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Study of Lutetium (177Lu) Vipivotide Tetraxetan in mCRPC Participants With Moderately and Severely Impaired and With Normal Renal Function

Primary Purpose

Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Status
Not yet recruiting
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
AAA617
68Ga-PSMA-11
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Metastatic Castration-Resistant Prostate Cancer (mCRPC) focused on measuring Progressive PSMA-Positive Metastatic Castration-Resistant Prostate Cancer, Prostate-specific membrane antigen, PSMA, Metastatic Castration-Resistant Prostate Cancer, mCRPC, Renal impairment, Moderately impaired renal function, Severely impaired renal function, Normal renal function, lutetium (177Lu) vipivotide tetraxetan, AAA617, Dosimetry, QTc prolongation, post marketing requirement

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)MaleDoes not accept healthy volunteers

Key Inclusion Criteria: An Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 68Ga-PSMA-11 Positron emission tomography (PET)/CT scan positive, and eligible as determined by the sponsor's central reader. A castrate level of serum/plasma testosterone (< 50 ng/dL or < 1.7 nmol/L). Documented progressive mCRPC will be based on at least 1 of the following criteria: Serum/plasma Prostate-Specific Antigen (PSA) progression defined as 2 consecutive increases in PSA over a previous reference value measured at least 1 week prior. The minimal start value is 2.0 ng/mL Soft-tissue progression defined as an increase >= 20% in the sum of the diameter (SOD) (short axis for nodal lesions and long axis for non-nodal lesions) of all target lesions based on the smallest SOD since treatment started or the appearance of one or more new lesions. Progression of bone disease: evaluable disease or new bone lesions(s) by bone scan (2+2 PCWG3 criteria) Documented stable renal disease without evidence of renal progressive disease (stable renal disease is defined as no significant change, such as a stable eGFR, within 4 weeks prior to study entry) Kidney function based on eGFR by Modification of Diet in Renal Disease (MDRD) equation: Normal renal function: participants with eGFR >= 90 mL/min Moderate renal impairment: participants with eGFR >= 30 to =< 59 mL/min Severe renal impairment: participants with eGFR >= 15 to =< 29 mL/min Key Exclusion Criteria: Previous treatment with PSMA-targeted radioligand therapy. Previous treatment with any of the following within 6 months of enrollment confirmation: Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223 or hemi-body irradiation. Use of agents known to prolong the QT interval from start of screening to end of Cycle 1, unless they can be permanently discontinued for the duration of study. Current severe urinary incontinence, hydronephrosis, severe voiding dysfunction, any level of urinary obstruction requiring indwelling/condom catheters. Participants with postrenal impairment, like obstructions, retroperitoneal fibrosis (eg after prostectomy) must be excluded or first resolved to ≤ Grade 1. 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 Other protocol-defined inclusion/exclusion criteria may apply.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm Type

    Experimental

    Arm Label

    AAA617

    Arm Description

    Participants will receive a dose of 7.4 GBq (200 mCi) +/- 10% of AAA617 which will be administered once every 6 weeks (1 cycle) for 3 to 6 cycles according to eGFR calculation at screening and radiation absorbed dose results from Cycle1 Day1.

    Outcomes

    Primary Outcome Measures

    Absorbed radiation dose in kidneys and selected organs
    The absorbed dose in kidneys and selected organs will be summarized with descriptive statistics.
    Concentrations of AAA617 in blood over time
    Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Blood concentration of [177Lu]Lu-PSMA-617 will be summarized with descriptive statistics.
    Area under the serum concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of 177Lu-PSMA-617
    Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUClast will be listed and summarized using descriptive statistics.
    Time of maximum observed drug concentration occurrence (Tmax) of 177Lu-PSMA-617
    Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Tmax will be listed and summarized using descriptive statistics.
    Observed maximum plasma concentration (Cmax) of 177Lu-PSMA-617
    Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmax will be listed and summarized using descriptive statistics.
    Terminal elimination half-life (T^1/2) of 177Lu-PSMA-617
    Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. The half-live will be listed and summarized using descriptive statistics
    Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUCinf) of 177Lu-PSMA-617
    Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUC(0-inf) will be listed and summarized using descriptive statistics.
    Total systemic clearance for intravenous administration (CL) of 177Lu-PSMA-617
    Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. CL will be listed and summarized using descriptive statistics.
    Volume of distribution during the terminal phase following intravenous elimination (Vz) of 177Lu-PSMA-617
    Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Vz will be listed and summarized using descriptive statistics.
    Renal clearance of 177Lu-PSMA-617
    The volume of each urine collection will be measured and the radioactivity concentration (KBq/mL) determined in order to calculate the total radioactivity excreted from the body from the start of infusion until 72h.
    Change from baseline in eGFR
    Dose modifications for AAA617
    Dose modifications (dose interruptions and reductions) for AAA617 will be assessed and summarized using descriptive statistics.
    Dose intensity for AAA617
    Dose intensity for AAA617 will be assessed and summarized using descriptive statistics.

    Secondary Outcome Measures

    Change from baseline in QTcF interval (ΔQTcF)
    Relationship between drug concentrations and QTcF
    The relationship between 177Lu-PSMA-617 plasma concentrations and ΔQTcF will be investigated using a linear mixed-effects modeling approach with ΔQTcF as the dependent variable, time-matched 177Lu-PSMA-617 plasma concentration as the explanatory variable, centered baseline QTcF (i.e., baseline QTcF for individual patient minus the population mean baseline QTcF for all patients) as an additional covariate, a fixed intercept, and a random intercept and slope per patient, when applicable (Garnett et al1).
    Overall Response Rate (ORR)
    Objective response rate (ORR) (CR + PR) as measured by PCWG3-modified RECIST v1.1 response in soft tissue, lymph node and visceral lesions as per local review and according to PCWG3-modified RECIST v1.1. CR and PR must be confirmed by repeat assessments that should be performed not less than 4 weeks after the criteria for response are first met.
    Disease Control Rate (DCR)
    Disease Control Rate (DCR) (CR + PR + stable disease [SD]) as measured by PCWG3-modified RECIST v1.1 response in soft tissue, lymph node and visceral lesions. DCR will be analyzed using the same analytical conventions as ORR.
    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

    Full Information

    First Posted
    June 29, 2023
    Last Updated
    August 16, 2023
    Sponsor
    Novartis Pharmaceuticals
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    1. Study Identification

    Unique Protocol Identification Number
    NCT06004661
    Brief Title
    Study of Lutetium (177Lu) Vipivotide Tetraxetan in mCRPC Participants With Moderately and Severely Impaired and With Normal Renal Function
    Official Title
    An Open-label Dosimetry, Biodistribution, Tolerability and Safety Study of Lutetium (177Lu) Vipivotide Tetraxetan in Participants With Progressive PSMA-Positive Metastatic Castration-Resistant Prostate Cancer (mCRPC) With Moderately and Severely Impaired and With Normal Renal Function.
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    August 2023
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    December 29, 2023 (Anticipated)
    Primary Completion Date
    March 20, 2026 (Anticipated)
    Study Completion Date
    May 1, 2026 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Novartis Pharmaceuticals

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    Yes
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    No

    5. Study Description

    Brief Summary
    This study will address health authorities' requests to determine whether moderate and severe renal impairment have an impact on the biodistribution, dosimetry and safety of lutetium (177Lu) vipivotide tetraxetan (AAA617) administered to participants with progressive PSMA-positive metastatic castration-resistant prostate cancer. The study will also characterize the risk of QT prolongation of AAA617 in this participant population.
    Detailed Description
    This open-label, non-randomized, multicenter, single arm phase II study in mCRPC participants aims to better characterize the safety and tolerability of AAA617 in participants with moderate and severe renal impairment compared with normal renal function. Since both severe and moderate renal impairment have very low incidence within mCRPC participant population compared to participants with normal renal function, the enrollment will occur in parallel for the 3 cohorts; participants will be stratified in one of the three cohorts (A:normal, B: moderate or C: severe) based on their eGFR at screening. All participants will undergo a 68Ga-PSMA-11 PET/CT scan at screening to confirm PSMA positivity. Participants will receive a dose of 7.4 GBq (±10%) of AAA617 once every 6 weeks for a planned 6 cycles for cohorts A and B and for 3 cycles (and 3 additional cycles) for cohort C. After treatment period, participants will be asked to join a long term follow up (LTFU) study to monitor their safety up to 10 years after the 1st dose of AAA617. In case of the LTFU study is not available at the time of end of treatment period (safety follow-up visit), participants will continue in Long Term Follow-up period in this study for up to one year until they can roll over into the separate LTFU study. The primary outcome will be to determine the effect of radiation absorption in kidney and other organs at risk as well as the concentration in blood and radioactivity in urine in PSMA- positive mCRPC participants with moderate and severe renal impairment. In addition, the study will assess the relationship between drug concentrations and QTcF. 20 participants with 6 countries are expected to be included with at least 6 evaluable participantts per cohort.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Metastatic Castration-Resistant Prostate Cancer (mCRPC)
    Keywords
    Progressive PSMA-Positive Metastatic Castration-Resistant Prostate Cancer, Prostate-specific membrane antigen, PSMA, Metastatic Castration-Resistant Prostate Cancer, mCRPC, Renal impairment, Moderately impaired renal function, Severely impaired renal function, Normal renal function, lutetium (177Lu) vipivotide tetraxetan, AAA617, Dosimetry, QTc prolongation, post marketing requirement

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 2
    Interventional Study Model
    Single Group Assignment
    Model Description
    Participants confirmed for enrollment in IRT will be stratified in one of the three cohorts based on eGFR calculated (MDRD formula) at screening: Cohort A: normal renal function eGFR >= 90 mL/min, Cohort B: moderate renal impairment eGFR >= 30 to =< 59 mL/min Cohort C: severe renal impairment eGFR >= 15 to =< 29 mL/min.
    Masking
    None (Open Label)
    Allocation
    N/A
    Enrollment
    20 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    AAA617
    Arm Type
    Experimental
    Arm Description
    Participants will receive a dose of 7.4 GBq (200 mCi) +/- 10% of AAA617 which will be administered once every 6 weeks (1 cycle) for 3 to 6 cycles according to eGFR calculation at screening and radiation absorbed dose results from Cycle1 Day1.
    Intervention Type
    Drug
    Intervention Name(s)
    AAA617
    Other Intervention Name(s)
    Pluvicto, 177Lu-Lu-PSMA-617
    Intervention Description
    Administered intravenously once every cycles (1 cycle = 6 weeks)
    Intervention Type
    Drug
    Intervention Name(s)
    68Ga-PSMA-11
    Intervention Description
    Single intravenous dose of approximately 150 MBq
    Primary Outcome Measure Information:
    Title
    Absorbed radiation dose in kidneys and selected organs
    Description
    The absorbed dose in kidneys and selected organs will be summarized with descriptive statistics.
    Time Frame
    Up to 36 weeks
    Title
    Concentrations of AAA617 in blood over time
    Description
    Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Blood concentration of [177Lu]Lu-PSMA-617 will be summarized with descriptive statistics.
    Time Frame
    Cycle (C) 1 Day (D) 1 (pre dose, end of infusion, 20 minutes (min), 60 min, 2 and 4 hours (h) post infusion), C1 D2 (24 h post infusion), C1 D3 (48 h post infusion), C1 D4 (72 h post infusion), C1 D6 (156-168 h post infusion). Cycle=6 weeks
    Title
    Area under the serum concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of 177Lu-PSMA-617
    Description
    Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUClast will be listed and summarized using descriptive statistics.
    Time Frame
    Cycle (C) 1 Day (D) 1 (pre dose, end of infusion, 20 minutes (min), 60 min, 2 and 4 hours (h) post infusion), C1 D2 (24 h post infusion), C1 D3 (48 h post infusion), C1 D4 (72 h post infusion), C1 D6 (156-168 h post infusion). Cycle=6 weeks
    Title
    Time of maximum observed drug concentration occurrence (Tmax) of 177Lu-PSMA-617
    Description
    Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Tmax will be listed and summarized using descriptive statistics.
    Time Frame
    Cycle (C) 1 Day (D) 1 (2 and 4 hours (h) post infusion), C1 D2 (24 h post infusion), C1 D3 (48 h post infusion), C1 D4 (72 h post infusion), C1 D6 (156-168 h post infusion). Cycle = 6 weeks
    Title
    Observed maximum plasma concentration (Cmax) of 177Lu-PSMA-617
    Description
    Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmax will be listed and summarized using descriptive statistics.
    Time Frame
    Cycle (C) 1 Day (D) 1 (pre dose, end of infusion, 20 minutes (min), 60 min, 2 and 4 hours (h) post infusion), C1 D2 (24 h post infusion), C1 D3 (48 h post infusion), C1 D4 (72 h post infusion), C1 D6 (156-168 h post infusion). Cycle=6 weeks
    Title
    Terminal elimination half-life (T^1/2) of 177Lu-PSMA-617
    Description
    Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. The half-live will be listed and summarized using descriptive statistics
    Time Frame
    Cycle (C) 1 Day (D) 1 (pre dose, end of infusion, 20 minutes (min), 60 min, 2 and 4 hours (h) post infusion), C1 D2 (24 h post infusion), C1 D3 (48 h post infusion), C1 D4 (72 h post infusion), C1 D6 (156-168 h post infusion). Cycle=6 weeks
    Title
    Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUCinf) of 177Lu-PSMA-617
    Description
    Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUC(0-inf) will be listed and summarized using descriptive statistics.
    Time Frame
    Cycle (C) 1 Day (D) 1 (pre dose, end of infusion, 20 minutes (min), 60 min, 2 and 4 hours (h) post infusion), C1 D2 (24 h post infusion), C1 D3 (48 h post infusion), C1 D4 (72 h post infusion), C1 D6 (156-168 h post infusion). Cycle=6 weeks
    Title
    Total systemic clearance for intravenous administration (CL) of 177Lu-PSMA-617
    Description
    Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. CL will be listed and summarized using descriptive statistics.
    Time Frame
    Cycle (C) 1 Day (D) 1 (pre dose, end of infusion, 20 minutes (min), 60 min, 2 and 4 hours (h) post infusion), C1 D2 (24 h post infusion), C1 D3 (48 h post infusion), C1 D4 (72 h post infusion), C1 D6 (156-168 h post infusion). Cycle=6 weeks
    Title
    Volume of distribution during the terminal phase following intravenous elimination (Vz) of 177Lu-PSMA-617
    Description
    Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Vz will be listed and summarized using descriptive statistics.
    Time Frame
    Cycle (C) 1 Day (D) 1 (pre dose, end of infusion, 20 minutes (min), 60 min, 2 and 4 hours (h) post infusion), C1 D2 (24 h post infusion), C1 D3 (48 h post infusion), C1 D4 (72 h post infusion), C1 D6 (156-168 h post infusion). Cycle=6 weeks
    Title
    Renal clearance of 177Lu-PSMA-617
    Description
    The volume of each urine collection will be measured and the radioactivity concentration (KBq/mL) determined in order to calculate the total radioactivity excreted from the body from the start of infusion until 72h.
    Time Frame
    Cycle 1 Day 1: end of infusion to 2 hours, 2 hours to 4 hours, 4 hours to 24 hours, 24 hours to 48 hours, 48 hours to 72 hours post infusion. Cycle = 6 weeks
    Title
    Change from baseline in eGFR
    Time Frame
    at screening and at every visit, assessed up to 1 year after last treatment
    Title
    Dose modifications for AAA617
    Description
    Dose modifications (dose interruptions and reductions) for AAA617 will be assessed and summarized using descriptive statistics.
    Time Frame
    Up to 36 weeks
    Title
    Dose intensity for AAA617
    Description
    Dose intensity for AAA617 will be assessed and summarized using descriptive statistics.
    Time Frame
    Up to 36 weeks
    Secondary Outcome Measure Information:
    Title
    Change from baseline in QTcF interval (ΔQTcF)
    Time Frame
    During Cycle 1 at predose, End of Injection (EoI), 20 minutes (min), 60 min, 2 hours (h), 4h and 24h post EoI. Cycle=6 weeks
    Title
    Relationship between drug concentrations and QTcF
    Description
    The relationship between 177Lu-PSMA-617 plasma concentrations and ΔQTcF will be investigated using a linear mixed-effects modeling approach with ΔQTcF as the dependent variable, time-matched 177Lu-PSMA-617 plasma concentration as the explanatory variable, centered baseline QTcF (i.e., baseline QTcF for individual patient minus the population mean baseline QTcF for all patients) as an additional covariate, a fixed intercept, and a random intercept and slope per patient, when applicable (Garnett et al1).
    Time Frame
    During Cycle 1 at predose, End of Injection (EoI), 20 minutes (min), 60 min, 2 hours (h), 4h and 24h post EoI. Cycle=6 weeks
    Title
    Overall Response Rate (ORR)
    Description
    Objective response rate (ORR) (CR + PR) as measured by PCWG3-modified RECIST v1.1 response in soft tissue, lymph node and visceral lesions as per local review and according to PCWG3-modified RECIST v1.1. CR and PR must be confirmed by repeat assessments that should be performed not less than 4 weeks after the criteria for response are first met.
    Time Frame
    From the date of 1st dose until the date of first documented progression or date of death from any cause, whichever comes first, assessed up to approximately 36 weeks
    Title
    Disease Control Rate (DCR)
    Description
    Disease Control Rate (DCR) (CR + PR + stable disease [SD]) as measured by PCWG3-modified RECIST v1.1 response in soft tissue, lymph node and visceral lesions. DCR will be analyzed using the same analytical conventions as ORR.
    Time Frame
    From the date of 1st dose until the date of first documented progression or date of death from any cause, whichever comes first, assessed up to approximately 36 weeks
    Title
    PSA50 response
    Description
    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
    Time Frame
    From screening up to 1 year

    10. Eligibility

    Sex
    Male
    Gender Based
    Yes
    Gender Eligibility Description
    Prostate cancer
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Key Inclusion Criteria: An Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 68Ga-PSMA-11 Positron emission tomography (PET)/CT scan positive, and eligible as determined by the sponsor's central reader. A castrate level of serum/plasma testosterone (< 50 ng/dL or < 1.7 nmol/L). Documented progressive mCRPC will be based on at least 1 of the following criteria: Serum/plasma Prostate-Specific Antigen (PSA) progression defined as 2 consecutive increases in PSA over a previous reference value measured at least 1 week prior. The minimal start value is 2.0 ng/mL Soft-tissue progression defined as an increase >= 20% in the sum of the diameter (SOD) (short axis for nodal lesions and long axis for non-nodal lesions) of all target lesions based on the smallest SOD since treatment started or the appearance of one or more new lesions. Progression of bone disease: evaluable disease or new bone lesions(s) by bone scan (2+2 PCWG3 criteria) Documented stable renal disease without evidence of renal progressive disease (stable renal disease is defined as no significant change, such as a stable eGFR, within 4 weeks prior to study entry) Kidney function based on eGFR by Modification of Diet in Renal Disease (MDRD) equation: Normal renal function: participants with eGFR >= 90 mL/min Moderate renal impairment: participants with eGFR >= 30 to =< 59 mL/min Severe renal impairment: participants with eGFR >= 15 to =< 29 mL/min Key Exclusion Criteria: Previous treatment with PSMA-targeted radioligand therapy. Previous treatment with any of the following within 6 months of enrollment confirmation: Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223 or hemi-body irradiation. Use of agents known to prolong the QT interval from start of screening to end of Cycle 1, unless they can be permanently discontinued for the duration of study. Current severe urinary incontinence, hydronephrosis, severe voiding dysfunction, any level of urinary obstruction requiring indwelling/condom catheters. Participants with postrenal impairment, like obstructions, retroperitoneal fibrosis (eg after prostectomy) must be excluded or first resolved to ≤ Grade 1. 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 Other protocol-defined inclusion/exclusion criteria may apply.
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Novartis Pharmaceuticals
    Phone
    1-888-669-6682
    Email
    novartis.email@novartis.com
    First Name & Middle Initial & Last Name or Official Title & Degree
    Novartis Pharmaceuticals
    Phone
    +41613241111
    Email
    novartis.email@novartis.com
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Novartis Pharmaceuticals
    Organizational Affiliation
    Novartis Pharmaceuticals
    Official's Role
    Study Director

    12. IPD Sharing Statement

    Plan to Share IPD
    Yes
    IPD Sharing 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

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    Study of Lutetium (177Lu) Vipivotide Tetraxetan in mCRPC Participants With Moderately and Severely Impaired and With Normal Renal Function

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