PO.CT01.05 · 临床试验
Ga-68-NGUL和Lu-177-DGUL（pocuvotide satetraxetan）在mCRPC中的安全性、剂量学及RP2D确定：一项1/2期研究结果
Safety, dosimetry, and RP2D determination of Ga‑68‑NGUL and Lu‑177‑DGUL (pocuvotide satetraxetan) in mCRPC: Results from a phase 1/2 study
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：放射治疗诊断学是转移性去势抵抗性前列腺癌（mCRPC）一种新兴的治疗策略。本研究评估了治疗诊断配对物Ga-68-NGUL和Lu-177-DGUL在mCRPC患者中的安全性、剂量学和抗肿瘤活性。Ga-68-NGUL是一种新型PSMA靶向PET示踪剂，不含酰胺键，从而增强了对蛋白水解降解的稳定性。Lu-177-DGUL是一种对PSMA具有高亲和力的小分子，选择性靶向前列腺癌细胞并发射β粒子，同时保护正常组织。
方法：这项开放标签、单臂、多中心、1/2期试验评估了Ga-68-NGUL和Lu-177-DGUL。1期包括Ga-68-NGUL在健康志愿者和mCRPC患者中的剂量学，以及Lu-177-DGUL（150和200 mCi）的评估，以确定最大耐受剂量和器官剂量学。在2期中，患者以推荐2期剂量（RP2D）接受Lu-177-DGUL，每6周一次，最多6个周期。整个研究期间监测疗效和安全性（ClinicalTrials.gov NCT05547061）。
结果：在1期A部分中，对6名受试者分析了Ga-68-NGUL剂量学，显示在健康志愿者和mCRPC患者中膀胱和肾脏摄取最高。在150 mCi队列的4例患者中评估了Lu-177-DGUL剂量学，唾液腺接受的吸收剂量最高，其次是肾脏。在1期B部分的7名受试者中未观察到剂量限制性毒性（DLTs），支持200 mCi作为RP2D。在2期中，91例患者接受200 mCi的Lu-177-DGUL治疗。主要终点，即按RECIST 1.1的客观缓解率（ORR）为35.9%（7例完全缓解和21例部分缓解）。关键次要终点支持这些发现：按PCWG修订的RECIST v1.1的ORR为41.0%（32例缓解者）。分别在66.7%（52/78）和39.7%（31/78）的可评估患者中观察到PSA下降≥50%和≥80%。中位PSA倍增时间未达到（95% CI，258.0-NA）。发生率≥10%的治疗中出现的不良事件包括贫血（31.9%）和口干（13.2%），且总体可控。
结论：Ga-68-NGUL和Lu-177-DGUL在mCRPC中显示出良好的安全性特征、可预测的剂量学和有意义的抗肿瘤活性。1期确认了可接受的器官辐射暴露，2期显示在RP2D下具有临床相关缓解且毒性可控。这些发现支持在对照及后期试验中进一步评估Lu-177-DGUL。
查看英文原文 English abstract
Background: Radiotheranostics is an emerging therapeutic strategy for metastatic castration‑resistant prostate cancer (mCRPC). This study assessed the safety, dosimetry, and antitumor activity of the theranostic pair Ga‑68‑NGUL and Lu‑177‑DGUL in patients with mCRPC. Ga‑68‑NGUL is a novel PSMA‑targeting PET tracer that lacks an amide bond, providing enhanced stability against proteolytic degradation. Lu‑177‑DGUL, a small molecule with high PSMA affinity, selectively targets prostate cancer cells and emits beta‑particles while sparing normal tissues.
Methods: This open‑label, single‑arm, multicenter, Phase 1/2 trial assessed Ga‑68‑NGUL and Lu‑177‑DGUL. Phase 1 included dosimetry of Ga‑68‑NGUL in healthy volunteers and mCRPC patients, and evaluation of Lu‑177‑DGUL (150 and 200 mCi) to determine the maximum tolerated dose and organ dosimetry. In Phase 2, patients received Lu‑177‑DGUL at the recommended Phase 2 dose (RP2D) every 6 weeks for up to 6 cycles. Efficacy and safety were monitored throughout the study (ClinicalTrials.gov NCT05547061).
Results: In Phase 1, Part A, Ga‑68‑NGUL dosimetry was analyzed in 6 subjects, showing the highest uptake in the bladder and kidney in both healthy volunteers and mCRPC patients. Lu‑177‑DGUL dosimetry was evaluated in 4 patients in the 150 mCi cohort, with the salivary glands receiving the highest absorbed dose, followed by the kidneys. No dose‑limiting toxicities (DLTs) were observed in the 7 subjects in Phase 1, Part B, supporting 200 mCi as the RP2D. In Phase 2, 91 patients were treated with Lu‑177‑DGUL at 200 mCi. The primary endpoint, objective response rate (ORR) by RECIST 1.1, was 35.9% (7 complete responses and 21 partial responses). Key secondary endpoints supported these findings: ORR by PCWG‑modified RECIST v1.1 was 41.0% (32 responders). PSA declines of ≥50% and ≥80% were observed in 66.7% (52/78) and 39.7% (31/78) of evaluable patients, respectively. Median PSA doubling time was not reached (95% CI, 258.0-NA). Treatment‑emergent adverse events occurring in ≥10% of patients included anemia (31.9%) and dry mouth (13.2%), and were generally manageable.
Conclusions: Ga‑68‑NGUL and Lu‑177‑DGUL demonstrated a favorable safety profile, predictable dosimetry, and meaningful antitumor activity in mCRPC. Phase 1 confirmed acceptable organ radiation exposure, and Phase 2 showed clinically relevant responses with manageable toxicity at the RP2D. These findings support further evaluation of Lu‑177‑DGUL in comparative and later‑phase trials.
利益披露 Disclosure
S. Jeong, None..
C. Kwak, None..
C. Jeong, None..
S. Hong, None..
J. Lee, None..
E. Hwang, None..
K. Koo, None..
K. Kang, None..
G. Cheon, None..
M. Suh, None.