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（由申请人提供）：7-丁基-10-氨基氨基摄影（BACPT）作为水溶性二肽Pro-drug-BACPTDP，是一种新型的camptothecin类似物，在低氧/酸性肿瘤组织中具有增加活性，是快速生长的癌症的特征，其特征性地具有多种供应量为血液供应和膨胀性的血液，并产生了鲜血的供应。体外和体内研究都支持BACPTDP在胰腺癌治疗中的潜在实用性。审查了人类PANC-1异种移植模型与其他CPT对照中的BACPTDP的显着响应，以支持本应用中提出的临床前研究。该II阶段研究的具体目标将是：1。合成10-20 g数量的7-丁基-10-氨基氨基霉素二肽（BACPTDP） - 足以容纳临床前研究和配方研究。 2。进行小鼠和狗的毒性和药代动力学研究。 3。将药物形式为冻干粉末。记录稳定性和潜在的临床实用性。 4。开发和测定组织/血液生物标志物作为BACPTDP吸收和功效的指标（药效学）。 5。为将来的第一阶段研究准备IND。完成这些研究后，将提交FDA IND提交。 公共卫生相关性：BACPTDP是一种新型的camptothecins，最初是在杜克大学设计的，用于治疗具有酸性环境的低氧，血管化较差的肿瘤。在胰腺，结肠，卵巢和肺癌异种移植模型的第一阶段赠款中进行的研究，并在此进行了审查，支持我们决定将产品前进并准备好临床试验的决定。随后，Dekk-TEC与Duke和Research Triangle Institute（RTI）合作完成了临床前开发，准备IND并准备好了1阶段临床试验的产品。在后者之前，DEKK-TEC提出进行必要的临床毒性，药代动力学，配方和稳定性研究。所述的研究将满足设计I阶段研究的要求。