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Clinical Trials for Imaging and Therapy

影像和治疗的临床试验

基本信息

批准号：
9974489
负责人：
Suzanne Elizabeth Lapi
金额：
$ 29.63万
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/9974489
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 outcome forecast pancreatic neoplasm 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概要静脉注射用于癌症治疗的所有治疗剂都需要远远超过所需的剂量如果所有给药的药物都被放置在肿瘤内，这些高剂量会产生高的血液水平，最大化血液-组织浓度梯度，该梯度驱动药物被动地穿过血管壁，进入肿瘤。很多时候，尽管接近最大耐受剂量，只有非常小的一部分治疗剂量，药剂到达药物最有效的内部肿瘤。为了克服形成的限制性障碍，通过肿瘤血管内皮阻止治疗剂渗透到实体瘤中，我们探索小窝泵送系统的临床应用，以实现抗体药物的精确输送因此，本发明的药物组合物（ADC）和放射免疫疗法可直接用于原发性和转移性肿瘤。初步数据支持我们的方法的临床转化，这将进一步探索与严格的临床前在项目1和项目2中进行测试。这项工作的一部分将是人性化的铅窖- 靶向抗体。在项目3中，临床翻译将通过建立缺乏重要的与成像放射性核素缀合的靶向抗体（hAnnA 1）的人源化形式的毒性，以及随后以hAnnA 1-ADC的形式进行新的化疗。该项目的具体目标是： 1)临床前评价，以实现IND申报，包括放射性标记抗体的毒理学和安全性试验 2）89 Zr标记的hAnnA 1在非人灵长类动物中的初步成像临床试验; 实体瘤;和3）新型小窝靶向hAnnA 1-ADC的1期剂量递增研究。人源化抗体将在核心B中产生，核心B也将负责放大和cGMP生产。将用于临床试验的ADC。核心D将生产用于临床成像试验的放射性标记抗体。核心E将为统计分析和翻译/临床方案提供支持，包括设计，从制药商发起的试验中收集和分析数据。