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

Galera Treateutics正在开发选择性的小分子超氧化物歧化酶(SOD)模拟物 癌症患者辐射毒性的预防和癌症的治疗。体内研究 证明Galera模拟物不干扰标准化疗药物的抗肿瘤作用 或者放射治疗，事实上，基于对肺癌动物模型的临床前研究，这种模拟 可能对辐射敏感的肿瘤。其中一种名为GC4419的试剂最近完成了多中心1b/2a阶段 采用调强放射治疗(IMRT)联合顺铂治疗，以减少肺癌的发生率和 局部晚期口腔鳞癌患者口腔粘膜炎(OM)的严重程度 Ophphynx(Clinicaltrials.gov标识符NCT01921426)，目前正在招募患者参加一项 相似的患者群体(国家科学技术委员会02508389人)。在这个FastTrack应用程序中，Galera建议评估GC4419 立体定向全身放射治疗(SBRT)在肺部放射治疗中的应用 癌症。这项研究的进行将取决于NCT01921426/ NCT02508389和本提案第1阶段中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CT成像、免疫组织化学和组织学方法对暴露于类SBRT方案的小鼠进行检测， 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 用于评估后续临床研究的预测价值的标记物。 对于该提案的第二阶段，一项单一ARM第二阶段临床研究将评估GC4419对SBRT- 早期肺癌和局限性转移性肺病患者的相关肺毒性。它是 预测GC4419将减少SBRT后的DLCO损失水平，因为它能够抑制纤维化和 炎症并最终降低患者DLCO较基线有明显变化的频率。 本研究的GC4419剂量将根据正在进行的第一阶段OM试验的结果进行选择 (NCT01921426)和该应用程序第一阶段的体内研究。 第二阶段的具体目标是：1)评估GC4419在限制患者肺部毒性方面的疗效 接受由DLCO的肺功能测量的SBRT会改变主要终点，以及2) 评估临床和放射学肺炎的程度；肺纤维化的放射学证据；影响 GC4419和SBRT对无进展生存期的影响；获得关于GC4419和SBRT抗肿瘤作用的初步信息 GC4419和SBRT的结合。如果成功，这项研究的结果将使进一步的第二阶段 研究旨在改善非小细胞肺癌患者的治疗结果。

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.