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 例新发病例。放射治疗是治疗高危和慢性癌症的标准疗法之一。 中危患者，是低危患者的非手术治疗选择。联合放化疗 多项试验表明，与其他癌症相比，CRT 疗法可以提高多种癌症的生存率 单一疗法。然而，伴随 CRT 的全身化疗通常会以增加 毒性，因此需要两种方式同步以实现最大效益。在这里，立即 需要将药物特异性输送到局部复发患者的肿瘤部位，同时避免毒性 与全身递送相关，并导致与前列腺相比优先放射增敏 正常结构。东北大学和 Theranano LLC 与布莱根和布莱根的临床医生合作 妇女医院和达纳法伯癌症研究所开发了一种创新的组合疗法 使用改进的近距离放射治疗垫片平台的局部放化疗 (LCRT) 策略，形式为 将装有多西紫杉醇 (DTX) 的 INCeRT（放化疗植入物）间隔器放置在局部 使前列腺放射敏感，能够与使用较低放射剂量的协同治疗，从而导致 直肠放射毒性较小，化疗全身副作用最小。这些新的 INCeRT 垫片 物理上类似于前列腺近距离放射治疗中常规使用的惰性垫片，但现在装载了 DTX 制剂可以调整以在一周到几个月内释放药物有效负载。这 该技术已独家授权给 TheraNano LLC 进行商业化和临床转化。 第一阶段项目目标将通过以下具体目标来实现： 具体目标 1：发展， 装载多西紫杉醇的 INCeRT 近距离放射治疗间隔器的放大和质量控制。开发 INCERT 装载有 DTX 的近距离放射治疗垫片，并进行质量控制、再现性、载药量和药物分析 使用优化的 SOP 进行发布。东北大学的早期工作已批量生产INCeRT垫片 <20。在这里，我们计划扩大流程，以批量生产 DTX INCeRT 垫片 在 GLP 条件下几百秒。研究设计将包括建立一个制造试验工厂， 装载多西紫杉醇的 INCeRT 间隔物的表征和质量控制评估 GLP 条件下的重现性、大小、载药量和释放动力学。具体目标 2：体内 前列腺癌放化疗联合治疗的疗效及毒性评估 模型。我们将通过以下方式评估 INCeRT 间隔器联合近距离放射治疗/EBRT 的治疗效果： 将间隔物局部植入 PCa 动物模型的肿瘤部位。我们还将评估总体免疫毒性 与联合治疗有关。