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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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.

Conditions
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Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Intervention / Treatment
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* Drug: AAA617
* Drug: 68Ga-PSMA-11


Participation Criteria
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Eligibility Criteria
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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.

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
Intervention Model: Single Group Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AAA617<br>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. | Drug: AAA617<br>* Administered intravenously once every cycles (1 cycle = 6 weeks)<br>* Other names: 177Lu-Lu-PSMA-617;Drug: 68Ga-PSMA-11<br>* Single intravenous dose of approximately 150 MBq<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absorbed radiation dose in kidneys and selected organs | The absorbed dose in kidneys and selected organs will be summarized with descriptive statistics. | Up to 36 weeks | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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 | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| Change from baseline in eGFR |  | at screening and at every visit, assessed up to 1 year after last treatment | 
| Dose modifications for AAA617 | Dose modifications (dose interruptions and reductions) for AAA617 will be assessed and summarized using descriptive statistics. | Up to 36 weeks | 
| Dose intensity for AAA617 | Dose intensity for AAA617 will be assessed and summarized using descriptive statistics. | Up to 36 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in QTcF interval (ΔQTcF) |  | 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 | 
| 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). | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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 screening up to 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PSMA, Progressive PSMA-Positive Metastatic Castration-Resistant Prostate Cancer, Prostate-specific membrane antigen, 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