Camptothecin Analogs for Cancer Therapy

用于癌症治疗的喜树碱类似物

• 批准号: 7909166
• 负责人: Lee ROY MORGAN
• 金额: $ 44.49万
• 依托单位: DEKK-TEC, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-27 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7909166
• 关键词: Aminocamptothecin; Animals; Biological Assay; Biological Availability; Biological Markers; Blood; Camptothecin; Camptothecin Analogue; Canis familiaris; Characteristics; Clinical; Clinical Trials; Colon; Development; Dipeptides; Drug Formulations; Drug Kinetics; Environment; Future; Grant; Guidelines; Human; Hypoxia; In Vitro; Institutes; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Molecular; Mus; Ovarian; Pancreas; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Plasma; Powder dose form; Prodrugs; Research; Research Institute; Tissues; Toxic effect; Tumor Tissue; Universities; Vascular blood supply; Water; Xenograft Model; absorption; cancer therapy; design; in vivo; novel; phase 1 study; phase 2 study; pre-clinical; preclinical study; public health relevance; response; tumor

DESCRIPTION (provided by applicant): 7-Butyl-10-aminocamptothecin (BACPT), as a water-soluble dipeptide pro-drug - BACPTDP, is a novel camptothecin analog that has increased activity in hypoxic/acidic tumor tissues, characteristic of fast growing cancers that characteristically have deficient vasculature and outgrow their blood supply. Both in vitro and in vivo studies support the potential usefulness of BACPTDP in the treatment of pancreatic cancer. The significant responses seen with BACPTDP in the human PANC-1 xenograft model vs. other CPT controls are reviewed in support for the pre-clinical studies proposed in this application. The specific objectives of this Phase II study will be to: 1. Synthesize 7-butyl-10-aminocamptothecin dipeptide (BACPTDP) in 10-20 g quantities - sufficient for preclinical studies and formulation studies. 2. Conduct mouse and dog toxicity and pharmacokinetic studies. 3. Formulate the drug as a lyophilized powder. Document stability and potential clinical usefulness. 4. Develop and assay tissue/blood biomarkers as indicators for BACPTDP absorption and efficacy (pharmacodynamics). 5. Prepare the IND for future Phase I studies. Upon completion of these studies an FDA IND submission will be made. PUBLIC HEALTH RELEVANCE: BACPTDP is a novel camptothecins that was originally designed at Duke University to be used in the treatment of hypoxic, poorly vascularized tumors that possessed acidic environments. Studies conducted in the Phase I grant in pancreas, colon, ovarian and lung cancer xenograft models and reviewed herein, support our decision to move the product forward and ready it for clinical trials. Subsequently, DEKK-TEC has partnered with Duke and Research Triangle Institute (RTI) to complete the pre-clinical development, prepare the IND and ready the products for a Phase 1 clinical trial. Prior to the latter, DEKK-TEC proposes conducting the necessary pre- clinical toxicity, pharmacokinetic, formulation and stability studies. The studies as described will fulfill the requirements for a Phase I study to be designed.

描述（申请人提供）：7-丁基-10-氨基喜树碱（BACPT）是一种水溶性二肽前药 - BACPTDP，是一种新型喜树碱类似物，在缺氧/酸性肿瘤组织中具有增强的活性，具有快速生长的特征癌症的特征是脉管系统不足，血液供应不足。体外和体内研究都支持 BACPTDP 在治疗胰腺癌中的潜在用途。与其他 CPT 对照相比，对 BACPTDP 在人类 PANC-1 异种移植模型中观察到的显着反应进行了审查，以支持本申请中提出的临床前研究。该 II 期研究的具体目标是： 1. 合成 10-20 g 量的 7-丁基-10-氨基喜树碱二肽 (BACPTDP) - 足以进行临床前研究和制剂研究。 2. 进行小鼠和狗的毒性和药代动力学研究。 3. 将药物配制成冻干粉末。记录稳定性和潜在的临床用途。 4. 开发并测定组织/血液生物标志物作为 BACPTDP 吸收和功效（药效学）的指标。 5. 为未来 I 期研究准备 IND。这些研究完成后，将向 FDA 提交 IND 申请。 公共健康相关性：BACPTDP 是一种新型喜树碱，最初由杜克大学设计，用于治疗具有酸性环境的缺氧、血管化不良的肿瘤。在胰腺癌、结肠癌、卵巢癌和肺癌异种移植模型中进行的第一阶段研究并在此进行了回顾，支持我们推动该产品并为临床试验做好准备的决定。随后，DEKK-TEC 与杜克大学和三角研究院 (RTI) 合作完成临床前开发、准备 IND 并为产品的 1 期临床试验做好准备。在此之前，DEKK-TEC 建议进行必要的临床前毒性、药代动力学、配方和稳定性研究。所述研究将满足要设计的第一阶段研究的要求。