Clinical Evaluation of an Innovative PSMA-targeted Radiotherapy, CTT1403, in Prostate Cancer

项目摘要 前列腺特异性膜抗原(PSMA)是一种理想的肿瘤生物标志物，因为它在90%的ALL上表达 前列腺癌及其表达随着癌症的进展而增加。癌症靶向技术(CTT)已经 开发了一种独特的基于磷酰胺的支架，它与PSMA不可逆转地结合，导致&gt；90%的速度 肿瘤细胞的内化和选择性蓄积。在之前的SBIR赠款支持下，CTT创建了一架18F- 标记的PET诊断显像剂CTT1057，并于2017年8月完成了患者的I期临床试验 患有转移性前列腺癌。CTT1057对PSMA敏感的骨骼和内脏有明显的摄取作用 比标准护理扫描具有更高的特异性和敏感度。2018年1月，CTT许可了以下内容 用于高级加速器应用/诺华的PET显像剂。前列腺癌对辐射敏感，但仅限于 Re-223既没有特异性也没有选择性，已经作为晚期癌症的放射治疗药物进行了商业化。 阶段性疾病。根据额外的SBIR第一阶段/第二阶段快速通道合同，CTT修改了原始CTT1057 PSMA结合支架以开发一种特定和有效的伴随疗法CTT1403，放射性标记 有177个卢比。CTT1403与其他正在开发的PSMA靶向药物不同，它在这方面具有很高的创新性 它不可逆转地与PSMA结合，并使用白蛋白结合基序极大地减缓清除速度，结果 在前所未有的肿瘤摄取80%注射剂量/克肿瘤组织和显着的生存 在动物模型方面的优势。根据SBIR第二阶段合同，GMP-制造、放射性标记和IND- 完成了药理学、剂量学和初步动物安全性研究。FDA Pre-IND会议 已举行，IND将于2018年第四季度提交。此SBIR阶段IIB应用程序的目标是支持 首次在人体进行CTT1403的1期临床试验，并将该药定位为进一步的临床开发和快速 商业化。具体目标：目标1：CTT1403抵抗转移性去势的1期临床试验 前列腺癌(MCRPC)，评估安全性和初步疗效：CTT将进行加速剂量 MCRPC患者的升级/扩展试验。白蛋白结合、PSMA靶向、 177Lu标记的CTT1403药物被假设转化为有意义的生存优势。目标2：评估 GLP晚期放射安全性：CTT将评估犬重复剂量CTT1403的长期耐受性，以满足FDA的要求 在2期试验开始前提出延迟辐射安全建议。目标3：支助中的流程开发 进一步的临床开发：CTT将开发和扩展CTT1403制造方法，以支持 多剂量试验。这项创新的工作利用了细胞穿透不可逆的理想性能 利用白蛋白结合增加循环半衰期和肿瘤的小分子PSMA靶向药物 靶向治疗，降低肾毒性。CTT1403对诊断转移性前列腺癌有重要意义 通过减少有大量未得到满足的需求的患者群体的毒副作用来治疗癌症。

PROJECT ABSTRACT Prostate-Specific Membrane Antigen (PSMA) is an ideal tumor biomarker as it is expressed on >90% of all prostate cancers and expression increases as the cancer progresses. Cancer Targeted Technology (CTT) has developed a unique phosphoramidate-based scaffold that binds irreversibly to PSMA leading to > 90% rapid internalization and selective accumulation in tumor cells. With previous SBIR grant support, CTT created an 18F- labeled PET diagnostic imaging agent, CTT1057, and in Aug 2017 completed a Phase I clinical trial in patients with metastatic prostate cancer. CTT1057 demonstrated significant uptake in PSMA-avid bone and visceral lesions with far greater specificity and sensitivity than standard of care scans. In Jan 2018, CTT licensed this PET imaging agent to Advanced Accelerator Applications/Novartis. Prostate cancer is radiosensitive, but only Radium-223, which is neither specific nor selective, has been commercialized as a radiotherapeutic for advanced stage disease. Under an additional SBIR Phase I/II fast track contract, CTT modified the original CTT1057 PSMA-binding scaffold to develop a specific and potent companion therapeutic, CTT1403, radiolabeled with 177Lu. CTT1403, unlike other PSMA-targeting agents under development, is highly innovative in that it binds irreversibly to PSMA and uses an albumin-binding motif to dramatically slow clearance, resulting in an unprecedented tumor uptake of >80% injected dose/g of tumor tissue and a significant survival advantage in animal models. Under the SBIR Phase II contract, GMP-manufacturing, radiolabeling and IND- enabling pharmacology, dosimetry and initial animal safety studies were completed. An FDA pre-IND meeting was held, and the IND will be filed Q4 2018. The objective of this SBIR Phase IIB application is to support the first in human Phase 1 clinical trial of CTT1403 and to position the drug for further clinical development and rapid commercialization. Specific aims: AIM 1: Phase 1 clinical trial of CTT1403 in metastatic castration-resistant prostate cancer (mCRPC), assessing safety and initial efficacy: CTT will conduct an accelerated dose escalation/expansion trial in patients with mCRPC. Increased uptake of the albumin-binding, PSMA-targeted, 177Lu-labeled CTT1403 drug is hypothesized to translate into a meaningful survival advantage. AIM 2: Assess GLP late radiation safety: CTT will evaluate long term tolerance of repeat-dose CTT1403 in dogs to meet FDA late radiation safety recommendations prior to start of Phase 2 trials. AIM 3: Process development in support of further clinical development: CTT will develop and scale CTT1403 manufacturing methods in support of multiple dose trials. This innovative work harnesses the ideal performance of a cell-penetrating irreversible small-molecule PSMA-targeted drug that uses albumin binding to increase circulation half-life and tumor targeting and decrease renal toxicity. CTT1403 should have considerable significance for metastatic prostate cancer therapy by reducing toxic side effects in a patient population with a substantial unmet need.