Clinical Trials for Imaging and Therapy

影像和治疗的临床试验

基本信息

批准号：
10449307
负责人：
Suzanne Elizabeth Lapi
金额：
$ 86.49万
依托单位：
PROTEOGENOMICS RESEARCH INSTIT/SYS/ MED
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-08 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10449307
关键词：
Address Advanced Malignant Neoplasm Antibodies Antibody Formation Antibody-drug conjugates Blood Blood Vessels Caveolae Clinical Clinical Protocols Clinical Trials Collection Conjugating Agent Data Data Analyses Desmoplastic Development Diffusion Dose Drug Delivery Systems Drug Extravasation Drug Targeting Endothelial Cells Endothelium Extracellular Matrix Goals Human Image Immunoglobulin Fragments Institutional Review Boards Intravenous Label Lead Macaca Malignant Neoplasms Maximum Tolerated Dose Modern Medicine Mus Neoplasm Metastasis Neoplasms in Vascular Tissue Oncology Pathway interactions Patients Penetration Permeability Pharmaceutical Preparations Phase Positron-Emission Tomography Pre-Clinical Model Precision Medicine Initiative Primary Neoplasm Pump Quality of life Radiation therapy Radioimmunoconjugate Radioimmunotherapy Radionuclide Imaging Refractory Relapse Research Safety Sampling Solid Neoplasm Specificity Statistical Data Interpretation System Testing Therapeutic Therapeutic Agents Therapeutic Uses Therapy trial Time Tissues Toxic effect Toxicology Tumor Antibodies Vascular Endothelial Growth Factors Vascular Endothelium antibody conjugate base cGMP production cancer cell cancer imaging cancer therapy cell killing chemotherapeutic agent chemotherapy clinical imaging clinical translation cohort design dosimetry drug production effective therapy flexibility humanized antibody humanized monoclonal antibodies imaging agent improved interstitial investigator-initiated trial lead optimization nonhuman primate novel novel strategies novel therapeutics pancreatic neoplasm patient prognosis pre-clinical preclinical development preclinical evaluation preclinical study pressure prevent programs radiation delivery safety testing scale up small molecule targeted imaging time use tumor

项目摘要

PROJECT 3 SUMMARY All therapeutic agents injected intravenously for cancer therapy require doses well in excess of that needed if all the administered drug was placed inside the tumors; these elevated doses create high blood levels to maximize the blood-to-tissue concentration gradient that drives the drug passively across the vascular wall and into the tumors. Many times, despite near maximal tolerated doses, only a very small fraction of the therapeutic agents reach the interior tumors where the drug can be most effective. To overcome the restrictive barrier formed by the tumor vascular endothelium that prevents therapeutic agents from penetrating into solid tumors, we are exploring the clinical utility of the caveolae-pumping system to enable precision delivery of antibody-drug conjugates (ADC) and radioimmunotherapies directly into primary and metastatic tumors. Preliminary data supports the clinical translation of our approach, which will be further explored with rigorous preclinical development in testing in Projects 1 and 2. Part of that effort will be the humanization of the lead caveola- targeting antibody. Here in Project 3, clinical translation will be done stepwise by establishing a lack of significant toxicity of the humanized form of the targeting antibody (hAnnA1) conjugated to an imaging radionuclide and subsequently to a novel chemotherapy in the form of hAnnA1-ADC. Specific Aims of this project are to conduct: 1) preclinical evaluations to enable IND filings, including toxicology and safety testing of the radiolabeled antibody and ADC in non-human primates; 2) pilot imaging clinical trial of 89Zr-labeled hAnnA1 in patients with metastatic solid tumors; and 3) Phase 1 dose escalation study of novel caveolae-targeting hAnnA1-ADC. The humanized antibody will be produced in Core B, that will also be responsible for the scale-up and cGMP production of the ADC that will be used in clinical trials. Core D will produce the radiolabeled antibody for the clinical imaging trial. Core E will provide support for the statistical analysis and translational/clinical protocols, including design, conduct collection and analysis of data, from the investigator-initiated trials.

项目 3 摘要所有静脉注射用于癌症治疗的治疗剂都需要远远超过所需的剂量如果所有施用的药物都放置在肿瘤内；这些升高的剂量会导致血液浓度升高最大化血液与组织的浓度梯度，驱动药物被动穿过血管壁，进入肿瘤。很多时候，尽管接近最大耐受剂量，但治疗效果的一小部分药剂到达药物最有效的内部肿瘤。克服所形成的限制性障碍通过肿瘤血管内皮阻止治疗药物渗透到实体瘤中，我们探索小窝泵系统的临床实用性，以实现抗体药物的精确输送结合物（ADC）和放射免疫疗法直接进入原发性和转移性肿瘤。初步数据支持我们方法的临床转化，将通过严格的临床前进一步探索项目 1 和 2 中测试的开发。这项工作的一部分将是主要小窝的人性化靶向抗体。在项目 3 中，临床转化将通过确定缺乏重要的证据来逐步完成。与成像放射性核素缀合的人源化形式的靶向抗体（hAnnA1）的毒性和随后采用 hAnnA1-ADC 形式的新型化疗。该项目的具体目标是： 1) 临床前评估以进行 IND 备案，包括放射性标记抗体的毒理学和安全性测试和非人类灵长类动物中的 ADC； 2) 89Zr标记的hAnnA1在转移性患者中的初步影像学临床试验实体瘤； 3)新型caveolae靶向hAnnA1-ADC的1期剂量递增研究。人性化的抗体将在核心 B 中生产，该核心还将负责该抗体的放大和 cGMP 生产将用于临床试验的ADC。 Core D 将生产用于临床成像试验的放射性标记抗体。 Core E 将为统计分析和转化/临床方案提供支持，包括设计、从研究者发起的试验中收集和分析数据。