A Phase I, Open-label, Multi-center Exploratory Safety and Efficacy Study With PSMA, SSTR2 and GRPR Targeted Radioligand Therapy in Metastatic Neuroendocrine Prostate Cancer.
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 31
- 试验地点
- 13
- 主要终点
- Number/extent of lesions with at least a moderate uptake of any of the Radioligand Imaging (RLI)
研究概览
简要总结
The purpose of this study is to evaluate the change in the expression of treatment targets on the surface of tumor cells (Prostate Specific Membrane Antigen (PSMA), Somatostatin Receptor 2 (SSTR2), and Gastrin Releasing Peptide Receptor (GRPR) between the baseline and following targeted radioligand therapy (RLT). Study will use radioligand imaging (RLI) to determine predominantly expressed target on the surface of tumor cells. Based on predominant expression of target, corresponding RLT targeting PSMA, SSTR2, or GRPR RLT will be given for up to 6 cycles every 6 weeks as intravenous (i.v.) injection in participants with metastatic neuroendocrine prostate cancer (mNEPC).
详细描述
The screening period for each participant includes imaging with 3 radioligand imaging (RLI) compounds to assess expression level of PSMA, SSTR2 and GRPR. Participants will be assigned to the radioligand treatment (RLT) corresponding to their predominantly expressed target based on blinded independent central review (BICR). During the treatment period, participants will receive up to 6 cycles of the assigned RLT, corresponding to a total dose of 44.4 GBq (+/-10%) for [177Lu]Lu-PSMA-617 or [177Lu]Lu-DOTA-TATE , and 55.5 GBq (+/-10%) for [177Lu]Lu-NeoB. No crossover to a different type of RLT is allowed.
At least six weeks after receiving the first cycle of RLT, participants must be scanned again with up to 3 RLIs but must be scanned, with at least with one RLI corresponding to the received RLT, which is recommended to be performed first. All post-baseline PET/CT scans should be performed using the same PET/CT imaging agent and same PET/CT camera, acquisition and reconstruction protocols as used for screening PET/CT for the participant.
The post-treatment follow-up period consists of a 42-days Safety follow-up visit.
The planned duration of treatment is up to 36 weeks for all treatment arms in this study, with treatment given every 6 weeks ±7 days. 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.
Protocol Amendment 7 follows the Sponsor's business decision to halt enrollment on 05-Jan-2026. The premature closure of the trial was not driven by any safety concerns identified in the study to date.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 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
- •Participants must have metastatic prostate cancer with neuroendocrine differentiation as determined by at least one of the following:
- •Histologically small cell or neuroendocrine cancer from a primary prostate or metastatic biopsy confirmed by local laboratory.
- •Expression of NEPC markers (e.g., chromogranin or synaptophysin) in tumor tissue by IHC confirmed by local laboratory
- •Progression of visceral metastases in the absence of PSA progression
- •Serum chromogranin A > 5x normal limit, or neuron-specific enolase > 2x normal limit with control for proton-pump inhibitors (PPI) drugs among concomitant treatment
- •Prostate adenocarcinoma with molecular features of neuroendocrine differentiated cancer (e.g., 2 of the following 3: PTEN, TP53, or RB loss)
- •PSMA and/or SSTR2 and/or GRPR PET-positive participants, with at least one measurable lesion per RECIST 1.1 with moderate target expression in at least one of the 3 PET/CT scans per BICR assessment
- •Castrate level of serum/plasma testosterone (< 50 ng/dl, or < 1.7 nmol/L) for participants with adenocarcinoma component or stable testosterone level for participants with pure neuroendocrine carcinoma
- •Recovered to ≤ Grade 2 from all clinically significant toxicities related to prior therapy
- •Participant has adequate bone marrow and organ function (as assessed by central laboratory for eligibility)
- •ECOG status =< 2
排除标准
- •Previous treatment with any of the following within 6 months prior to Screening: Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223, hemi-body irradiation
- •Previous PSMA, SSTR2, or GRPR targeted radioligand therapy
- •Other concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy or investigational therapy
- •History of CNS metastases that are neurologically unstable, symptomatic, or receiving corticosteroids for the purpose of maintaining neurologic integrity
- •Symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression
- •History or current diagnosis of ECG abnormalities indicating significant risk of safety for study participants
- •Other protocol-defined inclusion/exclusion criteria may apply.
研究组 & 干预措施
PSMA-predominant NEPC
干预措施: [68Ga]GA-DOTA-TATE (Drug)
PSMA-predominant NEPC
干预措施: [68Ga]Ga-NeoB (Drug)
PSMA-predominant NEPC
干预措施: [177Lu]Lu-PSMA-617 (Drug)
PSMA-predominant NEPC
干预措施: GnRH antagonists (Drug)
SSTR2-predominant NEPC
干预措施: [68Ga]GA-DOTA-TATE (Drug)
SSTR2-predominant NEPC
干预措施: [68Ga]Ga-NeoB (Drug)
SSTR2-predominant NEPC
干预措施: [177Lu]Lu-DOTA-TATE (Drug)
SSTR2-predominant NEPC
干预措施: L-Lysine HCl-L-Arginine HCl, 2.5 %, (Drug)
SSTR2-predominant NEPC
干预措施: GnRH antagonists (Drug)
SSTR2-predominant NEPC
干预措施: Metoclopramide (Drug)
GRPR-predominant NEPC
干预措施: [68Ga]GA-DOTA-TATE (Drug)
GRPR-predominant NEPC
干预措施: [68Ga]Ga-NeoB (Drug)
GRPR-predominant NEPC
干预措施: [177Lu]Lu-NeoB (Drug)
GRPR-predominant NEPC
干预措施: GnRH antagonists (Drug)
Somatostatin Receptor 2 (SSTR2)-predominant NEPC
干预措施: Antiemetics & antinauseants (Drug)
Somatostatin Receptor 2 (SSTR2)-predominant NEPC
干预措施: Gonadotropin-releasing hormone (GnRH) analogues (Drug)
PSMA-predominant Neuroendocrine prostate cancer (NEPC)
干预措施: GnRH antagonists (Drug)
Somatostatin Receptor 2 (SSTR2)-predominant NEPC
干预措施: [68Ga]Ga-NeoB (Drug)
PSMA-predominant Neuroendocrine prostate cancer (NEPC)
干预措施: [68Ga]GA-DOTA-TATE (Drug)
PSMA-predominant Neuroendocrine prostate cancer (NEPC)
干预措施: [68Ga]Ga-NeoB (Drug)
Somatostatin Receptor 2 (SSTR2)-predominant NEPC
干预措施: [177Lu]Lu-DOTA-TATE (Drug)
PSMA-predominant Neuroendocrine prostate cancer (NEPC)
干预措施: [177Lu]Lu-PSMA-617 (Drug)
Somatostatin Receptor 2 (SSTR2)-predominant NEPC
干预措施: Metoclopramide (Drug)
Gastrin Releasing Peptide Receptor (GRPR)-predominant NEPC
干预措施: Gonadotropin-releasing hormone (GnRH) analogues (Drug)
Gastrin Releasing Peptide Receptor (GRPR)-predominant NEPC
干预措施: GnRH antagonists (Drug)
Gastrin Releasing Peptide Receptor (GRPR)-predominant NEPC
干预措施: [68Ga]Ga-NeoB (Drug)
Gastrin Releasing Peptide Receptor (GRPR)-predominant NEPC
干预措施: [177Lu]Lu-NeoB (Drug)
Somatostatin Receptor 2 (SSTR2)-predominant NEPC
干预措施: GnRH antagonists (Drug)
Somatostatin Receptor 2 (SSTR2)-predominant NEPC
干预措施: L-Lysine HCl-L-Arginine HCl, 2.5 %, (Drug)
PSMA-predominant Neuroendocrine prostate cancer (NEPC)
干预措施: [68Ga]Ga-PSMA-11 (Drug)
PSMA-predominant Neuroendocrine prostate cancer (NEPC)
干预措施: Gonadotropin-releasing hormone (GnRH) analogues (Drug)
Somatostatin Receptor 2 (SSTR2)-predominant NEPC
干预措施: [68Ga]Ga-PSMA-11 (Drug)
Gastrin Releasing Peptide Receptor (GRPR)-predominant NEPC
干预措施: [68Ga]Ga-PSMA-11 (Drug)
Gastrin Releasing Peptide Receptor (GRPR)-predominant NEPC
干预措施: [68Ga]GA-DOTA-TATE (Drug)
Somatostatin Receptor 2 (SSTR2)-predominant NEPC
干预措施: [68Ga]GA-DOTA-TATE (Drug)
结局指标
主要结局
Number/extent of lesions with at least a moderate uptake of any of the Radioligand Imaging (RLI)
时间窗: Baseline (baseline imaging is performed during the 42 day screening period)
Number/extent of lesions with at least a moderate update of any of the RLIs according to visual assessment scoring scale on each corresponding targeted PET/CT scan based on blinded independent central review (BICR) assessment.
Number/extent of lesions with at least a moderate uptake of any of the Radioligand Imaging (RLI)
时间窗: Baseline (baseline imaging is performed during the 42 day screening period)
Number/extent of lesions with at least a moderate update of any of the RLIs according to visual assessment scoring scale on each corresponding targeted PET/CT scan based on blinded independent central review (BICR) assessment.
Percentage changes in quantitative PET parameters.
时间窗: Post-Baseline (from date of baseline imaging scans to post-baseline scans, at least 6 weeks after receiving the first cycle of radioligand treatment)
Percentage changes in quantitative PET/CT parameters (SUVmax, SUVmean, SUVpeak, target-positive Tumor Volume (target -TV), Total Lesion (target (TL-target)\] and changes in number of target-positive lesions (as per visual assessment) on each corresponding target PET/CT based on BICR.
次要结局
- Overall Response Rate (ORR)(From date of assignment to one of the treatment arms until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 31 months)
- Disease Control Rate (DCR)(From date of assignment to one of the treatment arms until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 31 months)
- Duration of response (DOR)(From first documented evidence of CR or PR (the response prior to confirmation) until time of documented disease progression or death due to any cause, whichever comes first, assessed up to approximately 31 months)
- Radiographic Progression-free Survival (rPFS)(From date of assignment to one of the treatment arms until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 31 months)
- Proportion of participants with a decline in PSA level(Baseline, Cycle 1 Day 1 (each cycle is 42 days), Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1, End Of Treatment, 6 weeks after End of Treatment)
- Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) for Radioligand Therapy (RLT)(Up to 42 days after last dose administration (Safety Follow-up) and every 12 weeks until end of long term follow up (Long-term FU) for selected AEs and SAEs)
- Dose modifications for [177Lu]Lu-PSMA-617, [177Lu]Lu-DOTA-TATE and [177Lu]Lu-NeoB(Up to 42 days after last dose administration (Safety Follow-up))
- Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) for Radioligand Imaging (RLI)(Continuously from informed consent for the first 6 weeks and selected AEs and SAEs thereafter)
- Blood radioactivity concentration of [177Lu]Lu-PSMA-617, [177Lu]Lu-DOTA-TATE, [177Lu]Lu-NeoB)(Cycle 1 Day 1 (each cycle is 42 days) pre-dose, post-dose/end of infusion (EOI) and then 0.5 hrs, 2 hrs, 4 hrs, 6 hrs 24 hrs, 48 hrs, 168 hrs post EOI. Cycle 3 Day 1 EOI, 1 hr, 48 hrs post EOI. Cycle 5 Day 1 EOI, and then 1 hr, 48 hrs post EOI.)
- Blood mass concentration of [177Lu]Lu-PSMA-617, [177Lu]Lu-DOTA-TATE, [177Lu]Lu-NeoB)(Cycle 1 Day 1 (each cycle is 42 days) pre-dose, post-dose/end of infusion (EOI) and then 0.5 hrs, 2 hr, 4 hr, 6 hrs, 24 hrs, 48 hrs 168 hrs post EOI. Cycle 3 Day 1 EOI, 1 hr, 48 hrs post EOI. Cycle 5 Day 1 EOI, and then 1 hr, 48 hrs post EOI.)
- Observed maximum blood concentrations (Cmax) of [177Lu]Lu-PSMA-617, [177Lu]Lu-DOTA-TATE and [177Lu]Lu-NeoB(Cycle 1 Day 1 (each cycle is 42 days) pre-dose, post-dose/end of infusion (EOI) and then 0.5 hrs , 2 hrs, 4 hrs, 6 hrs, 24 hrs, 48 hrs, 168 hrs post EOI. Cycle 3 Day 1 EOI, 1 hr, 48 hrs post EOI. Cycle 5 Day 1 EOI, and then 1 hr, 48 hrs post EOI.)
- Time of maximum blood concentration (Tmax) occurence of [177Lu]Lu-PSMA-617, [177Lu]Lu-DOTA-TATE and [177Lu]Lu-NeoB(Cycle 1 Day 1 (each cycle is 42 days) pre-dose, post-dose/end of infusion (EOI) and then 0.5 hours (h), 2 hrs, 4 hrs, 6 hrs, 24 hrs, 48 hrs, 168 hrs post EOI. Cycle 3 Day 1 EOI, 1 hr, 48 hrs post EOI. Cycle 5 Day 1 EOI, and then 1 hr, 48 hrs post EOI.)
- Area under the blood concentration time curve (AUC) of [177Lu]Lu-PSMA-617, [177Lu]Lu-DOTA-TATE and [177Lu]Lu-NeoB(Cycle 1 Day 1 (each cycle is 42 days) pre-dose, post-dose/end of infusion (EOI) and then 0.5 hrs , 2 hrs, 4 hrs, 6 hrs, 24 hrs, 48 hrs, 168 hrs post EOI. Cycle 3 Day 1 EOI, 1 hr, 48 hrs post EOI. Cycle 5 Day 1 EOI, and then 1 hr, 48 hrs post EOI.)
- Total systemic clerance (CL) of [177Lu]Lu-PSMA-617, [177Lu]Lu-DOTA-TATE and [177Lu]Lu-NeoB(Cycle 1 Day 1 (each cycle is 42 days) pre-dose, post-dose/end of infusion (EOI) and then 0.5 hrs, 2 hrs, 4 hrs, 6 hrs, 24 hrs, 48 hrs, 168 hrs post EOI. Cycle 3 Day 1 EOI, 1 hr, 48 hrs post EOI. Cycle 5 Day 1 EOI, and then 1 hr, 48 hrs post EOI.)
- Volume of distribution during the terminal phase (Vz) of [177Lu]Lu-PSMA-617, [177Lu]Lu-DOTA-TATE and [177Lu]Lu-NeoB(Cycle 1 Day 1 (each cycle is 42 days) pre-dose, post-dose/end of infusion (EOI) and then 0.5 hrs, 2 hrs, 4 hrs, 6 hrs, 24 hrs, 48 hrs, 168 hrs post EOI. Cycle 3 Day 1 EOI, 1 hr, 48 hrs post EOI. Cycle 5 Day 1 EOI, and then 1 hr, 48 hrs post EOI.)
- Terminal half-life (T^1/2) of [177Lu]Lu-PSMA-617, [177Lu]Lu-DOTA-TATE and [177Lu]Lu-NeoB(Cycle 1 Day 1 (each cycle is 42 days) pre-dose, post-dose/end of infusion (EOI) and then 0.5 hrs, 2 hrs, 4 hrs, 6 hrs, 24 hrs, 48 hrs, 168 hrs post EOI. Cycle 3 Day 1 EOI, 1 hr, 48 hrs post EOI. Cycle 5 Day 1 EOI, and then 1 hr, 48 hrs post EOI.)
- Absorbed radiation doses of [177Lu]Lu-PSMA-617, [177Lu]Lu-DOTA-TATE and [177Lu]Lu-NeoB(Cycle 1 Day 1 (each cycle is 42 days), Cycle 1 Day 2, Cycle 1 Day 3, Cycle 1 Day 8, Cycle 3 Day 1, Cycle 3 Day 3, Cycle 5 Day 1, Cycle 5 Day 3 (Cycle 3 Day 2, Cycle 3 Day 8, Cycle 5 Day 2 and Cycle 5 Day 8 where required by local authorities))
- Time Activity Curves (TACs) of [177Lu]Lu-PSMA-617, [177Lu]Lu-DOTA-TATE and [177Lu]Lu-NeoB(Cycle 1 Day 1 (each cycle is 42 days), Cycle 1 Day 2, Cycle 1 Day 3, Cycle 1 Day 8, Cycle 3 Day 1, Cycle 3 Day 3, Cycle 5 Day 1, Cycle 5 Day 3 (Cycle 3 Day 2, Cycle 3 Day 8, Cycle 5 Day 2 and Cycle 5 Day 8 where required by local authorities))