Long-Term Safety Evaluation of Lutetium (177Lu) Vipivotide Tetraxetan in Adult Prostate Cancer Patients: A Phase IV Post-Authorization Study

The primary objective of this Phase IV, post-authorization safety study is to further characterize the long-term outcome, up to 10 years after the first dose, of known or potential risks associated with **lutetium (177Lu) vipivotide tetraxetan** in adult participants with prostate cancer. These risks include myelosuppression, renal failure, xerostomia, xerophthalmia, and secondary malignancies such as myelodysplastic syndrome and acute myeloid leukemia (MDS/AML), as well as other serious adverse events causally related to the treatment. This objective is clinically relevant as it aims to provide comprehensive safety data over an extended period, which is crucial for understanding the long-term implications of the treatment and ensuring patient safety.

Secondary objectives include evaluating the incidence of death and determining if the dosimetry estimates in the kidney and selected organs, when collected in the parent treatment studies, are associated with any long-term safety events of AAA617. These objectives are important for assessing the broader safety profile and potential long-term effects of the treatment on organ function and overall survival.

The clinical trial involves a total of **406 participants** diagnosed with **prostate cancer**. The study population is exclusively male, with an age range that includes adults and the elderly. Participants were selected based on their prior involvement in a Novartis-sponsored interventional clinical trial for prostate cancer, where they received at least one dose of the investigational drug AAA617 and met the trial's requirements for continued participation. The trial does not include a vulnerable population, and no specific lifestyle considerations such as diet or physical activity are highlighted. The focus is on further characterizing the long-term outcomes and potential risks associated with AAA617, including myelosuppression, renal failure, xerostomia, xerophthalmia, and secondary malignancies such as myelodysplastic syndrome and acute myeloid leukemia.

The clinical trial is a **Phase IV, post-authorization safety study** designed to investigate the long-term safety of **lutetium (177Lu) vipivotide tetraxetan** in adult participants with **prostate cancer**. The trial employs a **randomized, double-blind, controlled** design to ensure the reliability and validity of the results. The overall duration of the trial is estimated to extend until July 2033, with recruitment starting in October 2023. Participants are expected to be involved for a maximum treatment period of 36 months, with the possibility of follow-up extending up to 10 years after the first dose of the investigational product.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility is confirmed based on the principal inclusion criterion that participants must have received at least one dose of AAA617 in a prior Novartis-sponsored clinical trial for prostate cancer. Following the screening, participants will undergo regular follow-up visits to monitor for adverse events (AEs) and serious adverse events (SAEs), as well as changes in laboratory values. The primary endpoint focuses on the number and proportion of participants experiencing selected AEs and SAEs. Secondary endpoints include the number and proportion of participants who have died and the potential correlation between absorbed radiation dose in selected organs and the safety of AAA617.

The end-of-study visit will conclude the participant's involvement, assessing long-term outcomes related to known or potential risks such as myelosuppression, renal failure, xerostomia, xerophthalmia, and secondary malignancies, including myelodysplastic syndrome and acute myeloid leukemia. Conditions that may lead to early termination from the study include the occurrence of significant adverse events or the participant's decision to withdraw consent. The trial is not categorized as low intervention, reflecting its comprehensive approach to safety monitoring and data collection.

The clinical trial involves the administration of **Pluvicto**, a **solution for injection/infusion** containing the active substance **lutetium (177Lu) vipivotide tetraxetan**. This experimental medication is provided in a concentration of 1,000 MBq/mL and is administered via the **intravenous route**. The maximum daily dose is set at 7.4 GBq, with a total cumulative dose not exceeding 44.4 GBq over the course of the treatment. The maximum treatment period is defined as 36 months. The pharmaceutical form is a solution specifically designed for injection or infusion, ensuring precise delivery of the active radiopharmaceutical agent. The active substance, lutetium (177Lu) vipivotide tetraxetan, is classified under the ATC code V10XX, indicating its use as a therapeutic radiopharmaceutical. The substance is derived from a protein of other origin, and it is not a pediatric formulation.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on the administration of Pluvicto to evaluate its long-term safety profile in adult participants diagnosed with prostate cancer. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the specified treatment regimen. The trial aims to further characterize the long-term outcomes and potential risks associated with the use of this radiopharmaceutical, including myelosuppression, renal failure, xerostomia, xerophthalmia, and secondary malignancies such as myelodysplastic syndrome and acute myeloid leukemia.

Efficacy in this clinical trial will be assessed through the evaluation of primary and secondary endpoints. The primary endpoints include the number and proportion of participants experiencing selected adverse events (AEs) and serious adverse events (SAEs), as well as changes in laboratory values. Secondary endpoints will focus on the number and proportion of participants who have died and the potential correlation between absorbed radiation dose in the kidney or other selected organs and the safety of **AAA617**, contingent upon the availability of sufficient dosimetry data from the parent treatment study.

The assessment of these endpoints will involve systematic data collection and analysis over the course of the study. The trial is designed to further characterize the long-term outcomes, up to 10 years after the first dose of **AAA617**, in adult participants with prostate cancer. This includes monitoring known or potential risks such as myelosuppression, renal failure, xerostomia, xerophthalmia, and secondary malignancies, including myelodysplastic syndrome and acute myeloid leukemia (MDS/AML), as well as other serious adverse events causally related to **AAA617**.