Investigational New Drugs最新文献_第2页

Clinical research progress of fruquintinib in the treatment of malignant tumors. 夫鲁喹替尼治疗恶性肿瘤的临床研究进展。

IF 3 3区医学

Investigational New Drugs Pub Date : 2024-12-01 Epub Date: 2024-10-01 DOI: 10.1007/s10637-024-01476-6

Shihao Zhao, Wenhui Wang, Jingyi Li, Zhigang Li, Zhanbo Liu, Shunchao Zhang, Zhaoqi Chen, Hongling Wang, Xiangqi Wang, Juntao Wang

{"title":"Clinical research progress of fruquintinib in the treatment of malignant tumors.","authors":"Shihao Zhao, Wenhui Wang, Jingyi Li, Zhigang Li, Zhanbo Liu, Shunchao Zhang, Zhaoqi Chen, Hongling Wang, Xiangqi Wang, Juntao Wang","doi":"10.1007/s10637-024-01476-6","DOIUrl":"10.1007/s10637-024-01476-6","url":null,"abstract":"Malignant tumors represent an important cause of mortality within the global population. Tumor angiogenesis, recognized as one of the key hallmarks of malignant tumors, is crucial for supplying essential nutrients and oxygen for tumor growth. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are key drivers of tumor angiogenesis. Targeted therapeutic interventions not only effectively inhibit tumor growth by specifically blocking tumor angiogenesis but have also made breakthroughs in the treatment of malignant tumors. Fruquintinib, an anti-angiogenic small molecule drug developed independently in China, functions as a potent tyrosine kinase inhibitor with high selectivity. It effectively curtails tumor growth by binding to and inhibiting VEGFR-1, VEGFR-2, and VEGFR-3. Additionally, fruquintinib offers several advantages including minimal off-target toxicity, robust resistance profiles, and commendable efficacy. This agent can be used alone or in combination with other treatments. It has shown high effectiveness and survival benefits across various malignant tumors such as colorectal cancer, gastric cancer, non-small cell lung cancer, breast cancer, and other malignant tumors. Therefore, this article conducts a systematic review encompassing the mechanism of action, pharmacokinetics, clinical efficacy, and safety profile of fruquintinib. Through this review, we aimed to offer a reference for the clinical application and subsequent development of fruquintinib.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"612-622"},"PeriodicalIF":3.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11625063/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142346819","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}

引用次数: 0

Modernizing the assessment and reporting of adverse events in oncology clinical trials using complementary statistical approaches: a case study of the MOTIVATE trial. 利用互补统计方法实现肿瘤临床试验中不良事件评估和报告的现代化：MOTIVATE 试验案例研究。

IF 3 3区医学

Investigational New Drugs Pub Date : 2024-12-01 Epub Date: 2024-11-04 DOI: 10.1007/s10637-024-01481-9

Mathilde Morisseau, Carlos Gomez-Roca, Marie Viala, Audrey Rabeau, Delphine Loirat, Nadia Munsch, Kristell Thomas, Cécile Pages, Iphigenie Korakis, Vincent Sibaud, Jean-Pierre Delord, Thomas Filleron, Bastien Cabarrou

{"title":"Modernizing the assessment and reporting of adverse events in oncology clinical trials using complementary statistical approaches: a case study of the MOTIVATE trial.","authors":"Mathilde Morisseau, Carlos Gomez-Roca, Marie Viala, Audrey Rabeau, Delphine Loirat, Nadia Munsch, Kristell Thomas, Cécile Pages, Iphigenie Korakis, Vincent Sibaud, Jean-Pierre Delord, Thomas Filleron, Bastien Cabarrou","doi":"10.1007/s10637-024-01481-9","DOIUrl":"10.1007/s10637-024-01481-9","url":null,"abstract":"The reporting of adverse events (AEs) is fundamental to characterize safety profiles of novel therapeutic drug classes, however, conventional analysis strategies are suboptimal tools for this task. We therefore attempted to contribute to the modernization of AE analysis by encompassing the dimension of time, the duration and the recurrent nature of AEs induced by these extended treatment durations. This paper presents and highlights the benefits of alternative approaches to modernize AE analysis based on the MOTIVATE prospective study modeling immune-related AEs (irAEs) in patients with solid tumors (regardless of the primary site) treated with immune checkpoint inhibitor irrespective of disease stage. The probability of presenting an irAE over time was estimated using the prevalence function. The time-to-onset (TTO) and the mean number of recurrent irAEs were also assessed. Among the 147 patients analyzed, 39.7% had a melanoma, 37.7% a non-small cell lung cancer (NSCLC) and 74.8% were treated for metastatic disease. Despite a higher proportion of melanoma patients presenting at least one irAE, the prevalence of irAEs was lower in melanoma than in NSCLC patients over time. TTO analysis showed that irAEs occurred earlier in NSCLC patients whereas melanoma patients experienced more recurrent irAEs over the long-term. The prevalence function of non-metastatic and metastatic patients revealed different long-term toxicity profiles. These alternative methodologies capture different toxicity patterns (time-to-onset, recurrent, acute episodic or long-term moderate AEs) and provide a more consistent safety assessment for new therapeutics, thereby assisting clinicians and health authorities in their therapeutic decision-making processes.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"664-674"},"PeriodicalIF":3.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568519","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}

引用次数: 0

Phase II trial of multi-tyrosine kinase inhibitor ESK981 in combination with PD-1 inhibitor nivolumab in patients with metastatic castration-resistant prostate cancer. 多酪氨酸激酶抑制剂 ESK981 联合 PD-1 抑制剂 nivolumab 治疗转移性耐阉割前列腺癌患者的 II 期试验。

IF 3 3区医学

Investigational New Drugs Pub Date : 2024-12-01 Epub Date: 2024-11-06 DOI: 10.1007/s10637-024-01482-8

Elisabeth I Heath, Wei Chen, Jae E Choi, Kimberlee Dobson, Melanie Smith, Tomasz Maj, Ilona Kryczek, Weiping Zou, Arul M Chinnaiyan, Yuanyuan Qiao

{"title":"Phase II trial of multi-tyrosine kinase inhibitor ESK981 in combination with PD-1 inhibitor nivolumab in patients with metastatic castration-resistant prostate cancer.","authors":"Elisabeth I Heath, Wei Chen, Jae E Choi, Kimberlee Dobson, Melanie Smith, Tomasz Maj, Ilona Kryczek, Weiping Zou, Arul M Chinnaiyan, Yuanyuan Qiao","doi":"10.1007/s10637-024-01482-8","DOIUrl":"10.1007/s10637-024-01482-8","url":null,"abstract":"Increasing the response rates of immune checkpoint inhibitors in patients with metastatic castration-resistant prostate cancer (mCRPC) presents a significant challenge. ESK981 is a multi-tyrosine kinase and PIKfyve lipid kinase inhibitor that augments immunotherapeutic responses. In this phase II study, ESK981 was combined with the PD-1 blocking monoclonal antibody nivolumab to test for potentially improved response rates in patients with mCRPC who have progressed on androgen receptor (AR)-targeted agents and chemotherapy. Eligible patients received ESK981 orally once daily for five consecutive days, followed by a two-day break. Patients were also treated with nivolumab intravenously on Day 1 of each 28-day cycle. The primary endpoints were a 50% reduction in prostate-specific antigen (PSA50), and safety. Secondary endpoints included radiographic progression free survival (rPFS) and overall survival (OS). Additional investigations included whole exome sequencing in patients. Ten patients were enrolled. The maximum PSA decline from baseline of 14% was achieved in only one patient. Grade 3 treatment-related adverse events (AEs) included fatigue, anemia, and lymphopenia. There were no Grade 4 events. The median rPFS was 3.7 months (95% CI, 1.6-8.4). The median OS was 9.6 months (95% CI, 1.8-22.4). The study was terminated due to futility after 10 patients. Whole exome sequencing identified AR amplification in 63% of patients (5/8). ESK981 + nivolumab showed no antitumor activity in patients with AR-positive (AR+) mCRPC. Further evaluation of ESK981 combined with the PD-1 inhibitor nivolumab in AR + mCRPC patients is not warranted. (Trial registration: ClinicalTrials.gov NCT04159896. Registration date: November 12, 2019.).","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"675-684"},"PeriodicalIF":3.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582791","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}

引用次数: 0

Neoadjuvant immunochemotherapy in locally advanced laryngeal cancer and hypopharyngeal cancer: higher objective response rate and organ-preservation rate. 局部晚期喉癌和下咽癌的新辅助免疫化疗：更高的客观反应率和器官保留率。

IF 3 3区医学

Investigational New Drugs Pub Date : 2024-12-01 Epub Date: 2024-11-28 DOI: 10.1007/s10637-024-01456-w

Shaoshi Chen, Qi Zhong, Shurong Zhang, Yang Zhang, Lizhen Hou, Hongzhi Ma, Shizhi He, Meng Lian, Yurong He, Ru Wang, Jugao Fang

{"title":"Neoadjuvant immunochemotherapy in locally advanced laryngeal cancer and hypopharyngeal cancer: higher objective response rate and organ-preservation rate.","authors":"Shaoshi Chen, Qi Zhong, Shurong Zhang, Yang Zhang, Lizhen Hou, Hongzhi Ma, Shizhi He, Meng Lian, Yurong He, Ru Wang, Jugao Fang","doi":"10.1007/s10637-024-01456-w","DOIUrl":"10.1007/s10637-024-01456-w","url":null,"abstract":"This study retrospectively analyzed the curative effect of neoadjuvant PD-1 inhibitors combined with chemotherapy of locally advanced laryngeal and hypopharyngeal cancer and compared with chemotherapy plus EGFR inhibitors and chemotherapy alone. From January 1 2018 to October 1 2023, a total of 113 patients in Beijing Tongren Hospital, who were diagnosed with locally advanced laryngeal cancer and hypopharyngeal cancer and received neoadjuvant immunochemotherapy, were enrolled. The primary outcome measures included objective response rate, organ-preservation rate, downstaging rate, and overall survival. Of 113 patients, including 34 patients were given immunochemotherapy, 38 patients chemotherapy plus EGFR inhibitor, and 41 patients chemotherapy. Most were male, and the median follow-up time in the immunochemotherapy group was 12 months. Neoadjuvant immunochemotherapy could improve the objective response rate (88.2%, p < 0.05), downstaging rate (79.41%, p < 0.05), and organ-preservation rate (97.1%, p < 0.05). However, compared with chemotherapy and chemotherapy plus EGFR inhibitors, immunochemotherapy did not significantly improve patients' 1-year and 2-year survival rates. Neoadjuvant PD-1 inhibitor combined with chemotherapy could improve the objective response rate, downstaging rate, and organ-preservation rate in patients with locally advanced laryngeal and hypopharyngeal cancer. Our study showed that this treatment regimen could more effectively protect the laryngeal function of patients. It provided a new treatment mode for patients with a strong desire to preserve the larynx. Further prospective studies are needed to confirm this conclusion.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"694-702"},"PeriodicalIF":3.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739454","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}

引用次数: 0

Exposure-response relationships of venetoclax in combination with carfilzomib and dexamethasone in relapsed/refractory t(11;14) multiple myeloma patients. Venetoclax与卡非佐米和地塞米松联合治疗复发/难治性t(11;14)多发性骨髓瘤患者的暴露-反应关系。

IF 3 3区医学

Investigational New Drugs Pub Date : 2024-12-01 Epub Date: 2024-10-10 DOI: 10.1007/s10637-024-01471-x

Mohamed Ali Badawi, Benjamin Engelhardt, Edyta Dobkowska, Rong Deng, Jonathan L Kaufman, Rajeev Menon, Ahmed Hamed Salem

{"title":"Exposure-response relationships of venetoclax in combination with carfilzomib and dexamethasone in relapsed/refractory t(11;14) multiple myeloma patients.","authors":"Mohamed Ali Badawi, Benjamin Engelhardt, Edyta Dobkowska, Rong Deng, Jonathan L Kaufman, Rajeev Menon, Ahmed Hamed Salem","doi":"10.1007/s10637-024-01471-x","DOIUrl":"10.1007/s10637-024-01471-x","url":null,"abstract":"Venetoclax is a first in class BCL-2 inhibitor, currently under investigation for the treatment of t(11;14) multiple myeloma (MM). The objective of this analysis was to characterize the exposure-efficacy and exposure-safety relationships of venetoclax when combined with carfilzomib and dexamethasone (VenKd) in t(11;14)-positive relapsed or refractory (R/R) MM patients from a phase 2 study. Fifty-seven patients receiving VenKd or Kd were included in the analysis. Efficacy endpoints included progression-free survival and clinical response rates of overall response, very good partial response or better and complete response or better. Grade ≥ 3 neutropenia, Grade ≥ 3 infections, Grade ≥ 3 treatment-emergent adverse events and any grade serious treatment-emergent adverse events were evaluated. The analysis demonstrated that adding venetoclax to Kd resulted in increased ORR, ≥VGPR and ≥ CR rates compared to the control arm. Within the venetoclax treatment arms (VenKd), no significant exposure-efficacy relationships were observed for ORR and ≥ VGPR rates. Higher ≥ CR rates trended with higher venetoclax exposures. While both 400 mg and 800 mg venetoclax in VenKd arms were generally tolerated, higher rates of Grade ≥ 3 neutropenia were observed with higher venetoclax exposures. Higher venetoclax exposures however were not associated with increased rates of Grade ≥ 3 treatment-emergent adverse events, Grade ≥ 3 infections, or serious treatment-emergent adverse events (any grade). These results confirm the benefit of adding venetoclax to carfilzomib and dexamethasone and support continued evaluation of venetoclax 400-800 mg once daily in this combination in t(11;14)-positive R/R MM patients. NCT02899052 registered April 18, 2017.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"635-643"},"PeriodicalIF":3.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11625073/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142465562","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}

引用次数: 0

Unraveling the potential biomarkers of immune checkpoint inhibitors in advanced ovarian cancer: a comprehensive review. 解读免疫检查点抑制剂在晚期卵巢癌中的潜在生物标志物：综述。

IF 3 3区医学

Investigational New Drugs Pub Date : 2024-12-01 Epub Date: 2024-10-21 DOI: 10.1007/s10637-024-01478-4

Jian-Rong Na, Yaqin Liu, Kun Fang, Yuan Tan, Pan-Pan Liang, Mei Yan, Jiao-Jiao Chu, Jian-Mei Gao, Dongsheng Chen, Shu-Xiang Zhang

引用次数: 0

Gremlin1: a BMP antagonist with therapeutic potential in Oncology. Gremlin1：一种具有肿瘤治疗潜力的 BMP 拮抗剂。

IF 3 3区医学

Investigational New Drugs Pub Date : 2024-12-01 Epub Date: 2024-09-30 DOI: 10.1007/s10637-024-01474-8

Zhao Jin, Yanshuo Cao

{"title":"Gremlin1: a BMP antagonist with therapeutic potential in Oncology.","authors":"Zhao Jin, Yanshuo Cao","doi":"10.1007/s10637-024-01474-8","DOIUrl":"10.1007/s10637-024-01474-8","url":null,"abstract":"Gremlins, originating from early 20th-century Western folklore, are mythical creatures known for causing mechanical malfunctions and electronic failures, aptly dubbed \"little devils\". Analogously, GREM1 acts like a horde of these mischievous entities by antagonizing the bone morphogenetic protein (BMP signaling) pathway or through other non-BMP dependent mechanisms (such as binding to Fibroblast Growth Factor Receptor 1and Epidermal Growth Factor Receptor) contributing to the malignant progression of various cancers. The overexpression of GREM1 promotes tumor cell growth and survival, enhances angiogenesis within the tumor microenvironment, and creates favorable conditions for tumor development and dissemination. Consequently, inhibiting the activity of GREM1 or blocking its interaction with BMP presents a promising strategy for suppressing tumor growth and metastasis. However, the role of GREM1 in cancer remains a subject of debate, with evidence suggesting both oncogenic and tumor-suppressive functions. Currently, several pharmaceutical companies are researching the GREM1 target, with some advancing to Phase I/II clinical trials. This article will provide a detailed overview of the GREM1 target and explore its potential role in cancer therapy.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"716-727"},"PeriodicalIF":3.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142346820","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}

引用次数: 0

Clinical characteristics, treatment, and outcomes of pembrolizumab-induced uveitis. 彭博利珠单抗诱发葡萄膜炎的临床特征、治疗和结果。

IF 3 3区医学

Investigational New Drugs Pub Date : 2024-10-01 Epub Date: 2024-08-14 DOI: 10.1007/s10637-024-01464-w

Zhaoquan Wu, Wei Sun, Chunjiang Wang

{"title":"Clinical characteristics, treatment, and outcomes of pembrolizumab-induced uveitis.","authors":"Zhaoquan Wu, Wei Sun, Chunjiang Wang","doi":"10.1007/s10637-024-01464-w","DOIUrl":"10.1007/s10637-024-01464-w","url":null,"abstract":"Pembrolizumab has been associated with episodes of uveitis, and the clinical characteristics between them are unknown. The aim of this study was to investigate the clinical characteristics of pembrolizumab-induced uveitis and to provide reference for prevention, diagnosis and treatment. We collected studies related to pembrolizumab-induced uveitis by searching databases for retrospective analysis until April 30, 2024. The median age of the 31 patients was 63 years (range 7, 82), and the median duration of uveitis onset was 12 weeks (range 0.4, 108). Decreased vision (41.9%) and blurred vision (25.8%) were the most common complaints. Uveitis can be manifested as Vogt-Koyanagi-Harada disease-like uveitis (22.6%) and Birdshot uveitis (6.5%). Uveitis mainly affects both eyes and is related to anterior uveitis (35.5%), panuveitis (25.8%) and posterior uveitis (19.4%). Patients receiving topical steroid drops, systemic steroids, and withdrawal of pembrolizumab significantly improved symptoms at a median time of 4 weeks (range 2, 16). The possibility of uveitis should be considered when patients are treated with pembrolizumab and experience eye symptoms such as blurred vision and decreased vision. Depending on the severity of uveitis, treatment with topical and systemic steroids may be selected.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"510-517"},"PeriodicalIF":3.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975692","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}

引用次数: 0

Post-marketing safety concerns with relugolix: a disproportionality analysis of the FDA adverse event reporting system. relugolix上市后的安全问题：对FDA不良事件报告系统的比例失调分析。

IF 3 3区医学

Investigational New Drugs Pub Date : 2024-10-01 Epub Date: 2024-08-12 DOI: 10.1007/s10637-024-01457-9

Chunyong Xia, Zhijing Liu, Jie Liu, Li Lin, Maohua Chen

{"title":"Post-marketing safety concerns with relugolix: a disproportionality analysis of the FDA adverse event reporting system.","authors":"Chunyong Xia, Zhijing Liu, Jie Liu, Li Lin, Maohua Chen","doi":"10.1007/s10637-024-01457-9","DOIUrl":"10.1007/s10637-024-01457-9","url":null,"abstract":"Background: Relugolix has been used to treat advanced prostate cancer. This study assessed adverse events (AEs) associated with relugolix from the US Food and Drug Administration Adverse Event Reporting System (FAERS).Methods: Disproportionality analysis, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) algorithms, were employed to quantify the signals of relugolix-associated AEs.Results: A total of 5,059,213 reports of AEs were collected from the FAERS database, of which 5,662 reports were identified with relugolix as the \"primary suspect (PS)\". A total of 70 significant disproportionality PTs conforming to the four algorithms were simultaneously retained. Unexpected new AEs, such as erectile dysfunction, gynaecomastia, testicular atrophy, male genital atrophy, libido decreased might also occur.Conclusion: This study found potential new AEs signals and might provide important support for clinical monitoring and risk identification of relugolix.","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"500-509"},"PeriodicalIF":3.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916687","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}

引用次数: 0

Phase II trial of multi-kinase inhibitor ESK981 in patients with metastatic castration-resistant prostate cancer. 多激酶抑制剂 ESK981 在转移性耐阉割前列腺癌患者中的 II 期试验。

IF 3 3区医学

Investigational New Drugs Pub Date : 2024-10-01 Epub Date: 2024-09-03 DOI: 10.1007/s10637-024-01463-x

Elisabeth I Heath, Wei Chen, Lance Heilbrun, Jae E Choi, Kimberlee Dobson, Melanie Smith, Tomasz Maj, Ulka Vaishampayan, Ilona Kryczek, Weiping Zou, Arul M Chinnaiyan, Yuanyuan Qiao

{"title":"Phase II trial of multi-kinase inhibitor ESK981 in patients with metastatic castration-resistant prostate cancer.","authors":"Elisabeth I Heath, Wei Chen, Lance Heilbrun, Jae E Choi, Kimberlee Dobson, Melanie Smith, Tomasz Maj, Ulka Vaishampayan, Ilona Kryczek, Weiping Zou, Arul M Chinnaiyan, Yuanyuan Qiao","doi":"10.1007/s10637-024-01463-x","DOIUrl":"10.1007/s10637-024-01463-x","url":null,"abstract":"ESK981 is a potent tyrosine kinase and PIKfyve lipid kinase inhibitor. This phase II trial evaluated the efficacy of ESK981 as a single agent in patients with androgen receptor-positive (AR +) metastatic castration-resistant prostate cancer (mCRPC). Eligible patients had mCRPC with progression on AR-targeted agents and without prior chemotherapy treatment. Each patient received 160 mg ESK981 once daily for 5 days per week for 4 weeks per cycle (except for an adverse event (AE) occurrence). The primary endpoints were a 50% reduction in prostate-specific antigen (PSA50), and safety. Secondary endpoints included the time and the duration of PSA response, PSA progression rates, PSA progression free survival (PFS) and overall survival (OS). Exploratory investigations included whole exome sequencing in patients before treatment, and morphological evaluation of biopsy samples pre- and post-treatment. PSA was evaluated in 13 patients. Only one patient (7.7% two-sided 95% Wilson CI (0.4%, 33.3%)) experienced a reduction in their PSA levels by 50% or more. The most common grade 3 treatment-related AEs were cardiac disorders, diarrhea, hypertension, alanine transaminase and aspartate transaminase elevations. No grade 4-5 events occurred. Median PFS was 1.8 months, and median OS was 12.1 months. Peripheral immune cells showed increased T cell activation and cytokine production in two patients who received 12-weeks of ESK981. Although relatively well tolerated, ESK981 alone showed no anti-tumor activity in patients with AR + mCRPC and its further evaluation as a single agent in AR + mCRPC is not warranted. (Trial registration: ClinicalTrials.gov, NCT03456804. Registration date: March 7, 2018).","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"566-574"},"PeriodicalIF":3.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142125715","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}

引用次数: 0