Improved Treatment of Colorectal Cancer with CF10

CF10 改善结直肠癌治疗

基本信息

批准号：
10698394
负责人：
William H Gmeiner
金额：
$ 96.45万
依托单位：
DEEP CREEK PHARMA, LLC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10698394
关键词：
Animal Model Award Biochemical Biodistribution COVID-19 vaccine Cancer Model Clinical Clinical Research Clinical Trials Clinical Trials Design Collaborations Colon Carcinoma Colonic Neoplasms Colorectal Colorectal Cancer DNA Data Disease Disease model Dose Drug Combinations Drug Kinetics FDA approved Fluorouracil Formulation Foundations Generations Genetic Human Immunotherapy Laboratories Leucovorin Lung Malignant neoplasm of gastrointestinal tract Metabolism Metastatic Neoplasm to the Liver Modeling Mus Nucleic Acids Outcome Patients Pharmaceutical Preparations Pharmacologic Substance Pharmacology Pharmacology Study Pharmacology and Toxicology Phase Physiological Physiology Polymers Preclinical Drug Development Preclinical Testing Property Rattus Refractory Regimen Research Rodent Rodent Model Safety Saline Schedule Small Business Technology Transfer Research Sterility Testing Therapeutic Toxic effect Toxicity Tests Toxicology Translating anticancer activity cancer cell chemotherapy clinical candidate clinical development colon cancer patients colorectal cancer treatment commercialization design efficacy testing fluoropyrimidine forest improved innovation lipid nanoparticle medical schools metastatic colorectal mortality mouse model nonhuman primate novel strategies oxaliplatin pharmacokinetic model pharmacologic phase 2 study preclinical study standard of care systemic toxicity targeted treatment therapy resistant tumor

项目摘要

PROJECT SUMMARY Decades of modulating the anti-cancer activity of fluoropyrimidine drugs (FPs) thru schedule optimization, biochemical modulation, and drug combinations have provided a significant, but limited, survival advantage for treating colorectal cancer (CRC) patients with locally advanced or metastatic disease (mCRC). However, outcomes remain poor for patients with mCRC and since targeted therapies and immunotherapies provide only a limited benefit to a sub-set of CRC patients, new approaches are urgently needed. Deep Creek Pharma together academic partner Wake Forest School of Medicine (WFSM) is developing CF10, the first DNA-based FP polymer, as an improved treatment for CRC. In pre-clinical studies through Phase 1 STTR support, we have demonstrated that CF10 is much more potent than 5-FU to CRC cells and demonstrated improved survival relative to 5-FU in multiple colon tumor models in rodents. Further, CF10 displayed reduced systemic toxicities relative to 5-FU making it a strong candidate for clinical development. We have also established CF10 displays distinct pharmacological and mechanistic properties relative to conventional FP drugs. Based on these findings, DeepCreek Pharma and WFSM/Gmeiner Lab propose to jointly investigate CF10 as a candidate for clinical development. A major unmet need is treatment of mCRC that is refractory to FOLFOX (5-FU, Leucovorin (LV), oxaliplatin), and other front-line therapies for mCRC. The proposed research in phase II will therefore focus on (Aim 1) Developing CF10 lipid nanoparticles (LNPs) and testing for improved activity, including in a therapy-resistant CRC liver metastasis model. LNP formulation has proven to be a robust delivery strategy for multiple nucleic acid drugs, and identifying a preferred LNP formulation will promote CF10 clinical development. In Aim 2 of the Phase II studies we will perform safety pharmacology studies of CF10 and CF10:LNPs in rodents while in Aim 3 we will evaluate pharmacokinetics (PK) and biodistribution in non-human primates (NHPs). Studies in NHPs accurately reflect human physiology and metabolism and are particularly important for regulatory apprval. Collectively, our Phase II STTR studies will provide critical data for to advance CF10 into clinical trials and ultimately its commercialization.

项目摘要数十年来调节氟嘧啶药物（FPS）的抗癌活性到计划优化，生化调制和药物组合为治疗局部晚期或转移性疾病（MCRC）的结直肠癌（CRC）患者。然而， MCRC患者的结局仍然很差，并且靶向疗法和免疫疗法仅提供迫切需要对CRC患者子组的益处有限。 Deep Creek Pharma 学术合作伙伴Wake Wake Forest医学院（WFSM）正在开发CF10，这是第一个基于DNA的 FP聚合物，作为CRC的改进治疗方法。在通过第1阶段STTR支持的临床前研究中，我们有证明CF10比5-FU对CRC细胞更有效，并且证明了提高的存活率相对于啮齿动物多种结肠肿瘤模型中的5-FU。此外，CF10显示出降低的全身毒性相对于5-FU，使其成为临床发育的有力候选者。我们还建立了CF10显示器相对于常规FP药物，不同的药理和机械特性。基于这些发现， DeepCreek Pharma和WFSM/Gmeiner Lab提议共同研究CF10作为临床的候选者发展。一个主要的未满足需要是对FOLFOX（5-FU，Leucovorin（LV），Oxaliptin）和Oxaliptin）和 MCRC的其他前线疗法。因此，第二阶段的拟议研究将集中于（目标1）开发 CF10脂质纳米颗粒（LNP）和改善活性的测试，包括在治疗的CRC肝脏中转移模型。 LNP公式已被证明是多种核酸药物的强大递送策略，并确定首选的LNP配方将促进CF10临床开发。在第二阶段的目标2中研究我们将对啮齿动物中的CF10和CF10：LNP进行安全药理学研究，而在AIM 3中，我们将评估非人类灵长类动物（NHP）中的药代动力学（PK）和生物分布。准确地研究NHP 反映人类的生理和代谢，对于监管批准尤为重要。总体而言，我们的第二阶段的STTR研究将为CF10推进临床试验，并最终提供关键数据商业化。