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

加莱拉治疗公司正在开发选择性的小分子超氧化物歧化酶（SOD）模拟物， 预防癌症患者中辐射诱导的毒性和用于治疗癌症。体内研究 证明加莱拉模拟物不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， 肿瘤对放射线敏感。其中一种药物GC 4419最近完成了多中心1b/2a期研究， 与调强放射治疗（IMRT）和并行顺铂，以减少发病率， 局部晚期口腔鳞状细胞癌患者的口腔粘膜炎（OM）严重程度，或 oropharynx（clinicaltrials.gov标识符NCT 01921426），目前正在招募患者进行2期试验， 相似的患者人群（NCT 02508389）。在本FastTrack申请中，加莱拉建议评价GC 4419 作为接受立体定向体部放射治疗（SBRT）治疗肺部疾病的患者的放射防护剂 癌本研究的开展将取决于NCT 01921426/ NCT 02508389和本提案1期中描述的临床前研究结果。 第1阶段的具体目标是：1）量化GC 4419预防肺损伤的能力 通过在暴露于SBRT样方案的小鼠中的CT成像、免疫组织化学和组织学， 和2）评估GC 4419对一组49种循环细胞因子、生长因子和氧化还原因子的影响， 标记物来衡量后续临床研究的预测值。 对于该提案的2期，一项单组2期临床研究将评估GC 4419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。是 预测GC 4419将降低SBRT后DLCO损失的水平，因为其能够抑制纤维化， 炎症，并最终降低DLCO较基线显著变化的患者频率。 将根据正在进行的I期OM试验的结果选择本研究的GC 4419剂量 （NCT 01921426）和本申请1期的体内研究。 II期的具体目的是：1）评估GC 4419在限制患者肺毒性方面的疗效 接受SBRT（通过DLCO肺功能测量）改变了主要终点，2） 评估临床和影像学肺炎水平;肺纤维化的影像学证据;影响 GC 4419和SBRT对无进展生存期的影响;获得有关抗肿瘤作用的初步信息 GC 4419和SBRT的组合。如果成功，这项研究的结果将使进一步的第二阶段 旨在改善NSCLC患者治疗结局的研究。

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.