Dan Liu, Jifang Gong, Muling Liu, Huan Zhou, Shumei Wang, Jian Yang, Chenwei Shang, Xinlei Guo, Cha Wang, Yanqiao Zhang, Lin Shen
{"title":"针对血管内皮生长因子受体-2 的新型全人源免疫球蛋白 G1 单克隆抗体 BC001 在晚期实体瘤中的 I 期研究","authors":"Dan Liu, Jifang Gong, Muling Liu, Huan Zhou, Shumei Wang, Jian Yang, Chenwei Shang, Xinlei Guo, Cha Wang, Yanqiao Zhang, Lin Shen","doi":"10.1002/cam4.70208","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>BC001 is a novel fully human immunoglobulin G1 monoclonal antibody blocking VEGFR2. This phase I study aimed to assess BC001 alone and plus chemotherapy in solid tumors.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>In dose escalation part, BC001 was assessed at dose levels of 2, 4, 8, 12, 16 mg/kg on day 1,15, every 28 days, followed an accelerated titration and “3 + 3” design. BC001 plus paclitaxel was assessed at dose level of 8, 10 mg/kg. The primary endpoints included the DLT, MTD and RDE of BC001. In dose expansion part, it aimed to assess the anti-tumor activity of BC001 alone and plus chemotherapy in gastric cancer as 2nd line treatment.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>Overall, 53 patients were finally enrolled in this study (phase Ia, <i>n</i> = 28; phase Ib, <i>n</i> = 25). In phase Ia part, 1 DLT (grade 4 neutropenia lasting 4 days) was observed in BC001(8 mg/kg) plus paclitaxel cohort. MTD was not reached. All patients experienced TEAEs of any grade. Twenty-four of them suffered ≥ grade 3 TEAEs. leukopenia (<i>n</i> = 33, 62.3%), hemoglobin decreased (<i>n</i> = 32, 60.4%), neutropenia (<i>n</i> = 29, 54.7%) were commonly observed hematological toxicities. The half-life of 140-240 h. And the PK parameters were not largely influenced by combination with paclitaxel. The serum sVEGFR-1, VEGF-A, sVEGFR-2 could not predict the efficacy. Based on the safety, PK and efficacy data, BC001 of 8 mg/kg was determined as RED. Among the GC patients(<i>n</i> = 21) who receiving BC001 plus paclitaxel as 2nd-line treatment in phase 1b part, 6 patients achieved PR and 10 patients experienced SD. The ORR was 28.6% (95% CI 11.3%, 52.2%) and the DCR was 76.2% (95% CI 52.8%, 91.8%), with the median PFS of 5.4 months (95% CI 1.9, 7.0) and OS of 9.4 months (95% CI 5.4, NA). The median DoR was 5.1 months (95% CI 2.6, NA).</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>BC001 showed acceptable safety profile and preliminary response in both single-agent and combination with chemotherapy cohorts, especially in GC.</p>\n </section>\n </div>","PeriodicalId":139,"journal":{"name":"Cancer Medicine","volume":"13 22","pages":""},"PeriodicalIF":2.9000,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cam4.70208","citationCount":"0","resultStr":"{\"title\":\"Phase I study of BC001, a novel fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2, in advanced solid tumors\",\"authors\":\"Dan Liu, Jifang Gong, Muling Liu, Huan Zhou, Shumei Wang, Jian Yang, Chenwei Shang, Xinlei Guo, Cha Wang, Yanqiao Zhang, Lin Shen\",\"doi\":\"10.1002/cam4.70208\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Background</h3>\\n \\n <p>BC001 is a novel fully human immunoglobulin G1 monoclonal antibody blocking VEGFR2. This phase I study aimed to assess BC001 alone and plus chemotherapy in solid tumors.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>In dose escalation part, BC001 was assessed at dose levels of 2, 4, 8, 12, 16 mg/kg on day 1,15, every 28 days, followed an accelerated titration and “3 + 3” design. BC001 plus paclitaxel was assessed at dose level of 8, 10 mg/kg. The primary endpoints included the DLT, MTD and RDE of BC001. In dose expansion part, it aimed to assess the anti-tumor activity of BC001 alone and plus chemotherapy in gastric cancer as 2nd line treatment.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>Overall, 53 patients were finally enrolled in this study (phase Ia, <i>n</i> = 28; phase Ib, <i>n</i> = 25). In phase Ia part, 1 DLT (grade 4 neutropenia lasting 4 days) was observed in BC001(8 mg/kg) plus paclitaxel cohort. MTD was not reached. All patients experienced TEAEs of any grade. Twenty-four of them suffered ≥ grade 3 TEAEs. leukopenia (<i>n</i> = 33, 62.3%), hemoglobin decreased (<i>n</i> = 32, 60.4%), neutropenia (<i>n</i> = 29, 54.7%) were commonly observed hematological toxicities. The half-life of 140-240 h. And the PK parameters were not largely influenced by combination with paclitaxel. The serum sVEGFR-1, VEGF-A, sVEGFR-2 could not predict the efficacy. Based on the safety, PK and efficacy data, BC001 of 8 mg/kg was determined as RED. Among the GC patients(<i>n</i> = 21) who receiving BC001 plus paclitaxel as 2nd-line treatment in phase 1b part, 6 patients achieved PR and 10 patients experienced SD. The ORR was 28.6% (95% CI 11.3%, 52.2%) and the DCR was 76.2% (95% CI 52.8%, 91.8%), with the median PFS of 5.4 months (95% CI 1.9, 7.0) and OS of 9.4 months (95% CI 5.4, NA). The median DoR was 5.1 months (95% CI 2.6, NA).</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusions</h3>\\n \\n <p>BC001 showed acceptable safety profile and preliminary response in both single-agent and combination with chemotherapy cohorts, especially in GC.</p>\\n </section>\\n </div>\",\"PeriodicalId\":139,\"journal\":{\"name\":\"Cancer Medicine\",\"volume\":\"13 22\",\"pages\":\"\"},\"PeriodicalIF\":2.9000,\"publicationDate\":\"2024-11-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cam4.70208\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cancer Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/cam4.70208\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Medicine","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/cam4.70208","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
背景 BC001 是一种新型全人源免疫球蛋白 G1 单克隆抗体，可阻断血管内皮生长因子受体 2。这项I期研究旨在评估BC001单独或联合化疗治疗实体瘤的效果。 方法 在剂量递增部分，BC001的剂量水平为2、4、8、12、16 mg/kg，第1天和第15天各一次，每28天一次，采用加速滴定和 "3 + 3 "设计。BC001 加紫杉醇的剂量为 8、10 毫克/千克。主要终点包括BC001的DLT、MTD和RDE。在剂量扩增部分，旨在评估BC001单药和联合化疗作为胃癌二线治疗的抗肿瘤活性。 结果 最终有53名患者参与了这项研究（Ia期，28人；Ib期，25人）。在Ia期，BC001（8毫克/千克）加紫杉醇组出现了1例DLT（持续4天的4级中性粒细胞减少症）。未达到MTD。所有患者都出现了任何程度的 TEAEs。白细胞减少（33例，62.3%）、血红蛋白下降（32例，60.4%）、中性粒细胞减少（29例，54.7%）是常见的血液学毒性反应。半衰期为140-240 h，与紫杉醇联用对PK参数影响不大。血清sVEGFR-1、VEGF-A、sVEGFR-2不能预测疗效。根据安全性、PK和疗效数据，确定8 mg/kg的BC001为RED。在1b期接受BC001联合紫杉醇二线治疗的GC患者（21人）中，6人获得PR，10人获得SD。ORR为28.6% (95% CI 11.3%, 52.2%)，DCR为76.2% (95% CI 52.8%, 91.8%)，中位PFS为5.4个月 (95% CI 1.9, 7.0)，OS为9.4个月 (95% CI 5.4, NA)。中位DoR为5.1个月（95% CI为2.6，不确定）。 结论 BC001在单药和联合化疗组别中均显示出可接受的安全性和初步反应，尤其是在GC中。
Phase I study of BC001, a novel fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2, in advanced solid tumors
Background
BC001 is a novel fully human immunoglobulin G1 monoclonal antibody blocking VEGFR2. This phase I study aimed to assess BC001 alone and plus chemotherapy in solid tumors.
Methods
In dose escalation part, BC001 was assessed at dose levels of 2, 4, 8, 12, 16 mg/kg on day 1,15, every 28 days, followed an accelerated titration and “3 + 3” design. BC001 plus paclitaxel was assessed at dose level of 8, 10 mg/kg. The primary endpoints included the DLT, MTD and RDE of BC001. In dose expansion part, it aimed to assess the anti-tumor activity of BC001 alone and plus chemotherapy in gastric cancer as 2nd line treatment.
Results
Overall, 53 patients were finally enrolled in this study (phase Ia, n = 28; phase Ib, n = 25). In phase Ia part, 1 DLT (grade 4 neutropenia lasting 4 days) was observed in BC001(8 mg/kg) plus paclitaxel cohort. MTD was not reached. All patients experienced TEAEs of any grade. Twenty-four of them suffered ≥ grade 3 TEAEs. leukopenia (n = 33, 62.3%), hemoglobin decreased (n = 32, 60.4%), neutropenia (n = 29, 54.7%) were commonly observed hematological toxicities. The half-life of 140-240 h. And the PK parameters were not largely influenced by combination with paclitaxel. The serum sVEGFR-1, VEGF-A, sVEGFR-2 could not predict the efficacy. Based on the safety, PK and efficacy data, BC001 of 8 mg/kg was determined as RED. Among the GC patients(n = 21) who receiving BC001 plus paclitaxel as 2nd-line treatment in phase 1b part, 6 patients achieved PR and 10 patients experienced SD. The ORR was 28.6% (95% CI 11.3%, 52.2%) and the DCR was 76.2% (95% CI 52.8%, 91.8%), with the median PFS of 5.4 months (95% CI 1.9, 7.0) and OS of 9.4 months (95% CI 5.4, NA). The median DoR was 5.1 months (95% CI 2.6, NA).
Conclusions
BC001 showed acceptable safety profile and preliminary response in both single-agent and combination with chemotherapy cohorts, especially in GC.
期刊介绍：
Cancer Medicine is a peer-reviewed, open access, interdisciplinary journal providing rapid publication of research from global biomedical researchers across the cancer sciences. The journal will consider submissions from all oncologic specialties, including, but not limited to, the following areas:
Clinical Cancer Research
Translational research ∙ clinical trials ∙ chemotherapy ∙ radiation therapy ∙ surgical therapy ∙ clinical observations ∙ clinical guidelines ∙ genetic consultation ∙ ethical considerations
Cancer Biology:
Molecular biology ∙ cellular biology ∙ molecular genetics ∙ genomics ∙ immunology ∙ epigenetics ∙ metabolic studies ∙ proteomics ∙ cytopathology ∙ carcinogenesis ∙ drug discovery and delivery.
Cancer Prevention:
Behavioral science ∙ psychosocial studies ∙ screening ∙ nutrition ∙ epidemiology and prevention ∙ community outreach.
Bioinformatics:
Gene expressions profiles ∙ gene regulation networks ∙ genome bioinformatics ∙ pathwayanalysis ∙ prognostic biomarkers.
Cancer Medicine publishes original research articles, systematic reviews, meta-analyses, and research methods papers, along with invited editorials and commentaries. Original research papers must report well-conducted research with conclusions supported by the data presented in the paper.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
