest Med Center
    • El Paso, Texas, United States, 79912
      • Rio Grande Urology
    • Houston, Texas, United States, 77030
      • Houston Methodist Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 at the time of randomization. Intermittent administration of ADT is accepted before randomization if criterion for serum testosterone is met
• Castrate level of serum testosterone (< 1.7 nmol/l [50 ng/dl]) on GnRH agonist or antagonist therapy (continuous/intermittent) or after bilateral orchiectomy prior to randomization
• Participants must have evidence of PSMA-positive disease (N1 or M1) 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.
• 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 pelvic disease may be eligible (e.g., participants with enlarged lymph nodes below the bifurcation of common iliac arteries (N1))
• 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) < 3 months before randomization; CYP17 inhibitors (e.g., abiraterone acetate, orteronel, galeterone) < 3 months before randomization; ketoconazole (short duration ketoconazole treatment (<28 days) is permitted); radiopharmaceutical agents (e.g., Strontium-89) if wash-out period of at least 3 months is not completed, 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A; 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; Administration intravenously once every 6 weeks (1 cycle) for 6 cycles; Other Names: 177Lu-PSMA-617; Lutetium [177Lu] vipivotide tetraxetan; Drug: AAA517; Single intravenous dose of approx. 150 Megabecquerel (MBq) prior PSMA-PET scans; Other Names: 68Ga-PSMA-11; Drug: Piflufolastat F 18; Single intravenous dose of approx. 333 Megabecquerel (MBq) prior PSMA-PET scans; Drug: ADT; as prescribed by the local investigator; Other: Best supportive care; as prescribed by the local investigator
Experimental: Arm B; 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; Administration intravenously once every 6 weeks (1 cycle) for 6 cycles; Other Names: 177Lu-PSMA-617; Lutetium [177Lu] vipivotide tetraxetan; Drug: AAA517; Single intravenous dose of approx. 150 Megabecquerel (MBq) prior PSMA-PET scans; Other Names: 68Ga-PSMA-11; Drug: Piflufolastat F 18; Single intravenous dose of approx. 333 Megabecquerel (MBq) prior PSMA-PET scans; Drug: ADT; as prescribed by the local investigator; Other: Best supportive care; as prescribed by the local investigator; Drug: ARPI; Enzalutamide, Darolutamide, Apalutamide as prescribed by the local investigator

What is the study measuring?

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
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
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
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
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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): January 3, 2024
• Primary Completion (Estimated): December 23, 2026
• Study Completion (Estimated): December 23, 2026

Study Registration Dates

• First Submitted: April 27, 2023
• First Submitted That Met QC Criteria: April 27, 2023
• First Posted (Actual): May 8, 2023

Study Record Updates

• Last Update Posted (Actual): May 27, 2026
• Last Update Submitted That Met QC Criteria: May 25, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Enzalutamide; Androgen Deprivation Therapy; Castration Resistant Prostate Cancer; Apalutamide; Darolutamide; Prostate-specific membrane antigen (PSMA); Androgen Receptor Pathway Inhibitors (ARPI); gallium [68Ga] gozetotide (AAA517); piflufolastat F 18; Lutetium [177Lu] vipivotide tetraxetan (AAA617)
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Male Urogenital Diseases; Prostatic Neoplasms; Inorganic Chemicals; Elements; Metals; Transition Elements; Lanthanoid Series Elements; Metals, Rare Earth; Pluvicto; 2-(3-(1-carboxy-5-((6-fluoropyridine-3-carbonyl)amino)pentyl)ureido)pentanedioic acid; Lutetium-177; gallium 68 PSMA-11; Lutetium
• Other Study ID Numbers: CAAA617B12203; 2022-503040-41-00 (Other Identifier: EU CT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No