Kostos Louise, Buteau James P, Yeung Theresa, Iulio Juliana Di, Xie Jing, Cardin Anthony, Chin Kwang Y, Emmerson Brittany, Owen Katie L, Parker Belinda S, Fettke Heidi, Furic Luc, Azad Arun A, Hofman Michael S
Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.
Front Med (Lausanne). 2022 Nov 18;9:1059122. doi: 10.3389/fmed.2022.1059122. eCollection 2022.
BACKGROUND: [Lu]Lu-PSMA is a radioligand therapy used in metastatic castration-resistant prostate cancer (mCRPC). Despite a survival benefit, the responses for many patients receiving [Lu]Lu-PSMA are not durable, and all patients eventually develop progressive disease. The bone marrow is the most common site of progression. Micrometastases in this area likely receive an inadequate dose of radiation, as the emitted beta-particles from Lu travel an average range of 0.7 mm in soft tissue, well beyond the diameter of micrometastases. Radium-223 (Ra) is a calcium-mimetic and alpha-emitting radionuclide approved for use in men with mCRPC with bone metastases. The range of emitted alpha particles in soft tissue is much shorter (≤100 μm) with high linear energy transfer, likely more lethal for osseous micrometastases. We anticipate that combining a bone-specific alpha-emitter with [Lu]Lu-PSMA will improve eradication of micrometastatic osseous disease, and thereby lead to higher and longer responses. METHODS: This is a single-center, single-arm phase I/II trial evaluating the combination of Ra and [Lu]Lu-PSMA-I&T in men with mCRPC. Thirty-six patients will receive 7.4 GBq of [Lu]Lu-PSMA-I&T, concurrently with Ra in escalating doses (28 kBq/kg - 55kBq/kg), both given intravenously every six weeks for up to six cycles. Eligible patients will have at least two untreated bone metastases visible on bone scintigraphy, and PSMA-positive disease on PSMA PET scan. Patients must have adequate bone marrow and organ function and be willing to undergo tumor biopsies. Patients with discordant disease visible on FDG PET scan (defined as FDG positive disease with minimal or no PSMA expression and no uptake on bone scan) will be excluded. Other key exclusion criteria include the presence of diffuse marrow disease, prior treatment with Ra or [Lu]Lu-PSMA, or more than one prior line of chemotherapy for prostate cancer. The co-primary objectives of this study are to determine the maximum tolerated dose of Ra when combined with [Lu]Lu-PSMA-I&T and the 50% PSA response rate. CONCLUSION: The AlphaBet trial is a phase I/II study combining Ra with [Lu]Lu-PSMA-I&T in patients with mCRPC. We aim to enroll the first patient in Q3 2022, and recruitment is anticipated to continue for 24 months. STUDY REGISTRATION: NCT05383079.
背景：镥[Lu]Lu-PSMA是一种用于转移性去势抵抗性前列腺癌（mCRPC）的放射性配体疗法。尽管有生存获益，但许多接受镥[Lu]Lu-PSMA治疗的患者反应并不持久，所有患者最终都会出现疾病进展。骨髓是最常见的进展部位。该区域的微转移灶可能接受的辐射剂量不足，因为镥发射的β粒子在软组织中的平均射程为0.7毫米，远超过微转移灶的直径。镭-223（Ra）是一种模拟钙的α发射放射性核素，已被批准用于患有骨转移的mCRPC男性患者。发射的α粒子在软组织中的射程要短得多（≤100μm），且具有高线性能量传递，可能对骨微转移灶更具杀伤力。我们预计，将一种骨特异性α发射体与镥[Lu]Lu-PSMA联合使用将改善对骨微转移疾病的根除，从而带来更高和更长时间的反应。 方法：这是一项单中心、单臂I/II期试验，评估镭与镥[Lu]Lu-PSMA-I&T联合用于mCRPC男性患者的情况。36名患者将接受7.4GBq的镥[Lu]Lu-PSMA-I&T，同时接受递增剂量（28kBq/kg - 55kBq/kg）的镭，均每六周静脉注射一次，最多六个周期。符合条件的患者在骨闪烁显像上至少有两个未治疗的骨转移灶，且在PSMA PET扫描上显示PSMA阳性疾病。患者必须有足够的骨髓和器官功能，并愿意接受肿瘤活检。FDG PET扫描上显示疾病不一致的患者（定义为FDG阳性疾病且PSMA表达极少或无表达且骨扫描无摄取）将被排除。其他关键排除标准包括存在弥漫性骨髓疾病、先前接受过镭或镥[Lu]Lu-PSMA治疗，或先前接受过不止一线的前列腺癌化疗。本研究的共同主要目标是确定与镥[Lu]Lu-PSMA-I&T联合使用时镭的最大耐受剂量和50%的PSA反应率。 结论：AlphaBet试验是一项在mCRPC患者中联合使用镭与镥[Lu]Lu-PSMA-I&T的I/II期研究。我们的目标是在Q3 2022招募第一名患者，预计招募将持续24个月。 研究注册：NCT05383079。
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