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

• 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
• 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

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）Mimetics 预防辐射诱导的癌症患者和癌症治疗的毒性。体内研究 证明Galera Mimetics不会干扰标准化学治疗的抗肿瘤作用 或放射疗法，实际上，基于肺癌动物模型的临床前研究， 可能对辐射敏感的肿瘤。一个这样的代理GC4419最近完成了多中心1B/2A期 强度调制放射疗法（IMRT）和并发顺铂，以减少发生率和 口腔局部鳞状细胞癌的口腔粘膜炎的严重程度（OM）口腔癌或 口咽（ClinicalTrials.gov标识符NCT01921426），目前正在招募患者参加2期试验 相似的患者人群（NCT 02508389）。在此FastTrack应用程序中，Galera建议评估GC4419 作为接受立体定向身体放射疗法（SBRT）治疗肺部的辐射保护剂 癌症。这项研究的行为将取决于NCT01921426/的持续成功 NCT02508389和该提案第1阶段描述的临床前研究结果。 第1阶段的具体目的是：1）量化GC4419防止肺损伤的能力 通过CT成像，暴露于SBRT样方案的小鼠中的免疫组织化学和组织学， 2）评估GC4419对49个循环细胞因子，生长因子和氧化还原的影响 标记以评估随后的临床研究的预测价值。 对于该提案的2阶段，一项单臂2阶段临床研究将评估GC4419对SBRT-的影响 早期肺癌和有限转移性肺部疾病患者的肺毒性相关。这是 预测GC4419将由于抑制纤维化和 炎症并最终降低DLCO显着变化的患者的频率。 本研究的GC4419剂量将根据正在进行的I OM试验的结果选择 （NCT01921426）和本应用程序第1阶段的体内研究。 第2阶段的具体目的是：1）评估GC4419在限制肺毒性中的功效 通过DLCO通过肺功能测量的接收SBRT会改变主要终点，2） 评估临床和放射学肺炎的水平；肺纤维化的影像学证据；效果 GC4419和SBRT关于无进展生存的；获取有关抗肿瘤效应的初步信息 GC4419和SBRT的组合。如果成功，这项研究的结果将实现进一步的II期 研究旨在改善NSCLC患者的治疗结果。