RecruitingInterventionalPhase 1

A Phase I, Open-label, Multi-center Study of Radiation Dosimetry, Safety, and Tolerability of Extended Lutetium (177Lu) Vipivotide Tetraxetan Treatment in Chemo-naïve Adults With Metastatic Castration-resistant Prostate Cancer

NCT ID: NCT06531499Sponsor: Novartis PharmaceuticalsLast updated: 2025-12-31

Summary

The purpose of the study is to assess and evaluate dosimetry, safety, and tolerability following administration of up to 12 cycles of (177Lu) vipivotide tetraxetan (also referred to as \[177Lu\]Lu-PSMA-617 or 177Lu-PSMA-617 and hereafter identified as AAA617) in taxane-naïve adult participants with PSMA-positive mCRPC who progressed on a prior ARPI treatment with normal renal function or mild renal impairment (eGFR ≥ 60ml/min).

Detailed description

The study includes screening period, treatment period, and a post-treatment follow-up period. Screening Period: Approximately 106 participants will be enrolled to receive up to12 consecutive cycles of AAA617. Potential participants will be assessed for eligibility by verifying their baseline PSMA PET scan for mandatory confirmation of PSMA positivity prior to first cycle by local review. Treatment Period: Eligible participants will be treated with up to 12 cycles of 7.4 GBq AAA617 intravenously every 6 weeks, until radiographic progression, toxicity leading to treatment discontinuation, death, loss to follow-up, or withdrawal of consent, whichever occurs first. During treatment period, all participants who complete the initial 6 cycles of AAA617 treatment will undergo an additional PSMA-PET scan after Cycle 6 to re-assess PSMA expression level and to reassess eligibility of participants to receive additional AAA617 treatment cycles. Post-Treatment Follow-Up: All participants will undergo a PSMA-PET scan at end of treatment (EOT). The post-treatment follow-up period will consist of EOT; 42-days safety; EOT RLI; safety, survival and rPFS follow-up visits. The planned duration of treatment period is up to 74 weeks with treatment given every 6 weeks. Participants may be discontinued from treatment earlier due to unacceptable toxicity or disease progression, and/or at the discretion of the Investigator or the participant.

Arms & interventions

DrugAAA617
\[177Lu\]Lu-PSMA-617 will be administered as an intravenous infusion at a dose of 7.4 GBq (200mCi) (+/- 10%), every 6 weeks for up to 12 cycles.
DrugGonadotropin-releasing hormone (GnRH) analogues
Anatomical Therapeutic Chemical \[ATC\] code L02AE
DrugGonadotropin-releasing hormone (GnRH) antagonists
Degarelix, Relugolix

Outcome measures

Primary

Time activity curves (TACs) and absorbed radiation dose of AAA617 in organs
Time activity curve (TAC) will be generated from the amount radioactivity in one given tissue. Time integrated activity coefficient and absorbed dose will be calculated
Time frame: From Cycle 1 to Cycle 12; cycle = 42 days
Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs)
The distribution of adverse events for Radioligand Therapy (RLT) will be done via the analysis of frequencies for Adverse Event (AEs) and Serious Adverse Event (SAEs) through the monitoring of relevant clinical and laboratory safety parameters. Adverse event monitoring should be continued for at least 42 days following the end of treatment (EOT) visit. Participants receiving the study treatment will continue to be followed for safety every 12 weeks during the long-term follow-up for selected adverse events
Time frame: For up to 12 cycles in taxane-naive participants with progressive PSMA-positive mCRPC with nrmal kidney function or mild renal impairment; cycle = 42 days
Percentage of participants with AAA617 dose reductions, interruptions and discontinuations
The assessment of tolerability will be based on the frequency of participants with dose interruptions, reductions, and study treatment discontinuations. Dose reduction will be based on the worst toxicity demonstrated at the last dose.
Time frame: Up to 42 (+7) days after last AAA617 dose administration (Safety Follow-up)

Secondary

Time activity curves (TACs) and absorbed radiation dose AAA617 in tumors
Time frame: For up to 12 cycles; cycle = 42 days
Pharmacokinetic ( PK) concentration of AAA617 in blood over time
Time frame: Cycle 1, Cycle 4, Cycle 6, Cycle 7, Cycle 8, Cycle 9, Cycle 10, Cycle 11 and Cycle 12, cycle = 42 days
Pharmacokinetic (PK) parameter Cmax of AAA617 from blood radioactivity data
Time frame: Cycle 1, Cycle 4, Cycle 6, Cycle 7, Cycle 8, Cycle 9, Cycle 10, Cycle 11 and Cycle 12; cycle = 42 days
PK parameter Tmax of AAA617 from blood radioactivity data
Time frame: Cycle 1, Cycle 4, Cycle 6, Cycle 7, Cycle 8, Cycle 9, Cycle 10, Cycle 11 and Cycle 12; cycle = 42 days
PK parameter AUC of AAA617 from blood radioactivity data
Time frame: Cycle 1, Cycle 4, Cycle 6, Cycle 7, Cycle 8, Cycle 9, Cycle 10, Cycle 11 and Cycle 12; cycle = 42 days
PK parameter CL of AAA617 from blood radioactivity data
Time frame: Cycle 1, Cycle 4, Cycle 6, Cycle 7, Cycle 8, Cycle 9, Cycle 10, Cycle 11 and Cycle 12; cycle = 42 days
PK parameter VZ of AAA617 from blood radioactivity data
Time frame: Cycle 1, Cycle 4, Cycle 6, Cycle 7, Cycle 8, Cycle 9, Cycle 10, Cycle 11 and Cycle 12; cycle = 42 days
PK parameter terminal T1/2 of AAA617 from blood radioactivity data
Time frame: Cycle 1, Cycle 4, Cycle 6, Cycle 7, Cycle 8, Cycle 9, Cycle 10, Cycle 11, and Cycle 12; cycle = 42 days
Overall response rate (ORR)
Time frame: From first patient first visit (FPFV) to end of study, until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 58 months
Disease Control rate (DCR)
Time frame: From first patient first visit (FPFV) to end of study, until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 58 months
Duration of response (DOR)
Time frame: From first patient first visit (FPFV) to end of study, until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 58 months
Radiographic Progressive free survival (rPFS)
Time frame: From first patient first visit (FPFV) to end of study, until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 58 months
Prostate specific antigen (PSA) response
Time frame: Baseline, (Cycle (C), Day (D)) C1D1, C2D1, C3D1, C4D1, C5D1, C6D1, C6D42, C7D1, C8D1, C9D1, C10D1, C11D1, C12D1, End Of Treatment (EOT), 6 weeks after EOT, every 12 weeks after EOT up to 12 months; each cycle = 42 days
Overall survival (OS)
Time frame: Cycle 1 to death event, approx. 5 years, (cycle = 42 days)
Duration of exposure to AAA617 and dose intensity
Time frame: during treatment period (74 weeks)

Eligibility criteria

Sex: MaleAge: 18 Years to 100 YearsHealthy volunteers: No

Key Inclusion Criteria: * Signed informed consent must be obtained prior to participation in the study. * Participants must be adults ≥ 18 years of age. * Participants must have an ECOG performance status ≤ 1. * Participants must have histological confirmation of adenocarcinoma of the prostate. * Participants must be PSMA-positive per 68Ga-PSMA PET/CT scans at baseline * Participants must have a castrate level of serum/plasma testosterone (\< 50 ng/dL or \< 1.7 nmol/L) either by pharmaceutical or surgical methods. * Participants must have progressed only once on prior second generation ARPIs * Documented progressive mCRPC * Participants must have ≥ 1 metastatic lesion by conventional imaging that is present on screening/baseline CT, MRI, or bone scan * Renal: eGFR ≥ 60 mL/min/1.73m2 using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. * Participants must have recovered to ≤ Grade 2 from all clinically significant toxicities related to prior therapies except alopecia. Key exclusion Criteria: * Previous treatment with any of the following within 6 months of study enrollment: Strontium 89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223, hemi-body irradiation * Any previous radioligand therapy. * Prior treatment with cytotoxic chemotherapy for metastatic castration-resistant or metastatic hormone-sensitive prostate cancer (mHSPC) (e.g., taxanes, platinum, estramustine, vincristine, methotrexate, etc.), immunotherapy or biological therapy \[including monoclonal antibodies\]. \[Note: Taxane exposure (maximum 6 cycles) in the adjuvant or neoadjuvant setting is allowed if 12 months have elapsed since completion of this adjuvant or neoadjuvant therapy. Prior treatment with sipuleucel-T is allowed\]. * Concurrent therapies: cytotoxic chemotherapy, immunotherapy, radioligand therapy, PARP inhibitor, biological, or investigational therapy * History of myocardial infarction (MI), angina pectoris, or coronary artery bypass graft (CABG) within 6 months prior to ICF signature and/or clinically active significant cardiac disease * Concurrent serious acute or chronic nephropathy and/or moderate to severe renal impairment as determined by the principal investigator. * Diagnosed with other active malignancies that are expected to alter life expectancy or may interfere with disease assessment * Sexually active males unwilling to use a condom during intercourse while taking study treatment and for 14 weeks after stopping study treatment. * Concurrent urinary outflow obstruction or unmanageable urinary incontinence * History of somatic or psychiatric disease/condition that may interfere with the aims and assessments of the study. Other protocol-defined inclusion/exclusion criteria may apply.