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

PRRT难治性神经内分泌肿瘤患者的靶向α发射体治疗

• 批准号: 10324229
• 负责人: Izabela Tworowska
• 金额: $ 54.82万
• 依托单位: RADIOMEDIX, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-07 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10324229
• 关键词: Address; Affect; Agonist; Biological Markers; Clinical; Clinical Protocols; Clinical Research; Contracts; Control Groups; Development; Diagnosis; Disease; Dose; Drug Targeting; Enrollment; Funding; Grant; Heterogeneity; High-LET Radiation; In complete remission; Institutional Review Boards; Investigational Drugs; Investments; Label; Length; Location; Measures; Multi-site clinical study; Neoplasms; Neuroblastoma; Neuroendocrine Cell; Neuroendocrine Therapy; Neuroendocrine Tumors; Neurosecretory Systems; Normal tissue morphology; Octreotide; Operative Surgical Procedures; Organ; PET/CT scan; Patient-Focused Outcomes; Patients; Peptide Receptor; Pharmaceutical Preparations; Phase; Primary Neoplasm; Production; Progression-Free Survivals; Property; Protocols documentation; Radiology Specialty; Radionuclide therapy; Refractory; Research; Resistance; Safety; Small Business Innovation Research Grant; Somatostatin; Somatostatin Receptor; Symptoms; Targeted Radiotherapy; Testing; Time; X-Ray Computed Tomography; cancer cell; chemotherapy; clinical efficacy; clinical practice; cohort; commercialization; dosimetry; ds-DNA; effective therapy; efficacy evaluation; efficacy outcomes; improved; innovation; interest; liquid biopsy; manufacturing facility; meetings; next generation; objective response rate; open label; overexpression; partial response; phase 1 study; phase 2 study; physical property; response; side effect; somatostatin analog; somatostatin receptor 2; therapy development; treatment choice; tumor; tumor progression

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.

项目摘要 使用β-发射体标记的生长抑素类似物的肽受体放射性核素疗法（PRRT）显示， 177 Lu-dotatate治疗受试者的无进展生存期（PFS）增加，但目的是 与对照组相比，该组的有效率相当低，仅为18%。此外，完成 在Lutathera治疗的患者的日常临床实践中观察到的缓解和部分缓解也较低。这 由于神经内分泌肿瘤的异质性;诊断时疾病处于晚期;以及 更重要的是，在治疗过程中产生了对β-发射体PRRT的肿瘤抗性。目标阿尔法- 神经内分泌肿瘤的放射治疗（达特）可以克服这些局限性，我们的I期剂量递增 对212 Pb-DOTAMTATE（AlphaMeCl 4）的研究提供了支持这一说法的临床证据。我们的剂量 I期研究确定了AlphaMedixTM在PRRT初治患者中的安全和高度耐受剂量， 转移性神经内分泌肿瘤，无论原发肿瘤的位置。所有接受此治疗的患者 根据RECIST标准，有效剂量显示了客观放射学缓解（ORR 83%）， NETSPOT PET/CT成像显示完全缓解。拟议研究的主要目标是确定 在Lutathera治疗后失败并进展的PRRT难治性患者中，Alphamethrin的安全性、PK和疗效。 这将在I期临床研究（修订的IND 135150）期间完成，随后进行II期研究 （方案编号：RMX-Alpha-R 020）。 目的1.在PRRT难治性患者中进行的有效剂量阿法美司汀的I期安全性、疗效和PK研究 患者不论肿瘤的原发部位。随着这一目标的成功实现，我们将确认 推荐剂量的Alphamethrin的有效性和安全性，为II期临床研究编写所有模块 并要求召开B类会议，向IRB和FDA提交II期临床方案。 目标2. AlphaMeetrin用于PRRT的II期非随机、开放标签、多中心临床研究 难治性患者成功完成目标后，我们将确定无进展的中位数 NET患者的生存期（mPFS）和总生存期（OS），以及至肿瘤进展的时间 (TTP)和推荐剂量的AlphaMeetrin的安全性。