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.
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 23
- 试验地点
- 10
- 主要终点
- Absorbed radiation dose in kidneys and selected organs
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •An Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
- •68Ga-PSMA-11 Positron emission tomography (PET)/CT scan positive, and eligible as determined by the sponsor's central reader.
- •A castrate level of serum/plasma testosterone (< 50 ng/dL or < 1.7 nmol/L).
- •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)
- •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.
- •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
排除标准
- •Previous treatment with PSMA-targeted radioligand therapy.
- •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.
- •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.
- •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
- •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.
研究组 & 干预措施
AAA617
Participants will receive a dose of 7.4 GBq (200 mCi) ± 10% of AAA617 which will be administered once every 6 weeks (1 cycle) for up to 6 cycles if enrolled in Cohorts A or B. Participants with severe renal impairment (in cohort C) will receive a dose of 7.4 GBq of AAA617 for up to 3 cycles of treatment. 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.
干预措施: 68Ga-PSMA-11 (Drug)
AAA617
Participants will receive a dose of 7.4 GBq (200 mCi) ± 10% of AAA617 which will be administered once every 6 weeks (1 cycle) for up to 6 cycles if enrolled in Cohorts A or B. Participants with severe renal impairment (in cohort C) will receive a dose of 7.4 GBq of AAA617 for up to 3 cycles of treatment. 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.
干预措施: AAA617 (Drug)
结局指标
主要结局
Absorbed radiation dose in kidneys and selected organs
时间窗: Up to 36 weeks
The absorbed dose in kidneys and selected organs will be summarized with descriptive statistics.
Concentrations of AAA617 in blood over time
时间窗: 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
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.
Area under the serum concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of 177Lu-PSMA-617
时间窗: 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
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
时间窗: 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
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Tmax will be listed and summarized using descriptive statistics.
Observed maximum plasma concentration (Cmax) of 177Lu-PSMA-617
时间窗: 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
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
时间窗: 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
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
时间窗: 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
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
时间窗: 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
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
时间窗: 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
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
时间窗: at screening and at every visit, assessed up to 1 year after last treatment
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.
Dose modifications for AAA617
时间窗: Up to 36 weeks
Dose modifications (dose interruptions and reductions) for AAA617 will be assessed and summarized using descriptive statistics.
Dose intensity for AAA617
时间窗: Up to 36 weeks
Dose intensity for AAA617 will be assessed and summarized using descriptive statistics.
Absorbed radiation dose in kidneys and selected organs
时间窗: Up to 36 weeks
The absorbed dose in kidneys and selected organs will be summarized with descriptive statistics.
Change from baseline in eGFR
时间窗: at screening and at every visit, assessed up to 1 year after last treatment
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.
Dose modifications for AAA617
时间窗: Up to 36 weeks
Dose modifications (dose interruptions and reductions) for AAA617 will be assessed and summarized using descriptive statistics.
Dose intensity for AAA617
时间窗: Up to 36 weeks
Dose intensity for AAA617 will be assessed and summarized using descriptive statistics.
次要结局
- Relationship between drug concentrations and QTcF(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)(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)(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(From screening up to 1 year)
- Potential impact of moderate and severe renal impairment on AAA617 urine PK(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)
- Overall Response Rate (ORR)(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)(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(From screening up to 1 year)
- Relationship between drug concentrations and QTcF(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)