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，因为它表达于>90%的所有肿瘤细胞中。 前列腺癌和表达随着癌症进展而增加。癌症靶向技术（CTT） 开发了一种独特的基于氨基磷酸酯的支架，其不可逆地结合PSMA，导致> 90%的快速 在肿瘤细胞中内化和选择性积累。在以前的SBIR资助支持下，CTT创建了一个18 F- 标记的PET诊断成像剂CTT 1057，并于2017年8月在患者中完成了I期临床试验 转移性前列腺癌CTT 1057在亲PSMA的骨和内脏中表现出显著的摄取 病变的特异性和敏感性远高于标准护理扫描。2018年1月，CTT授权 PET显像剂，用于Advanced Accelerator Applications/Novartis。前列腺癌是放射敏感的，但只有 镭-223既无特异性也无选择性，已被商业化作为先进的放射性同位素。 阶段性疾病根据另一份SBIR I/II期快速通道合同，CTT修改了原CTT 1057 PSMA结合支架开发特异性和有效的伴随治疗剂CTT 1403，放射性标记 177路CTT 1403与其他正在开发的PSMA靶向剂不同， 它与PSMA不可逆地结合，并利用白蛋白结合基序显著减缓清除， 在>80%注射剂量/g肿瘤组织的前所未有的肿瘤摄取中， 动物模型的优势。根据SBIR第二阶段合同，GMP生产、放射性标记和IND- 完成了药理学、剂量测定和初步动物安全性研究。FDA Pre-IND会议 IND将于2018年第4季度提交。此SBIR阶段IIB应用程序的目标是支持 CTT 1403的首次人体I期临床试验，并将药物定位于进一步的临床开发和快速 商业化具体目的：目的1：CTT 1403在转移性去势抵抗性 前列腺癌（mCRPC），评估安全性和初始疗效：CTT将进行加速给药 在mCRPC患者中进行的递增/扩展试验。白蛋白结合，PSMA靶向， 假设177 Lu标记的CTT 1403药物转化为有意义的生存优势。目标2：评估 GLP晚期辐射安全性：CTT将评价犬重复给药CTT 1403的长期耐受性，以满足FDA要求 在2期试验开始之前，延迟辐射安全建议。目标3：支持流程开发 进一步的临床开发：CTT将开发和扩展CTT 1403的生产方法，以支持 多剂量试验这项创新工作利用了细胞穿透不可逆 一种小分子PSMA靶向药物，利用白蛋白结合增加循环半衰期和肿瘤 靶向和减少肾毒性。CTT 1403对前列腺转移有重要意义 通过减少具有大量未满足需求的患者群体中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.