Camptothecin Analogs for Cancer Therapy

描述（由申请人提供）：7-Butyl-10-aminocamptothecin (BACPT)，作为一种水溶性二肽前药- BACPTDP，是一种新的喜树碱类似物，在缺氧/酸性肿瘤组织中具有增加的活性，这是快速生长的癌症的特征，其特征是血管缺陷和血液供应不足。体外和体内研究均支持BACPTDP治疗胰腺癌的潜在有效性。与其他CPT对照相比，BACPTDP在人类PANC-1异种移植模型中的显著反应被回顾，以支持本应用中提出的临床前研究。这项第二期研究的具体目标是：1。合成7-丁基-10-氨基琥珀酸二肽（BACPTDP），量为10-20克-足以用于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. 将该药配制成冻干粉。文件稳定性和潜在的临床用途。4. 开发和测定组织/血液生物标志物作为BACPTDP吸收和疗效（药效学）的指标。5. 为未来的I期研究准备IND。完成这些研究后，将向FDA提交IND申请。

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.