Pub Date : 2024-06-01DOI: 10.1007/s10637-024-01444-0
Andrew J Armstrong, Ravit Geva, Hyun Cheol Chung, Charlotte Lemech, Wilson H Miller, Aaron R Hansen, Jong-Seok Lee, Frank Tsai, Benjamin J Solomon, Tae Min Kim, Christian Rolfo, Vincent Giranda, Yixin Ren, Fang Liu, Bhargava Kandala, Tomoko Freshwater, Judy S Wang
{"title":"Correction to: CXCR2 antagonist navarixin in combination with pembrolizumab in select advanced solid tumors: a phase 2 randomized trial.","authors":"Andrew J Armstrong, Ravit Geva, Hyun Cheol Chung, Charlotte Lemech, Wilson H Miller, Aaron R Hansen, Jong-Seok Lee, Frank Tsai, Benjamin J Solomon, Tae Min Kim, Christian Rolfo, Vincent Giranda, Yixin Ren, Fang Liu, Bhargava Kandala, Tomoko Freshwater, Judy S Wang","doi":"10.1007/s10637-024-01444-0","DOIUrl":"10.1007/s10637-024-01444-0","url":null,"abstract":"","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11164789/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141065402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The aim of the present study was to determine whether the trough plasma concentrations (C0) of regorafenib and its metabolites, the N-oxide metabolite (M-2) and the desmethyl N-oxide metabolite (M-5), in 21 patients receiving regorafenib therapy were affected by albumin-bilirubin (ALBI) grade. Regorafenib was administered at dosages ranging from 40 to 160 mg once daily on a 3-week-on, 1-week-off cycle. C0 values of regorafenib and its major metabolites were measured by high-performance liquid chromatography on day 8 after treatment initiation. The C0 values of regorafenib and metabolites M-2 and M-5 were significantly lower in patients with ALBI grade 2 as compared with grade 1 (P = 0.023, 0.003 and 0.017, respectively). The total C0 of regorafenib and its metabolites was significantly higher in ALBI grade 1 patients relative to grade 2 (3.489 μg/mL vs. 1.48 μg/mL; P = 0.009). The median relative dose intensity (RDI) of patients categorized as ALBI grade 2 was significantly lower than that of grade 1 patients (21.9% vs. 62.9%; P = 0.006). In 15 colorectal cancer patients among the total 21 patients, patients with ALBI grade 2 (n = 9) had a significantly shorter median overall survival time than patients with grade 1 (n = 6; P = 0.013). Administering a low dose of regorafenib to patients with ALBI grade 2 reduces the RDI of regorafenib and lowers treatment efficacy, as an appropriate C0 of regorafenib is not maintained. Monitoring the C0 of regorafenib regularly is necessary to guide dose adjustment.
{"title":"Association between albumin-bilirubin grade and plasma trough concentrations of regorafenib and its metabolites M-2 and M-5 at steady-state in Japanese patients.","authors":"Kazuma Fujita, Daiki Taguchi, Koji Fukuda, Taichi Yoshida, Kazuhiro Shimazu, Hanae Shinozaki, Hiroyuki Shibata, Masatomo Miura","doi":"10.1007/s10637-024-01429-z","DOIUrl":"10.1007/s10637-024-01429-z","url":null,"abstract":"<p><p>The aim of the present study was to determine whether the trough plasma concentrations (C<sub>0</sub>) of regorafenib and its metabolites, the N-oxide metabolite (M-2) and the desmethyl N-oxide metabolite (M-5), in 21 patients receiving regorafenib therapy were affected by albumin-bilirubin (ALBI) grade. Regorafenib was administered at dosages ranging from 40 to 160 mg once daily on a 3-week-on, 1-week-off cycle. C<sub>0</sub> values of regorafenib and its major metabolites were measured by high-performance liquid chromatography on day 8 after treatment initiation. The C<sub>0</sub> values of regorafenib and metabolites M-2 and M-5 were significantly lower in patients with ALBI grade 2 as compared with grade 1 (P = 0.023, 0.003 and 0.017, respectively). The total C<sub>0</sub> of regorafenib and its metabolites was significantly higher in ALBI grade 1 patients relative to grade 2 (3.489 μg/mL vs. 1.48 μg/mL; P = 0.009). The median relative dose intensity (RDI) of patients categorized as ALBI grade 2 was significantly lower than that of grade 1 patients (21.9% vs. 62.9%; P = 0.006). In 15 colorectal cancer patients among the total 21 patients, patients with ALBI grade 2 (n = 9) had a significantly shorter median overall survival time than patients with grade 1 (n = 6; P = 0.013). Administering a low dose of regorafenib to patients with ALBI grade 2 reduces the RDI of regorafenib and lowers treatment efficacy, as an appropriate C<sub>0</sub> of regorafenib is not maintained. Monitoring the C<sub>0</sub> of regorafenib regularly is necessary to guide dose adjustment.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11164767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140189713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2024-05-03DOI: 10.1007/s10637-024-01437-z
Wenjie Li, Wei Wang
MET exon 14 skipping alterations and MET amplifications are recognized as oncogenic and targetable genetic changes in cancer patients. The treatment of MET-selective tyrosine kinase inhibitors (TKIs) in this specific population has shown encouraging therapeutic results. However, a comprehensive understanding of the potential toxicities linked to these agents is still lacking. The present pharmacovigilance analysis was carried out using the FDA Adverse Event Reporting System database to assess notable adverse events associated with MET-selective TKIs. Gastrointestinal disorders, respiratory toxicity, hepatotoxicity, and disturbances in metabolism and nutrition demonstrated a substantial prevalence and significance among the adverse event (AE) categories. Particularly notable were the occurrences of peripheral oedema, nausea, dysphagia, fatigue, and dyspnoea, which emerged as the foremost five reported AEs. The majority of these AEs were observed within the initial months of initiating treatment with MET-selective TKIs and persistently thereafter. Notably, our investigation unveiled a significant correlation between the usage of capmatinib and the incidence of hearing loss and difficulty in swallowing. Diligent monitoring and the implementation of supportive care strategies are essential in managing the toxicities associated with MET-selective TKIs, particularly those related to gastrointestinal disorders, respiratory toxicity, hepatotoxicity, and ototoxicity.
MET第14外显子跳变和MET扩增被认为是癌症患者的致癌和靶向基因变化。MET 选择性酪氨酸激酶抑制剂(TKIs)在这一特定人群中的治疗效果令人鼓舞。然而,目前仍缺乏对这些药物潜在毒性的全面了解。本药物警戒分析利用美国食品药物管理局不良事件报告系统数据库来评估与 MET 选择性 TKIs 相关的显著不良事件。在各类不良事件(AE)中,胃肠功能紊乱、呼吸系统毒性、肝毒性以及代谢和营养紊乱的发生率较高,且具有重要意义。尤其值得注意的是,外周水肿、恶心、吞咽困难、疲劳和呼吸困难成为报告的最主要的五种不良反应。这些不良反应大多出现在开始使用 MET 选择性 TKIs 治疗的最初几个月内,之后持续出现。值得注意的是,我们的调查揭示了使用卡马替尼与听力损失和吞咽困难发生率之间的显著相关性。在管理与MET选择性TKIs相关的毒性,尤其是与胃肠道功能紊乱、呼吸系统毒性、肝毒性和耳毒性相关的毒性时,必须进行严格监测并实施支持性护理策略。
{"title":"Toxicity burden patterns of MET-selective tyrosine kinase inhibitors: evidence from real-world pharmacovigilance.","authors":"Wenjie Li, Wei Wang","doi":"10.1007/s10637-024-01437-z","DOIUrl":"10.1007/s10637-024-01437-z","url":null,"abstract":"<p><p>MET exon 14 skipping alterations and MET amplifications are recognized as oncogenic and targetable genetic changes in cancer patients. The treatment of MET-selective tyrosine kinase inhibitors (TKIs) in this specific population has shown encouraging therapeutic results. However, a comprehensive understanding of the potential toxicities linked to these agents is still lacking. The present pharmacovigilance analysis was carried out using the FDA Adverse Event Reporting System database to assess notable adverse events associated with MET-selective TKIs. Gastrointestinal disorders, respiratory toxicity, hepatotoxicity, and disturbances in metabolism and nutrition demonstrated a substantial prevalence and significance among the adverse event (AE) categories. Particularly notable were the occurrences of peripheral oedema, nausea, dysphagia, fatigue, and dyspnoea, which emerged as the foremost five reported AEs. The majority of these AEs were observed within the initial months of initiating treatment with MET-selective TKIs and persistently thereafter. Notably, our investigation unveiled a significant correlation between the usage of capmatinib and the incidence of hearing loss and difficulty in swallowing. Diligent monitoring and the implementation of supportive care strategies are essential in managing the toxicities associated with MET-selective TKIs, particularly those related to gastrointestinal disorders, respiratory toxicity, hepatotoxicity, and ototoxicity.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140857372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Pembrolizumab plus epacadostat (indoleamine 2,3-dioxygenase-1 inhibitor) was well tolerated in Japanese patients with advanced solid tumors in part A of the nonrandomized, open-label, phase 1 KEYNOTE-434 study (NCT02862457). We report results from part B, which evaluated epacadostat plus pembrolizumab and chemotherapy in Japanese patients with advanced non-small-cell lung cancer (NSCLC).
Methods: Eligible patients aged ≥ 20 years had histologically or cytologically confirmed stage IIIB or IV NSCLC with no prior systemic therapy, and ECOG performance status of 0 or 1. Patients received epacadostat 100 mg orally twice-daily, pembrolizumab 200 mg intravenously every-3-weeks for ≤ 35 cycles, and 4 cycles of chemotherapy (cohort 1: cisplatin plus pemetrexed, non-squamous; cohort 2: carboplatin plus pemetrexed, non-squamous; cohort 3: carboplatin plus paclitaxel, squamous or non-squamous). Primary endpoint was incidence of dose-limiting toxicities (DLTs). Following unfavorable results from other studies, a protocol amendment removed epacadostat from the treatment combination.
Results: Of 19 patients, 7 were enrolled in cohort 1, and 6 each in cohorts 2 and 3. Median follow-up was 13.7 (range, 4.2-27.8) months. Five of 17 (29%) DLT-evaluable patients experienced ≥ 1 DLT (cohort 1, n = 1; cohorts 2 and 3, n = 2 each); most commonly maculopapular rash (grade 3, n = 3) and increased alanine aminotransferase (grade 2, n = 1; grade 3, n = 2). All patients experienced treatment-related adverse events (AEs); 58% experienced grade 3 or 4 treatment-related AEs. Objective response rate was 47%.
Conclusion: The combination of epacadostat plus pembrolizumab and chemotherapy was found to be tolerable in Japanese patients with advanced NSCLC.
{"title":"KEYNOTE-434 part B: A phase 1 study evaluating the combination of epacadostat, pembrolizumab, and chemotherapy in Japanese patients with previously untreated advanced non-small-cell lung cancer.","authors":"Noboru Yamamoto, Miyako Satouchi, Toshihiko Doi, Yutaka Fujiwara, Noriko Yanagitani, Yoshitaka Kawa, Kiyotaka Yoh, Lance Leopold, Mihaela Munteanu, Takashi Sawada, Shirong Han, Kazuo Noguchi, Makoto Nishio","doi":"10.1007/s10637-024-01422-6","DOIUrl":"10.1007/s10637-024-01422-6","url":null,"abstract":"<p><strong>Background: </strong>Pembrolizumab plus epacadostat (indoleamine 2,3-dioxygenase-1 inhibitor) was well tolerated in Japanese patients with advanced solid tumors in part A of the nonrandomized, open-label, phase 1 KEYNOTE-434 study (NCT02862457). We report results from part B, which evaluated epacadostat plus pembrolizumab and chemotherapy in Japanese patients with advanced non-small-cell lung cancer (NSCLC).</p><p><strong>Methods: </strong>Eligible patients aged ≥ 20 years had histologically or cytologically confirmed stage IIIB or IV NSCLC with no prior systemic therapy, and ECOG performance status of 0 or 1. Patients received epacadostat 100 mg orally twice-daily, pembrolizumab 200 mg intravenously every-3-weeks for ≤ 35 cycles, and 4 cycles of chemotherapy (cohort 1: cisplatin plus pemetrexed, non-squamous; cohort 2: carboplatin plus pemetrexed, non-squamous; cohort 3: carboplatin plus paclitaxel, squamous or non-squamous). Primary endpoint was incidence of dose-limiting toxicities (DLTs). Following unfavorable results from other studies, a protocol amendment removed epacadostat from the treatment combination.</p><p><strong>Results: </strong>Of 19 patients, 7 were enrolled in cohort 1, and 6 each in cohorts 2 and 3. Median follow-up was 13.7 (range, 4.2-27.8) months. Five of 17 (29%) DLT-evaluable patients experienced ≥ 1 DLT (cohort 1, n = 1; cohorts 2 and 3, n = 2 each); most commonly maculopapular rash (grade 3, n = 3) and increased alanine aminotransferase (grade 2, n = 1; grade 3, n = 2). All patients experienced treatment-related adverse events (AEs); 58% experienced grade 3 or 4 treatment-related AEs. Objective response rate was 47%.</p><p><strong>Conclusion: </strong>The combination of epacadostat plus pembrolizumab and chemotherapy was found to be tolerable in Japanese patients with advanced NSCLC.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov , NCT02862457.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11164788/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140293542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2024-05-22DOI: 10.1007/s10637-024-01445-z
Shannon S Stockton, G Dan Ayers, Cody Lee, Heather Laferriere, Satya Das, Jordan Berlin
In the era of precision oncology (PO), systemic therapies for patients (pts) with solid tumors have shifted from chemotherapy (CT) to targeted therapy (TT) and immunotherapy (IO). This systematic survey describes features of trials enrolling between 2010 and 2020, focusing on inclusion criteria, type of dose escalation scheme (DES) utilized, and use of expansion cohorts (ECs). A literature search identified phase I studies in adults with solid tumors published January 1, 2000- December 31, 2020 from 12 journals. We included only studies enrolling between 2010 and 2020 to better capture the PO era. Two reviewers abstracted data; a third established concordance. Of 10,744 studies, 10,195 were non-topical or enrolled prior to 2010; 437 studies were included. The most common drug classes were TT (47.6%), IO (22%), and CT (6.9%). In studies which reported race, patients were predominantly white (61.7%) or Asian (25.7%), followed by black (6.5%) or other (6.1%). Heterogeneity was observed in the reporting and specification of study inclusion criteria. Only 40.1% of studies utilized ECs, and among the studies which used ECS, 46.6% were defined by genomic selection. Rule-based DES were used in 89% of trials; a 3+3 design was used in 80.5%. Of all drugs tested, 37.5% advanced to phase II, while 10.3% garnered regulatory licensure (for an indication tested in phase I). In the era of PO, TT and IO have emerged as the most studied agents in phase I trials. Rule-based DES, which are more relevant for escalating CT, are still chiefly utilized.
在精准肿瘤学(PO)时代,实体瘤患者(pts)的全身疗法已从化疗(CT)转向靶向治疗(TT)和免疫疗法(IO)。本系统调查描述了2010年至2020年间入组试验的特点,重点关注纳入标准、采用的剂量递增方案(DES)类型以及扩增队列(EC)的使用。文献检索确定了12种期刊中2000年1月1日至2020年12月31日发表的针对成人实体瘤的I期研究。我们仅纳入了 2010 年至 2020 年间的研究,以更好地捕捉 PO 时代的研究。两名审稿人对数据进行了摘录;第三名审稿人确定了数据的一致性。在 10,744 项研究中,10,195 项为非局部用药或在 2010 年之前入选;437 项研究被纳入其中。最常见的药物类别是TT(47.6%)、IO(22%)和CT(6.9%)。在报告种族的研究中,患者主要是白人(61.7%)或亚裔(25.7%),其次是黑人(6.5%)或其他种族(6.1%)。在研究纳入标准的报告和说明方面存在异质性。只有40.1%的研究使用了EC,而在使用ECS的研究中,46.6%是通过基因组选择定义的。89%的试验采用了基于规则的DES;80.5%的试验采用了3+3设计。在所有试验药物中,37.5%的药物进入了II期,10.3%的药物获得了监管部门的许可(针对I期试验的适应症)。在 PO 时代,TT 和 IO 已成为 I 期试验中研究最多的药物。基于规则的 DES 更适用于 CT 的升级,但仍主要用于 CT 的升级。
{"title":"Evolving or immutable - phase I solid tumor trials in the era of precision oncology.","authors":"Shannon S Stockton, G Dan Ayers, Cody Lee, Heather Laferriere, Satya Das, Jordan Berlin","doi":"10.1007/s10637-024-01445-z","DOIUrl":"10.1007/s10637-024-01445-z","url":null,"abstract":"<p><p>In the era of precision oncology (PO), systemic therapies for patients (pts) with solid tumors have shifted from chemotherapy (CT) to targeted therapy (TT) and immunotherapy (IO). This systematic survey describes features of trials enrolling between 2010 and 2020, focusing on inclusion criteria, type of dose escalation scheme (DES) utilized, and use of expansion cohorts (ECs). A literature search identified phase I studies in adults with solid tumors published January 1, 2000- December 31, 2020 from 12 journals. We included only studies enrolling between 2010 and 2020 to better capture the PO era. Two reviewers abstracted data; a third established concordance. Of 10,744 studies, 10,195 were non-topical or enrolled prior to 2010; 437 studies were included. The most common drug classes were TT (47.6%), IO (22%), and CT (6.9%). In studies which reported race, patients were predominantly white (61.7%) or Asian (25.7%), followed by black (6.5%) or other (6.1%). Heterogeneity was observed in the reporting and specification of study inclusion criteria. Only 40.1% of studies utilized ECs, and among the studies which used ECS, 46.6% were defined by genomic selection. Rule-based DES were used in 89% of trials; a 3+3 design was used in 80.5%. Of all drugs tested, 37.5% advanced to phase II, while 10.3% garnered regulatory licensure (for an indication tested in phase I). In the era of PO, TT and IO have emerged as the most studied agents in phase I trials. Rule-based DES, which are more relevant for escalating CT, are still chiefly utilized.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11164775/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141075939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2024-05-03DOI: 10.1007/s10637-024-01439-x
Xinyi Liu, Zihan Guo, Lin Su, Anli Zuo, Min Gao, Xiang Ji, Jiameng Lu, Shuran Yang, Yunxiu Jiang, Degan Lu
Background: Platinum-based doublet chemotherapy is commonly used in the treatment of non-small cell lung cancer (NSCLC). A growing body of evidence indicates that incorporating antiangiogenic agents into platinum-based chemotherapy may enhance the survival outcomes for NSCLC patients. However, the optimal administration protocol for intravenous recombinant human endostatin (rh-endostatin), an antiangiogenic agent, remains uncertain at present.
Aim: This study aims to investigate the efficacy and safety of 5-d continuous intravenous infusion of rh-endostatin in combination with chemotherapy for patients with advanced NSCLC. The predictive biomarkers for this treatment regimen were further probed.
Methods: This prospective, single-arm multicenter study enrolled a total of 48 patients with advanced NSCLC who were histologically or cytologically confirmed but had not received any prior treatment from January 2021 to December 2022. Prior to the chemotherapy, these patients received a continuous intravenous infusion of rh-endostatin (210 mg) over a period of 120 h, using an infusion pump. The chemotherapy regimen included a combination of platinum with either pemetrexed or paclitaxel, given in 21-day cycles. The primary endpoint of the study was median progression-free survival (mPFS), and the secondary endpoints included median overall survival (mOS), objective response rate (ORR), disease control rate (DCR), and assessment of adverse events (AEs).
Results: The mPFS was 6.5 months (95% confidence interval (CI): 3.8-9.1 m) while the mOS was 12.3 months (95% CI: 7.6-18.5 m). The ORR and DCR was 52.1% and 75.0%, respectively. Leukopenia (52.1%), anemia (33.3%), and thrombocytopenia (20.8%) were the most common adverse effects and these toxicities were deemed acceptable and manageable. In addition, a correlation was noted between elevated serum carcinoembryonic antigen (CEA) levels and decreased PFS and OS.
Conclusions: The incorporation of a 5-day continuous intravenous infusion of rh-endostatin into platinum-based doublet chemotherapy has demonstrated both safety and efficacy in the treatment of advanced NSCLC. Furthermore, the baseline serum levels of CEA may potentially function as a predictor for the efficacy of rh-endostatin when combined with chemotherapy in NSCLC patients.
Clinicaltrials: GOV: NCT05574998.
背景:铂类双药化疗常用于治疗非小细胞肺癌(NSCLC)。越来越多的证据表明,在铂类化疗中加入抗血管生成药物可提高 NSCLC 患者的生存率。目的:本研究旨在探讨5天连续静脉输注rh-内司他丁联合化疗治疗晚期NSCLC患者的有效性和安全性。方法:这是一项前瞻性单臂多组研究:这项前瞻性、单臂多中心研究在2021年1月至2022年12月期间共招募了48名经组织学或细胞学确诊但之前未接受过任何治疗的晚期NSCLC患者。化疗前,这些患者使用输液泵在120小时内持续静脉输注rh-内司他汀(210毫克)。化疗方案包括铂与培美曲塞或紫杉醇的组合,以21天为一个周期。研究的主要终点是中位无进展生存期(mPFS),次要终点包括中位总生存期(mOS)、客观反应率(ORR)、疾病控制率(DCR)以及不良事件(AEs)评估:mPFS为6.5个月(95%置信区间(CI):3.8-9.1个月),mOS为12.3个月(95%置信区间(CI):7.6-18.5个月)。ORR和DCR分别为52.1%和75.0%。白细胞减少(52.1%)、贫血(33.3%)和血小板减少(20.8%)是最常见的不良反应,这些毒性被认为是可以接受和控制的。此外,血清癌胚抗原(CEA)水平升高与 PFS 和 OS 下降之间存在相关性:结论:在以铂类为基础的双联化疗中连续5天静脉输注rh-内托铂,在晚期NSCLC的治疗中表现出了安全性和有效性。此外,血清中CEA的基线水平有可能作为NSCLC患者联合化疗时rh-endostatin疗效的预测指标:GOV:NCT05574998。
{"title":"The efficacy and safety of continuous intravenous infusion of rh-endostatin combined with platinum-based doublet chemotherapy for advanced non-small-cell lung cancer.","authors":"Xinyi Liu, Zihan Guo, Lin Su, Anli Zuo, Min Gao, Xiang Ji, Jiameng Lu, Shuran Yang, Yunxiu Jiang, Degan Lu","doi":"10.1007/s10637-024-01439-x","DOIUrl":"10.1007/s10637-024-01439-x","url":null,"abstract":"<p><strong>Background: </strong>Platinum-based doublet chemotherapy is commonly used in the treatment of non-small cell lung cancer (NSCLC). A growing body of evidence indicates that incorporating antiangiogenic agents into platinum-based chemotherapy may enhance the survival outcomes for NSCLC patients. However, the optimal administration protocol for intravenous recombinant human endostatin (rh-endostatin), an antiangiogenic agent, remains uncertain at present.</p><p><strong>Aim: </strong>This study aims to investigate the efficacy and safety of 5-d continuous intravenous infusion of rh-endostatin in combination with chemotherapy for patients with advanced NSCLC. The predictive biomarkers for this treatment regimen were further probed.</p><p><strong>Methods: </strong>This prospective, single-arm multicenter study enrolled a total of 48 patients with advanced NSCLC who were histologically or cytologically confirmed but had not received any prior treatment from January 2021 to December 2022. Prior to the chemotherapy, these patients received a continuous intravenous infusion of rh-endostatin (210 mg) over a period of 120 h, using an infusion pump. The chemotherapy regimen included a combination of platinum with either pemetrexed or paclitaxel, given in 21-day cycles. The primary endpoint of the study was median progression-free survival (mPFS), and the secondary endpoints included median overall survival (mOS), objective response rate (ORR), disease control rate (DCR), and assessment of adverse events (AEs).</p><p><strong>Results: </strong>The mPFS was 6.5 months (95% confidence interval (CI): 3.8-9.1 m) while the mOS was 12.3 months (95% CI: 7.6-18.5 m). The ORR and DCR was 52.1% and 75.0%, respectively. Leukopenia (52.1%), anemia (33.3%), and thrombocytopenia (20.8%) were the most common adverse effects and these toxicities were deemed acceptable and manageable. In addition, a correlation was noted between elevated serum carcinoembryonic antigen (CEA) levels and decreased PFS and OS.</p><p><strong>Conclusions: </strong>The incorporation of a 5-day continuous intravenous infusion of rh-endostatin into platinum-based doublet chemotherapy has demonstrated both safety and efficacy in the treatment of advanced NSCLC. Furthermore, the baseline serum levels of CEA may potentially function as a predictor for the efficacy of rh-endostatin when combined with chemotherapy in NSCLC patients.</p><p><strong>Clinicaltrials: </strong>GOV: NCT05574998.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11164818/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140860986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Breast cancer is a leading cause of death in women worldwide. Cancer therapy based on stem cells is considered as a novel and promising platform. In the present study, we explore the therapeutic effects of human amniotic mesenchymal stromal cells (hAMSCs) through the reduction of focal adhesion kinase (FAK) activity, SHP-2, and cell adhesion proteins such as Paxillin, Vinculin, Fibronectin, Talin, and integrin αvβ3 expression in MDA-MB-231 breast cancer cells. For this purpose, we employed a co-culture system using 6-well plate transwell. After 72 h, hAMSCs-treated MDA-MB-231 breast cancer cells, the activity of focal adhesion kinase (FAK) and the expression of SHP-2 and cell adhesion proteins such as Paxillin, Vinculin, Fibronectin, Talin, and integrin αvβ3 expression were analyzed using western blot. The shape and migration of cells were also analyzed. Based on our results, a significant reduction in tumor cell motility through downregulation of the tyrosine phosphorylation level of FAK (at Y397 and Y576/577 sites) and cell adhesion expression in MDA-MB-231 breast cancer cells was demonstrated. Our findings indicate that hAMSCS secretome has therapeutic effects on cancer cell migration through downregulation of FAK activity and expression of cell adhesion proteins.
{"title":"The suppression of cell motility through the reduction of FAK activity and expression of cell adhesion proteins by hAMSCs secretome in MDA-MB-231 breast cancer cells.","authors":"Fatemeh Safari, Setareh Bararpour, Fatemeh Omidi Chomachaei","doi":"10.1007/s10637-024-01434-2","DOIUrl":"10.1007/s10637-024-01434-2","url":null,"abstract":"<p><p>Breast cancer is a leading cause of death in women worldwide. Cancer therapy based on stem cells is considered as a novel and promising platform. In the present study, we explore the therapeutic effects of human amniotic mesenchymal stromal cells (hAMSCs) through the reduction of focal adhesion kinase (FAK) activity, SHP-2, and cell adhesion proteins such as Paxillin, Vinculin, Fibronectin, Talin, and integrin αvβ3 expression in MDA-MB-231 breast cancer cells. For this purpose, we employed a co-culture system using 6-well plate transwell. After 72 h, hAMSCs-treated MDA-MB-231 breast cancer cells, the activity of focal adhesion kinase (FAK) and the expression of SHP-2 and cell adhesion proteins such as Paxillin, Vinculin, Fibronectin, Talin, and integrin αvβ3 expression were analyzed using western blot. The shape and migration of cells were also analyzed. Based on our results, a significant reduction in tumor cell motility through downregulation of the tyrosine phosphorylation level of FAK (at Y397 and Y576/577 sites) and cell adhesion expression in MDA-MB-231 breast cancer cells was demonstrated. Our findings indicate that hAMSCS secretome has therapeutic effects on cancer cell migration through downregulation of FAK activity and expression of cell adhesion proteins.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140305652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Osimertinib is used as the first-line therapy for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, early dose reduction is often required due to adverse events (AEs). This study aimed to evaluate the effect of early dose reduction of osimertinib on efficacy and safety. This was a retrospective study including patients with EGFR-mutated NSCLC who were started on osimertinib as the first-line therapy between August 2018 and December 2021. Patients whose doses were reduced to less than 80 mg/day within 6 months of osimertinib initiation or started at 40 mg/day were defined as the dose reduction group. The primary endpoint was progression-free survival (PFS). Factors affecting PFS were explored using the Cox proportional hazards model. A total of 85 patients were included in this study. No significant differences in patient characteristics were observed between the dose reduction (n = 25) and standard dose groups (n = 60). The median PFS in the dose reduction group was significantly prolonged compared with that in the standard dose group (26.0 months vs. 12.0 months, p = 0.03). Multivariable analysis of 84 patients, excluding a patient with unknown brain metastasis, revealed that EGFR exon 21 L858R mutation, malignant pleural effusion or pleural metastasis, liver metastasis, and dose reduction within 6 months were independent factors affecting PFS. Early dose reduction of osimertinib is an effective therapeutic strategy for prolonging PFS in patients with EGFR-mutated NSCLC.
{"title":"Effect of early dose reduction of osimertinib on efficacy in the first-line treatment for EGFR-mutated non-small cell lung cancer.","authors":"Tomoki Hori, Kazuhiro Yamamoto, Takefumi Ito, Shigeki Ikushima, Tomohiro Omura, Ikuko Yano","doi":"10.1007/s10637-024-01432-4","DOIUrl":"10.1007/s10637-024-01432-4","url":null,"abstract":"<p><p>Osimertinib is used as the first-line therapy for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, early dose reduction is often required due to adverse events (AEs). This study aimed to evaluate the effect of early dose reduction of osimertinib on efficacy and safety. This was a retrospective study including patients with EGFR-mutated NSCLC who were started on osimertinib as the first-line therapy between August 2018 and December 2021. Patients whose doses were reduced to less than 80 mg/day within 6 months of osimertinib initiation or started at 40 mg/day were defined as the dose reduction group. The primary endpoint was progression-free survival (PFS). Factors affecting PFS were explored using the Cox proportional hazards model. A total of 85 patients were included in this study. No significant differences in patient characteristics were observed between the dose reduction (n = 25) and standard dose groups (n = 60). The median PFS in the dose reduction group was significantly prolonged compared with that in the standard dose group (26.0 months vs. 12.0 months, p = 0.03). Multivariable analysis of 84 patients, excluding a patient with unknown brain metastasis, revealed that EGFR exon 21 L858R mutation, malignant pleural effusion or pleural metastasis, liver metastasis, and dose reduction within 6 months were independent factors affecting PFS. Early dose reduction of osimertinib is an effective therapeutic strategy for prolonging PFS in patients with EGFR-mutated NSCLC.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11164814/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140305651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-11DOI: 10.1007/s10637-024-01436-0
Bei Cao, Tingting Ma, Yuqiang Zhang, Lei Huang, Hui Lin, Huanhuan Jiang, Yu Zhao, Yan Geng, Yuanxun Yang, Sumin Cao, Juan Li
Sutetinib is an irreversible inhibitor of epidermal growth factor receptor (EGFR) and showed favorable efficacy and safety in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harbouring nondrug-resistant rare EGFR mutations. To evaluate the potential food effect, eighteen healthy Chinese subjects were enrolled in a single-centre, randomized, open-label, two-sequence, two-period crossover study. Sutetinib was administered as a single oral 100 mg under fasting or fed conditions, and pharmacokinetic sampling was performed following each dose and analysed by a validated liquid chromatography/mass spectrometry method. Safety and tolerability were also evaluated. Food intake slightly decreased maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time 0 to infinity (AUC0 − inf) of sutetinib (geometric least-squares mean [GLSM] ratio, 80.94% and 86.11%; 90% confidence interval [CI], 68.43–95.72 and 75.88–97.73) and its active metabolite sutetinib N-Oxide (GLSM ratio, 75.58% and 84.00%; 90% CI, 65.69–86.95 and 75.42–93.56), respectively. In addition, the time to maximum plasma concentration (Tmax) of both sutetinib and its metabolite has been prolonged by 2 h under fed conditions. A total of 31 adverse events (AEs) occurred during the study, with no serious adverse events (SAE) reported, and no obvious difference was observed between the fasting and fed groups. Our results demonstrated that a high-fat and high-calorie diet caused a significant delay in drug absorption and a marginal reduction in drug exposure. Sutetinib was generally well tolerated in healthy Chinese subjects. (This trial was registered at http://www.chinadrugtrials.org.cn. The registration No. is CTR20201933, and the date of registration is 2020-10-16).
{"title":"The effect of food on the pharmacokinetics of Sutetinib maleate capsule, an irreversible EGFR tyrosine kinase inhibitor, in healthy Chinese subjects","authors":"Bei Cao, Tingting Ma, Yuqiang Zhang, Lei Huang, Hui Lin, Huanhuan Jiang, Yu Zhao, Yan Geng, Yuanxun Yang, Sumin Cao, Juan Li","doi":"10.1007/s10637-024-01436-0","DOIUrl":"https://doi.org/10.1007/s10637-024-01436-0","url":null,"abstract":"<p>Sutetinib is an irreversible inhibitor of epidermal growth factor receptor (EGFR) and showed favorable efficacy and safety in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harbouring nondrug-resistant rare EGFR mutations. To evaluate the potential food effect, eighteen healthy Chinese subjects were enrolled in a single-centre, randomized, open-label, two-sequence, two-period crossover study. Sutetinib was administered as a single oral 100 mg under fasting or fed conditions, and pharmacokinetic sampling was performed following each dose and analysed by a validated liquid chromatography/mass spectrometry method. Safety and tolerability were also evaluated. Food intake slightly decreased maximum plasma concentration (C<sub>max</sub>) and area under the plasma concentration-time curve from time 0 to infinity (AUC<sub>0 − inf</sub>) of sutetinib (geometric least-squares mean [GLSM] ratio, 80.94% and 86.11%; 90% confidence interval [CI], 68.43–95.72 and 75.88–97.73) and its active metabolite sutetinib N-Oxide (GLSM ratio, 75.58% and 84.00%; 90% CI, 65.69–86.95 and 75.42–93.56), respectively. In addition, the time to maximum plasma concentration (T<sub>max</sub>) of both sutetinib and its metabolite has been prolonged by 2 h under fed conditions. A total of 31 adverse events (AEs) occurred during the study, with no serious adverse events (SAE) reported, and no obvious difference was observed between the fasting and fed groups. Our results demonstrated that a high-fat and high-calorie diet caused a significant delay in drug absorption and a marginal reduction in drug exposure. Sutetinib was generally well tolerated in healthy Chinese subjects. (This trial was registered at http://www.chinadrugtrials.org.cn. <i>The registration No. is CTR20201933, and the date of registration is 2020-10-16</i>).</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140602936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}