Targeted alpha-emitter therapy of patients with PRRT refractory neuroendocrine tumors

项目总结 一种使用β-发射体标记的生长抑素类似物的多肽受体放射性核素疗法(PRRT)显示 177Lu-DOTATE治疗的受试者无进展生存(PFS)的增加，然而目标是 本组有效率较低，仅为对照组的18%。此外，完成的数量 在每天的临床实践中，接受卢塔瑟拉治疗的患者的反应和部分反应也很低。这 是由于神经内分泌肿瘤的异质性；确诊时疾病处于晚期；以及 更重要的是，在治疗过程中，肿瘤对β-发射体PRRT产生了抵抗力。目标阿尔法- 神经内分泌肿瘤的发射体治疗(TAT)可以克服这些限制，我们的I期剂量递增 对~(212)Pb-DOTAMTATE(AlphaMedex)的研究提供了支持这一说法的临床证据。我们的剂量 I期研究确定AlphaMedixTM在PRRT幼稚患者中的安全和高效剂量 转移性神经内分泌肿瘤，不论原发肿瘤的位置。所有接受过这种治疗的患者 根据RECIST标准，有效剂量显示出客观的放射反应(ORR 83%)，几乎 通过NetSpot PET/CT成像实现完全应答。拟议研究的主要目标是确定 Alphamedix对PRRT失败和Lutathera后进展的难治性患者的安全性、PK和疗效。 这将在第一阶段临床研究(修订IND 135150)期间完成，随后是第二阶段研究 (协议号：RMX-Alpha-R020)。 目的1.Alphamedix治疗PRRT耐药的有效剂量的I期安全性、有效性和PK研究 患者无论肿瘤的原发来源如何。随着这一目标的圆满完成，我们将确认 推荐剂量的Alphamedix的有效性和安全性，汇编II期临床研究的所有模块 并要求召开B类会议，并向IRB和FDA提交II期临床方案。 目标2：AlphaMedex在PRRT中的II期非随机、开放标签、多中心临床研究 难治的病人。随着目标的成功完成，我们将确定自由进展的中位数 NETS患者的生存期(MPFS)和总生存期(OS)以及他们的肿瘤进展时间 (TTP)，以及推荐剂量的AlphaMedex的安全性。

PROJECT SUMMARY A peptide receptor radionuclide therapy (PRRT) using beta-emitter-labeled somatostatin analogs has showed increase in the progression-free-survival (PFS) of 177Lu-dotatate treated subjects, however the objective response rate of this group is rather low only 18% compare to control group. In addition, the number of complete responses and partial responses seen in the daily clinical practice in Lutathera treated patients is also low. This is due to the heterogeneity of neuroendocrine tumors; advanced stage of disease at the time of diagnosis; and more importantly tumor resistance to beta-emitter PRRT developed during the therapy. The targeted alpha- emitter therapy (TAT) of neuroendocrine tumors can overcome these limitations and our Phase I dose escalation studies of 212Pb-DOTAMTATE (AlphaMedix) provide clinical evidence supporting this statement. Our dose Phase I study determined SAFE and HIGHLY EFFECTIVE DOSE of AlphaMedixTM in PRRT naïve patients with metastatic neuroendocrine tumors regardless of the location of the primary tumor. All patients treated with this effective dose have shown the Objective Radiologic Response (ORR 83%) by RECIST criteria and almost complete response by NETSPOT PET/CT imaging. The main objective of proposed study is determination of the safety, PK, and efficacy of Alphamedix in PRRT refractory patients who failed and progressed after Lutathera. This will be accomplished during Phase I clinical study (amended IND 135150), followed by Phase II study (Protocol Number: RMX-Alpha-R020). OBJECTIVE 1. Phase I safety, efficacy and PK studies of the effective dose of Alphamedix in PRRT-refractory patients regardless the primary origin the tumor. With successful completion of this objective, we will confirm the efficacy and safety of recommended doses of Alphamedix, compile all modules for Phase II clinical studies and request type B meeting and submit Phase II clinical protocol to IRB and FDA. OBJECTIVE 2. Phase II non-randomized, open-label, multi-center clinical studies of AlphaMedix in PRRT refractory patients. With successful completion of the objective, we will determine the median Progression free survival (mPFS) and the Overall Survival (OS) of NETs patients, as well as their Time to Tumor Progression (TTP), and safety of the recommended doses of AlphaMedix.