Drug-eluting Brachytherapy Implants for Chemo-radiation Therapy

用于放化疗的药物洗脱近距离放射治疗植入物

• 批准号: 9466175
• 负责人: SRINIVAS SRIDHAR
• 金额: $ 22.5万
• 依托单位: THERANANO, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2019-09-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9466175
• 关键词: Adverse effects; Alternative Therapies; American; Animal Cancer Model; Animals; Brachytherapy; Cancer Etiology; Cessation of life; Clinic; Clinical; Clinical Trials; Collaborations; Combined Modality Therapy; Dana-Farber Cancer Institute; Data; Development; Disease; Disease-Free Survival; Dose; Drug Utilization; External Beam Radiation Therapy; Formulation; Foundations; Goals; Hospitals; Implant; International; Kinetics; Lead; Letters; Licensing; Local Therapy; Low Dose Radiation; Malignant Neoplasms; Malignant neoplasm of prostate; Modality; Mus; Operative Surgical Procedures; PC3 cell line; Patient risk; Patients; Pharmaceutical Preparations; Phase; Plants; Price; Process; Prostate; Prostate Cancer therapy; Quality Control; Radiation; Radiation Toxicity; Radiation therapy; Radiation-Sensitizing Agents; Radiosensitization; Recurrence; Reproducibility; Research Design; Site; Small Business Technology Transfer Research; Structure; Technology; Therapeutic; Therapeutic Effect; Toxic effect; Translating; Translations; Treatment Efficacy; Tumor Suppression; Universities; Visual; Weight; Woman; Work; cancer recurrence; cancer therapy; chemoradiation; chemotherapy; combinatorial; commercialization; curative treatments; docetaxel; image guided radiation therapy; immunotoxicity; improved; in vivo; innovation; manufacturing scale-up; men; phase 2 study; prostate cancer model; radiosensitizing; rectal; scale up; success; treatment choice; treatment strategy; tumor

Prostate cancer (PCa) is the second leading cause of cancer death in American men, with 26,130 deaths and 161,360 new cases estimated in the US in 2017. Radiation therapy is one of the standard therapies for high and intermediate risk patients, and is a non-surgical therapy option for low risk patients. A combined chemo-radiation therapy (CRT) approach has been shown in several trials to improve survival in multiple cancers, compared with monotherapies. However, systemic chemotherapy accompanying CRT typically come at the price of increased toxicity and thus require synchronization of the two modalities to achieve maximum benefit. Here, an immediate need exists to deliver the drug specifically at tumor site in locally recurrent patients while avoiding toxicities associated with systemic delivery and resulting in preferential radiosensitization of the prostate compared to the normal structures. Northeastern University and Theranano LLC in collaboration with clinicians at Brigham and Womens Hospital and Dana Farber Cancer Institute have developed an innovative combinatorial treatment strategy of Local Chemo-Radiation Therapy (LCRT) using a modified brachytherapy spacer platform in the form of a INCeRT (ImplaNts for ChemoRadiation Therapy) spacer loaded with Docetaxel (DTX) to locally radiosensitize the prostate, enabling a synergistic cure with the use of lower radiation doses, thereby leading to less rectal radiation toxicity and minimal chemotherapeutic systemic side effects. These new INCeRT spacers are physically similar to the inert spacers routinely used in prostate brachytherapy but now loaded with formulations of DTX which can be tuned to release the drug payload from a week to several months. The technology has been exclusively licensed to TheraNano LLC for commercialization and translation to the clinic. The phase 1 project goals will be achieved through the following specific aims: Specific Aim 1: Development, scale up and quality control of docetaxel loaded INCeRT brachytherapy spacers. Develop INCeRT brachytherapy spacers loaded with DTX with analysis of quality control, reproducibility, drug loading and drug release using optimized SOPs. Earlier work at Northeastern University has produced INCeRT spacers in batches of <20. Here, we plan to scale-up the process to routinely manufacture DTX INCeRT spacers in batches of several 100s in GLP conditions. The study design will include setting up a pilot plant for fabrication, characterization of INCeRT spacers loaded with docetaxel and quality control assessment in terms of reproducibility, size, drug loading and release kinetics under GLP conditions. Specific Aim 2: In vivo therapeutic efficacy of combined Chemo-Radiation treatment and toxicity assessment in Prostate cancer models. We will evaluate the therapeutic efficacy of INCeRT spacers combined with Brachytherapy/EBRT by locally implanting the spacers at the tumor site in PCa animal models. We will also assess gross immunotoxicity associated with the combined treatment.

前列腺癌（PCa）是美国男性癌症死亡的第二大原因，有26，130人死亡， 2017年美国估计有161，360例新病例。放射治疗是高、中、低放射性肿瘤的标准治疗方法之一， 中等风险患者，并且是低风险患者的非手术治疗选择。化疗和放疗的结合 在几项试验中，CRT治疗（CRT）方法已被证明可以提高多种癌症的生存率， 单一疗法然而，伴随CRT的全身化疗通常以增加的化疗剂量为代价。 毒性，因此需要两种模式的同步以实现最大益处。在这里，立即 需要在局部复发患者的肿瘤部位特异性地递送药物，同时避免毒性 与全身递送相关，并导致前列腺的优先放射增敏， 正常结构。东北大学和Theranano LLC与布里格姆的临床医生合作， 妇女医院和达纳法伯癌症研究所开发了一种创新的组合治疗方法 局部化学放射治疗（LCRT）策略，使用改良的近距离放射治疗间隔器平台， 一个装有多西他赛（DTX）的INCeRT（用于化学放射治疗的植入物）间隔器， 放射增敏前列腺，使得能够使用较低的放射剂量进行协同治疗，从而导致 直肠放射毒性小，化疗全身副作用小。这些新的INCeRT间隔物 在物理上类似于前列腺近距离放射治疗中常规使用的惰性间隔物， DTX的制剂，其可以被调整以从一周到几个月释放药物有效载荷。的 该技术已被独家授权给TheraNano LLC，用于商业化和转化为临床。 第一阶段的项目目标将通过以下具体目标实现：具体目标1：发展， 装载多西他赛的INCeRT近距离放射治疗间隔器的放大和质量控制。开发INCeRT 载有DTX的近距离放射治疗间隔器的质量控制、再现性、载药量和药物分析 使用优化的SOP放行。东北大学的早期工作已经批量生产了INCeRT间隔物 的<20。在这里，我们计划扩大工艺规模，以批量常规生产DTX INCeRT垫片， 在GLP条件下达到100 s。研究设计将包括建立一个用于制造的试验工厂， 载有多西他赛的INCeRT间隔物的表征和质量控制评估 在GLP条件下的重现性、大小、药物负载和释放动力学。具体目标2：体内 放化疗联合治疗前列腺癌的疗效及毒副反应评价 模型我们将通过以下方式评价INCeRT间隔器联合近距离放射治疗/EBRT的治疗效果： 在PCa动物模型的肿瘤部位局部植入间隔物。我们还将评估总体免疫毒性 与联合治疗有关。