Multi-center, randomized, double-blind, placebo-controlled, exploratory study to evaluate the efficacy and safety of HAD-B1 for dose-finding in EGFR positive and locally advanced or metastatic NSCLC subjects who need Afatinib therapy: Study protocol clinical trial (SPIRIT Compliant).
多中心，随机，双盲，安慰剂对照，在需要阿法替尼治疗的EGFR阳性和局部晚期或转移性NSCLC受试者中评估HAD-B1 剂量发现的有效性和安全性的探索性研究: 研究方案临床试验 (SPIRIT依从性)。
- 作者列表："Park SJ","Kang HJ","Jun HJ","Shin SH","Yoo HS
BACKGROUND:In recent studies, afatinib, a second-generation inhibitor, showed superior outcomes, when compared to the first-generation of EGFR-tyrosine kinase inhibitors (TKIs), such as erlotinib and gefitinib, in patients with advanced non-small cell lung cancer (NSCLC) harboring mutations of epidermal growth factor receptor (EGFR). Patients who receive TKIs with a significant initial efficacy, inevitably experience an acquired resistance (AR) within 9 to 13 months. Traditional Korean medicine may have synergistic effects when combined with chemotherapy or radiotherapy. The purpose of this trial is to assess whether afatinib plus HAD-B1 improves disease control rates (DCRs) compared with afatinib alone and to evaluate the efficacy and safety of HAD-B1 for finding the proper dose. METHODS:This is a randomized, double-blind, placebo-controlled, multi-center, therapeutic, exploratory clinical trial. This trial is designed to determine whether HAD-B1 combined with afatinib results in better DCRs with less toxicity than afatinib alone. A total of 66 NSCLC patients with EGFR mutations will be randomly assigned to treatment group 1 (afatinib 40 mg/day plus HAD-B1 972 mg), treatment group 2 (afatinib 40 mg/day plus HAD-B1 1944 mg) and a control group (afatinib 40 mg/day). Afatinib combined with HAD-B1 or with a placebo will be administered to the participants for 12 weeks. The primary endpoint is a comparison of the DCRs among groups. Secondary endpoints are comparisons of the complete response (CR) and the partial response (PR) to the treatment, the stability of the disease (SD), progression free survival (PFS), time to progression (TTP), and tumor marker (CEA, NSE) and WBC differential count (LMR, NLR) and natural killer cell activity and quality of life (QOL) among groups. DISCUSSION:The results from this clinical trial will provide evidence of efficacy and safety of HAD-B1 in EGFR positive and locally advanced or metastatic NSCLC patients who need afatinib therapy.
背景: 在最近的研究中，与第一代EGFR-酪氨酸激酶抑制剂 (TKIs) 相比，阿法替尼，第二代抑制剂，如厄洛替尼和吉非替尼，在具有表皮生长因子受体 (EGFR) 突变的晚期非小细胞肺癌 (NSCLC) 患者中。接受具有显著初始功效的tki的患者不可避免地在 9 至 13 个月内经历获得性抗性 (AR)。韩国传统医学在与化疗或放疗联合使用时可能具有协同作用。本试验的目的是评估与单用阿法替尼相比，阿法替尼加HAD-B1 是否能提高疾病控制率 (DCRs)，并评估HAD-B1 寻找合适剂量的有效性和安全性。 方法: 这是一项随机、双盲、安慰剂对照、多中心、治疗性、探索性临床试验。本试验旨在确定HAD-B1 与阿法替尼联合使用是否比单独使用阿法替尼产生更好的毒性更小的dcr。共有 66 名EGFR突变的NSCLC患者将被随机分配到治疗组 1 (阿法替尼 40 mg/天加HAD-B1 972 mg mg)，治疗组 2 (阿法替尼 40 mg/天加HAD-B1 1944 mg) 和对照组 (阿法替尼 40 mg/天)。阿法替尼联合HAD-B1 或安慰剂将给予参与者 12 周。主要终点是组间dcr的比较。次要终点是对治疗的完全反应 (CR) 和部分反应 (PR) 、疾病的稳定性 (SD) 、无进展生存期 (PFS) 、进展时间 (TTP) 、肿瘤标志物 (CEA、NSE) 和白细胞分类计数 (LMR、NLR)组间自然杀伤细胞活性和生活质量 (QOL)。 讨论: 该临床试验的结果将为需要阿法替尼治疗的EGFR阳性和局部晚期或转移性NSCLC患者提供HAD-B1 的疗效和安全性证据。
METHODS::Pulmonary artery sling is a rare congenital anomaly of the origin and course of the left pulmonary artery. Patients with this condition typically present with respiratory failure in young infancy, and asymptomatic cases are uncommon. We describe the case of an adult patient with a lung adenocarcinoma of the right upper lobe, extending into the hilum and superior mediastinum, and with a previously unknown pulmonary artery sling anomaly. The local invasiveness of the tumor and the peculiar vascular anatomy contributed to a unique surgical scenario, wherein multiple reconstructive procedures were required.
METHODS::Patients with idiopathic pulmonary fibrosis (IPF) have higher risk of developing lung cancer, for example, squamous cell carcinoma (SCC), and show poor prognosis, while the molecular basis has not been fully investigated. Here we conducted DNA methylome analysis of lung SCC using 20 SCC samples with/without IPF, and noncancerous lung tissue samples from smokers/nonsmokers, using Infinium HumanMethylation 450K array. SCC was clustered into low- and high-methylation epigenotypes by hierarchical clustering analysis. Genes hypermethylated in SCC significantly included genes targeted by polycomb repressive complex in embryonic stem cells, and genes associated with Gene Ontology terms, for example, "transcription" and "cell adhesion," while genes hypermethylated specifically in high-methylation subgroup significantly included genes associated with "negative regulation of growth." Low-methylation subgroup significantly correlated with IPF (78%, vs. 17% in high-methylation subgroup, p = 0.04), and the correlation was validated by additional Infinium analysis of SCC samples (n = 44 in total), and data from The Cancer Genome Atlas (n = 390). The correlation between low-methylation subgroup and IPF was further validated by quantitative methylation analysis of marker genes commonly hypermethylated in SCC (HOXA2, HOXA9 and PCDHGB6), and markers specifically hypermethylated in high-methylation subgroup (DLEC1, CFTR, MT1M, CRIP3 and ALDH7A1) in 77 SCC cases using pyrosequencing (p = 0.003). Furthermore, low-methylation epigenotype significantly correlated with poorer prognosis among all SCC patients, or among patients without IPF. Multivariate analysis showed that low-methylation epigenotype is an independent predictor of poor prognosis. These may suggest that lung SCC could be stratified into molecular subtypes with distinct prognosis, and low-methylation lung SCC that significantly correlates with IPF shows unfavorable outcome.
METHODS::The role of Fyn-related kinase (FRK) in malignant tumors remains controversial. Our study investigated the function of FRK in lung cancer. Immunohistochemistry staining and generating a knockout of FRK by CRISPR/Cas9 in H1299 (FRK-KO-H1299) cells were strategies used to explore the role of FRK. Immunohistochemistry staining indicated that FRK expression was elevated in 223 lung cancer tissues compared to 26 distant normal lung tissues. FRK contributed to poor survival status in lung cancer patients and acted as a predictor for poor prognosis of lung cancer. Knockout of FRK by CRISPR/Cas9 markedly inhibited proliferation, invasion, colony formation and epithelial-mesenchymal transition (EMT) process in the lung cancer cell line H1299. Further exploration indicated that FRK-KO damaged the stemness phenotype of H1299 by inhibiting CD44 and CD133 expression. Seahorse detection and a U-13 C flux assay revealed that FRK-KO induced metabolism reprogramming by inhibiting the Warburg effect and changing the energy type in H1299 cells. Epidermal growth factor stimulation recovered the expression of FRK and biological functions, metabolic reprogramming and stemness phenotype of H1299 cells. FRK plays an oncogenic role in lung cancer cells via a novel regulation mechanism of enhancing the stemness of H1299 cells by inducing metabolism reprogramming, which finally promotes EMT and metastasis. Our study also indicates that FRK could be used as a potential therapeutic target for drug development.