Clinical trial NCT06004661: Study of Lutetium (177Lu) Vipivotide Tetraxetan in mCRPC Participants With Moderately and Severely Impaired and With Normal Renal Function
Official title: 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.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Metastatic Castration-Resistant Prostate Cancer (mCRPC)
Keywords: Progressive PSMA-Positive Metastatic Castration-Resistant Prostate Cancer
Prostate-specific membrane antigen
PSMA
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
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2023-08-22
Enrollment: 20
Sex: MALE
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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 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)
6. 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:

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 prostectomy) 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 (physical exam or 12 lead ECG) \<60 bpm

Other protocol-defined inclusion/exclusion criteria may apply.

Primary outcomes:
measure: Absorbed radiation dose in kidneys and selected organs
timeFrame: Up to 36 weeks
measure: Concentrations of AAA617 in blood over time
timeFrame: 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
measure: Area under the serum concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of 177Lu-PSMA-617
timeFrame: 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
measure: Time of maximum observed drug concentration occurrence (Tmax) of 177Lu-PSMA-617
timeFrame: 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
measure: Observed maximum plasma concentration (Cmax) of 177Lu-PSMA-617
timeFrame: 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
measure: Terminal elimination half-life (T^1/2) of 177Lu-PSMA-617
timeFrame: 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
measure: Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUCinf) of 177Lu-PSMA-617
timeFrame: 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
measure: Total systemic clearance for intravenous administration (CL) of 177Lu-PSMA-617
timeFrame: 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
measure: Volume of distribution during the terminal phase following intravenous elimination (Vz) of 177Lu-PSMA-617
timeFrame: 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
measure: Renal clearance of 177Lu-PSMA-617
timeFrame: 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
measure: Change from baseline in eGFR
timeFrame: at screening and at every visit, assessed up to 1 year after last treatment
measure: Dose modifications for AAA617
timeFrame: Up to 36 weeks
measure: Dose intensity for AAA617
timeFrame: Up to 36 weeks
Secondary outcomes:
measure: Change from baseline in QTcF interval (ΔQTcF)
timeFrame: 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
measure: Relationship between drug concentrations and QTcF
timeFrame: 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
measure: Overall Response Rate (ORR)
timeFrame: 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
measure: Disease Control Rate (DCR)
timeFrame: 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
measure: PSA50 response
timeFrame: From screening up to 1 year
Other outcomes:
Locations:
city: New York
country: United States
facility: Mount Sinai Hosp School of Med
state: New York
city: Paris
country: France
facility: Novartis Investigative Site
city: Vandoeuvre Les Nancy
country: France
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Muenchen
country: Germany
facility: Novartis Investigative Site
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Granada
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: El Palmar
country: Spain
facility: Novartis Investigative Site
state: Murcia
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: