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

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.

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.

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 3 cycles for cohort C. Based on the emerging safety data and if the investigators deem the participant is still benefiting from study drug, 3 additional cycles may be administered for cohort C participants.

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 derived PK parameters from radioactivity in blood in PSMA-positive mCRPC participants with moderate and severe renal impairment. In addition, the study will assess the relationship between drug concentrations and QTcF.

Approximately 20 participants will be enrolled in the study with at least 6 evaluable participants per cohort.

Key Inclusion Criteria:

1. An Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2

2. 68Ga-PSMA-11 Positron emission tomography (PET)/CT scan positive, and eligible as determined by the sponsor's central reader.

3. A castrate level of serum/plasma testosterone (< 50 ng/dL or < 1.7 nmol/L).

4. 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)

5. Documented stable chronic renal disease without evidence of further deterioration in renal function (stable chronic renal disease is defined as no significant change in renal function within 4 weeks prior to study entry.

6. Kidney function based on eGFR by Modification of Diet in Renal Disease (MDRD) equation:

   • Normal renal function: participants with eGFR >= 90 mL/min/1.73m2
   • Moderate renal impairment: participants with eGFR >= 30 to =< 59 mL/min/1.73m2
   • Severe renal impairment: participants with eGFR >= 15 to =< 29 mL/min/1.73m2

Key Exclusion Criteria:

1. Previous treatment with PSMA-targeted radioligand therapy.

2. 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.

3. 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.

4. 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 prostatectomy) must be excluded or first resolved to ≤ Grade 1.

5. 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 (12 lead ECG) <60 bpm

Other protocol-defined inclusion/exclusion criteria may apply.