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

Phase 2RecruitingNCT06004661

Novartis Pharmaceuticals20 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

Eligibility

Sex: MALEMin age: 18 YearsMax age: 100 Years

Medical Language ↔ Plain English

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.

Locations (9)

Mount Sinai Hosp Med School

New York, New York, United States

RECRUITING

Novartis Investigative Site

Paris, France

RECRUITING

Novartis Investigative Site

Vandœuvre-lès-Nancy, France

RECRUITING

Novartis Investigative Site

Essen, Germany

RECRUITING

Novartis Investigative Site

München, Germany

RECRUITING

Novartis Investigative Site

Milan, MI, Italy

RECRUITING

Novartis Investigative Site

Napoli, Italy

RECRUITING

Novartis Investigative Site

Granada, Andalusia, Spain

RECRUITING

Novartis Investigative Site

El Palmar, Murcia, Spain

RECRUITING

Outcomes

Primary Outcomes

Absorbed radiation dose in kidneys and selected organs

The absorbed dose in kidneys and selected organs will be summarized with descriptive statistics.

Time frame: 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.

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 (120-144 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.

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.

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 (120-144 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.

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.

Change from baseline in eGFR

Change from baseline of eGFR will be summarized for each post-dose (post-baseline) timepoint. The summary includes table with descriptive statistics at baseline, post-baseline time points and change from baseline to post-baseline timepoints.

Time frame: 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.

Time frame: Up to 36 weeks

Dose intensity for AAA617

Dose intensity for AAA617 will be assessed and summarized using descriptive statistics.

Time frame: Up to 36 weeks

Secondary Outcomes

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).

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

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.

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

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.

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

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

Time frame: From screening up to 1 year

Potential impact of moderate and severe renal impairment on AAA617 urine PK

Derived urine PK parameters from urine PK radioactivity data (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.)

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

Overview

Conditions

Interventions

Eligibility

Locations (9)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts