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.
Public Health Relevance Statement: Stereotactic Body Radiation Therapy (SBRT) is emerging as an important tool in the treatment of poorly controlled lung cancers. GC4419, a drug under development to reduce radiation side-effects in cancer patients, recently completed a clinical trial in head and neck cancer patients. Based on the results from this study, GC4419 has the potential to improve the treatment of lung cancer patients by reducing radiation side- effects and potentially increasing the effectiveness of radiation therapy.
Project Terms: Adverse effects; Aftercare; Animal Model; Animals; antitumor effect; arm; base; Biological; Cancer Patient; cancer therapy; chemokine; Chest wall structure; Chi-Square Tests; Cisplatin; Clinical; Clinical Research; Clinical Trials; cohort; cytokine; design; Development; Diagnostic radiologic examination; Diffusion; Disease; Dose; Early treatment; Effectiveness; Eligibility Determination; Enrollment; Epithelial Cells; Esophagitis; Fibrosis; follow-up; Frequencies; Growth Factor; head and neck cancer patient; Histology; Image; Immunohistochemistry; improved; in vivo; in vivo Model; Incidence; Inflammation; Infusion procedures; Intensity-Modulated Radiotherapy; intraperitoneal; Intravenous infusion procedures; Investigational Therapies; Lesion; Literature; Lung; Lung diseases; Malignant neoplasm of lung; Maximum Tolerated Dose; Measures; Medical center; mimetics; mouth squamous cell carcinoma; Mus; Non-Small-Cell Lung Carcinoma; oral mucositis; Oropharyngeal; Oxidation-Reduction; Pain; patient population; Patients; Peripheral; Pharmaceutical Preparations; Phase; phase 2 study; Phase II Clinical Trials; Pre-Clinical Model; preclinical study; Predictive Value; prevent; Prevention; Progression-Free Survivals; Pulmonary Diffusing Capacity; Pulmonary Fibrosis; pulmonary function; Pulmonary Inflammation; Radiation; Radiation Fibrosis; Radiation Oncology; Radiation therapy; randomized trial; Regimen; Research Personnel; research study; response; response biomarker; Sample Size; Schedule; Severities; Side; Signal Transduction; Site; Small Business Innovation Research Grant; small molecule; Structure of parenchyma of lung; success; Superoxide Dismutase; Therapeutic; Therapy Evaluation; Time; Tissues; tool; Toxic effect; Treatment outcome; tumor; X-Ray Computed Tomography
