GC4419, an SOD Mimetic, as a Radiomodulator in Lung Cancer Patients Treated with SBRT

GC4419（一种 SOD 模拟物）作为接受 SBRT 治疗的肺癌患者的放射调节剂

基本信息

批准号：
10243628
负责人：
Jeffery Lynn Keene
金额：
$ 86.87万
依托单位：
GALERA THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-05 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10243628
关键词：
Aftercare Animal Model Animals Biological Cancer Patient Chest wall structure Chi-Square Tests Cisplatin Clinical Clinical Research Clinical Trials Development Diagnostic radiologic examination Diffusion Disease Dose Early treatment Effectiveness Enrollment Epithelial Cells Esophagitis Exposure to Fibrosis Frequencies Growth Factor Histology Image Immunohistochemistry Incidence Inflammation Infusion procedures Intensity-Modulated Radiotherapy Intravenous infusion procedures Investigational Therapies Lesion Literature Lung Lung diseases Malignant neoplasm of lung Maximum Tolerated Dose Measures Medical center Mus Non-Small-Cell Lung Carcinoma Oropharyngeal Oxidation-Reduction Pain Patients Peripheral Pharmaceutical Preparations Phase Pre-Clinical Model Predictive Value Prevention Progression-Free Survivals Pulmonary Diffusing Capacity Pulmonary Fibrosis Pulmonary Inflammation Radiation Radiation Fibrosis Radiation Oncology Radiation therapy Regimen Research Personnel Sample Size Schedule Severities Side Signal Transduction Site Small Business Innovation Research Grant Structure of parenchyma of lung Superoxide Dismutase Therapeutic Therapy Evaluation Time Tissues Toxic effect Treatment outcome X-Ray Computed Tomography antitumor effect arm base cancer therapy chemokine cohort cytokine design follow-up head and neck cancer patient improved in vivo in vivo Model intraperitoneal investigator-initiated trial mimetics mouth squamous cell carcinoma oral mucositis patient population phase 2 study phase II trial preclinical study prevent primary endpoint pulmonary function randomized trial research study response response biomarker side effect small molecule success tool tumor

项目摘要

Galera Therapeutics is developing selective, small molecule, superoxide dismutase (SOD) mimetics for the prevention of radiation-induced toxicities in cancer patients and for the treatment of cancer. In vivo studies demonstrated that Galera mimetics did not interfere with the anti-tumor actions of standard chemotherapeutic or radiation therapy, and in fact, based on preclinical studies in an animal model of lung cancer, the mimetics may sensitive tumors to radiation. One such agent, GC4419, recently completed a multicenter Phase 1b/2a with Intensity Modulated Radiation Therapy (IMRT) and concurrent cisplatin, to reduce the incidence and severity of oral mucositis (OM) in patients with locally advanced squamous cell carcinoma of the oral cavity or oropharynx (clinicaltrials.gov identifier NCT01921426) and is currently enrolling patients for a Phase 2 trial in a similar patient population (NCT 02508389). In this FastTrack application, Galera proposes to evaluate GC4419 as a radioprotectant in patients receiving Stereotactic Body Radiation Therapy (SBRT) for the treatment of lung cancer. The conduct of this research study will be contingent on the continued success in NCT01921426/ NCT02508389 and the results of the preclinical studies described in Phase 1 of this proposal. The specific aims for Phase 1 are: 1) to quantify the ability of GC4419 to prevent pulmonary damage measured via CT imaging, immunohistochemistry and histology in mice exposed to SBRT-like regimens, and 2) to evaluate the effect of GC4419 on a panel of 49 circulating cytokines, growth factors and redox markers to gauge the predictive value for subsequent clinical studies. For Phase 2 of the proposal, a single arm Phase 2 clinical study will assess the effects of GC4419 on SBRT- related pulmonary toxicity in patients with early stage lung cancer and limited metastatic lung disease. It is predicted that GC4419 will reduce the levels of DLCO loss post-SBRT due to its ability to suppress fibrosis and inflammation and ultimately reduce the frequency of patients with significant DLCO changes from baseline. The dose of GC4419 for the present study will be selected based on results from the ongoing Phase I OM trial (NCT01921426) and from the in vivo studies in Phase 1 of this application. The specific aims for Phase 2 are: 1) to assess the efficacy of GC4419 in limiting pulmonary toxicity in patients receiving SBRT as measured by pulmonary function with DLCO changes the primary endpoint, and 2) to evaluate levels of clinical and radiographic pneumonitis; radiographic evidence of pulmonary fibrosis; the effect of GC4419 and SBRT on progression free survival; obtain preliminary information about the anti-tumor effect of the combination of GC4419 and SBRT. If successful, the results of this study will enable further Phase II studies intended to improve the treatment outcomes for NSCLC patients.

Galera Therapeutics 正在开发选择性小分子超氧化物歧化酶 (SOD) 模拟物预防癌症患者的辐射引起的毒性和治疗癌症。体内研究证明 Galera 模拟物不会干扰标准化疗药物的抗肿瘤作用或放射治疗，事实上，基于肺癌动物模型的临床前研究，模拟物可能肿瘤对辐射敏感。其中一种药物 GC4419 最近完成了多中心 1b/2a 期调强放射治疗 (IMRT) 和同步顺铂，以减少发生率局部晚期口腔鳞状细胞癌患者口腔粘膜炎 (OM) 的严重程度或 oropharynx（clinicaltrials.gov 标识符 NCT01921426）目前正在招募患者参加一项 2 期试验类似的患者群体 (NCT 02508389)。在此 FastTrack 应用中，Galera 建议评估 GC4419 作为接受立体定向放射治疗 (SBRT) 治疗肺部疾病的患者的放射防护剂癌症。这项研究的进行将取决于 NCT01921426/ 的持续成功 NCT02508389 以及本提案第一阶段描述的临床前研究结果。第一阶段的具体目标是：1）量化 GC4419 预防肺损伤的能力通过对接受 SBRT 类疗法的小鼠进行 CT 成像、免疫组织化学和组织学检查， 2) 评估 GC4419 对 49 种循环细胞因子、生长因子和氧化还原的影响标记物来衡量后续临床研究的预测价值。对于该提案的第 2 期，一项单臂第 2 期临床研究将评估 GC4419 对 SBRT 的影响早期肺癌和局限性转移性肺病患者的相关肺毒性。这是预测 GC4419 由于其抑制纤维化的能力，将降低 SBRT 后 DLCO 损失的水平炎症并最终减少 DLCO 较基线发生显着变化的患者频率。本研究的 GC4419 剂量将根据正在进行的 I 期 OM 试验的结果选择 (NCT01921426) 以及本申请第一阶段的体内研究。第 2 阶段的具体目标是：1）评估 GC4419 在限制患者肺部毒性方面的功效接受 DLCO 通过肺功能测量的 SBRT 改变了主要终点，并且 2) 评估临床和放射学肺炎的水平；肺纤维化的放射学证据；效果 GC4419 和 SBRT 对无进展生存期的影响；获得抗肿瘤作用的初步信息 GC4419 和 SBRT 的组合。如果成功，这项研究的结果将有助于进一步开展第二阶段研究研究旨在改善非小细胞肺癌患者的治疗结果。