Open-label Phase 1b Study of Ulixertinib and Cetuximab or Ulixertinib in Combination with Cetuximab and Encorafenib in Patients with Unresectable or Metastatic Colorectal Cancer Who Have Previously Received EGFR or BRAF-directed Therapy

To find the recommended dose of ulixertinib that can be given in combination with cetuximab and/or encorafenib to patients with unresectable/metastatic CRC and who have received EGFR or BRAF-directed therapy in the past.

开始日期2024-01-18

申办/合作机构

The University of Texas MD Anderson Cancer Center

[+2]

NCT05804227 / Recruiting早期临床1期IIT

Window-of-Opportunity Trial of Ulixertinib for MAPK-Activated Low-Grade Gliomas in Adults

To learn if the study drug, ulixertinib, can cross over the blood-brain barrier in patients with recurrent brain tumors

开始日期2023-04-20

申办/合作机构

The University of Texas MD Anderson Cancer Center

[+1]

100 项与优立替尼相关的临床结果

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100 项与优立替尼相关的转化医学

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100 项与优立替尼相关的专利（医药）

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项与优立替尼相关的文献（医药）

2024-10-11·CURRENT MEDICINAL CHEMISTRY

FOXN3-AS1: A Candidate Prognostic Marker and Epigenetic Target with Immunotherapeutic Implications in Acute Myeloid Leukemia

Article

作者: Huang, Xiaoli ; Wang, Yulu ; Wang, Zifeng ; Schmidt-Wolf, Ingo G.H. ; Sharma, Amit ; Schmid, Matthias ; Chen, Peng ; Dakal, Tikam Chand ; Jaehde, Ulrich ; Ge, Fangfang ; Essler, Markus

Aim::

We focused on the FOXN3 gene and selected its antisense transcripts (FOXN3-AS1) to investigate its potential involvement in acute myeloid leukemia (AML).

Background::

Several integrated multi-omics datasets have expanded the horizons of the cancer landscape. With the emergence of new high-throughput technologies, a large number of non-coding RNAs have been confirmed to be involved in the pathogenesis of different types of hematological malignancies.

Methods::

We conducted experimental validation using quantitative polymerase chain reaction (qPCR) with bone marrow specimens from AML patients. Then, Kaplan-Meier (KM) and Receiver Operating Characteristic (ROC) curves were used to substantiate the prognostic association between FOXN3-AS1 and AML patients within the TCGA database. Correlation between FOXN3-AS1 expression and gene mutation, immune, and immune function using Spearman correlation analysis. To explore the physical and functional interaction between FOXN3-AS1 and the DNMT1 protein, we utilized the RPISeq web tool from Iowa State University. Subsequently, we performed qPCR experiments to test the effect of 5AzaC (DNMT1 inhibitor) on FOXN3-AS1 expression AML cell lines (THP1 and OCI-AML3). We leveraged the “OncoPredict” R package in conjunction with the Genomics of Drug Sensitivity (GDSC) database to predict drug response in AML patients expressing FOXN3-AS1.

Results::

We observed a significant upregulation of FOXN3-AS1 expression in AML patients compared to healthy controls using clinical samples. The TCGA database revealed an association between high FOXN3-AS1 expression and adverse prognosis. In our subsequent analysis, genes with poor prognostic implications in AML patients were exclusively identified in the FOXN3-AS1 high-expression group, further corroborating this relationship. AML patients with higher FOXN3-AS1 expression levels may respond less optimally to immunotherapy than patients with lower levels. Besides, we computationally predicted the interaction of FOXN3- AS1 and DNMT1 protein and experimentally confirmed that DNMT1i (GSK-3484862) affects the expression level of FOXN3-AS1. We also found that the chemotherapy drugs (5-Fluorouralic, Cisplatin, Dactolisib, Sapitinib, Temozolomide, Ulixertinib, Vinorelbine, Ruxolitinib, Osimertinib and Cisplatin) showed favorable responses in AML patients with high FOXN3-AS1 expression levels.

Conclusion::

Our candidate approach identifies FOXN3-AS1 as a prognostic indicator of survival in AML with a potential immune-related role. The preliminary observations we made on FOXN3-AS1/DNMT1 crosstalk warrant more in-depth invested immunotherapeutic approaches in AML.

2024-06-01·JCO Precision Oncology

Phase II Study of Ulixertinib in Children and Young Adults With Tumors Harboring Activating Mitogen-Activated Protein Kinase Pathway Alterations: APEC1621J of the National Cancer Institute-Children's Oncology Group Pediatric MATCH Trial

Article

作者: Piao, Jin ; Jaju, Alok ; Takebe, Naoko ; Alonzo, Todd A. ; Reid, Joel M. ; Sabnis, Amit J. ; Tricoli, James V. ; Coffey, Brent ; Seibel, Nita L. ; Fox, Elizabeth ; Patton, David R. ; Vo, Kieuhoa T. ; Hawkins, Douglas S. ; Williams, P. Mickey ; Parsons, D. Williams ; Mooney, Margaret M. ; Berg, Stacey L. ; Janeway, Katherine A. ; Saguilig, Lauren ; Roy-Chowdhuri, Sinchita ; Weigel, Brenda J.

PURPOSE:

The National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric MATCH trial assigns patients age 1-21 years with refractory malignancies to phase II treatment arms of molecularly targeted therapies on the basis of genetic alterations detected in their tumor. Patients with activating alterations in the mitogen-activated protein kinase pathway were treated with ulixertinib, an extracellular signal-regulated kinase (ERK)1/2 inhibitor.

METHODS:

As there were no previous pediatric data, ulixertinib was initially tested in a dose escalation cohort to establish the recommended phase II dose (RP2D) before proceeding to the phase II cohort. Ulixertinib was administered at 260 mg/m2/dose orally twice a day (dose level 1 [DL1], n = 15) or 350 mg/m2/dose orally twice a day (DL2, n = 5). The primary end point was objective response rate; secondary end points included safety/tolerability and progression-free survival (PFS).

RESULTS:

Twenty patients (median 12 years; range, 5-20) were treated, all evaluable for response. CNS tumors comprised 55% (11/20) of diagnoses, with high-grade glioma and low-grade glioma most common (n = 5 each). All CNS tumors except one harbored BRAF fusions or V600E mutations. Rhabdomyosarcoma (n = 5) was the most frequent non-CNS diagnosis. DL1 was declared the RP2D in the dose escalation cohort after dose-limiting toxicities in Cycle 1 occurred in 1/6 patients at DL1 and 2/5 patients at DL2, including fatigue, anorexia, rash, nausea, vomiting, diarrhea, dehydration, hypoalbuminemia, and hypernatremia. No objective responses were observed. Six-month PFS was 37% (95% CI, 17 to 58). Three patients with BRAF-altered CNS tumors achieved stable disease >6 months.

CONCLUSION:

Ulixertinib, a novel targeted agent with no previous pediatric data, was successfully evaluated in a national precision medicine basket trial. The pediatric RP2D of ulixertinib is 260 mg/m2/dose orally twice a day. Limited single-agent efficacy was observed in a biomarker-selected cohort of refractory pediatric tumors.

2024-05-21·Cancer research communications

A Phase II Study of ERK Inhibition by Ulixertinib (BVD-523) in Metastatic Uveal Melanoma

Article

作者: Liu, David ; Sullivan, Ryan J ; Haq, Rizwan ; Lawrence, Donald P ; Buchbinder, Elizabeth I ; Tarantino, Giuseppe ; Hodi, F Stephen ; Cohen, Justine V ; Knoerzer, Deborah ; Giobbie-Hurder, Anita ; Lian, Christine G

Abstract:

Purpose::

Uveal melanoma is a rare and aggressive subset of melanoma that is minimally responsive to traditional therapies. Greater than 80% of uveal melanomas have a mutation in GNAQ or GNA11 which lead to downstream signaling through the MAPK pathway. Ulixertinib (BVD-523) is a potent and reversible small-molecule ATP-competitive inhibitor of both ERK1 and ERK2 protein kinases.

Materials and Methods::

We performed a phase II study to determine the efficacy and safety of BVD-523 in patients with metastatic uveal melanoma. This was conducted as a Simon two-stage design with a sample size of 25 patients and an initial evaluation of efficacy after 13 patients.

Results::

From April 2018 to April 2019, 13 patients were enrolled. Patients were predominantly female (69%) with a median age of 64 years (34–76). Sites of metastases included liver (84.6%) and lung (30.8%). Grade 3 and 4 toxicities associated with therapy were consistent with ERK inhibitors and included liver function test (LFT) elevation, hyponatremia, pruritis, amylase elevation, anemia, and rash. The best response, per RECIST 1.1, was stable disease in 4 patients, and disease progression in 7 patients. Two patients were unevaluable for response due to withdrawal from study. Median time to progression was 2.0 months. There were eight deaths due to disease progression with a median overall survival of 6.9 months.

Conclusions::

ERK inhibition with ulixertinib (BVD-523) did not demonstrate activity in patients with metastatic uveal melanoma. The toxicities observed were consistent with what would be expected with MAPK pathway inhibition.

Significance::

Uveal melanoma is a difficult to treat disease with minimal therapy options. The majority of uveal melanomas have mutations in GNAQ or GNA11 leading to activation of the MAPK pathway. Efforts to target MEK in uveal melanoma has had mixed results. This phase II trial of ERK inhibition with BVD-523 examined the potential role of this agent in uveal melanoma therapy.

项与优立替尼相关的新闻（医药）

2023-03-23

·PRNewswire

Clarivate Announces Gordon Samson as President, Intellectual Property and Nominates Dr. Saurabh Saha as New Independent Director

Naming the first of three business leaders for its newly created market segments and nominating new Independent Director to its Board LONDON, March 23, 2023 /PRNewswire/ -- Clarivate Plc (NYSE: CLVT), a global leader in connecting people and organizations to intelligence they can trust, today announced that Gordon Samson, currently Chief Product Officer, has been appointed President of its Intellectual Property (IP) market segment, effective April 1. The Company also announced that it has nominated Dr. Saurabh Saha to stand for election as a director at its 2023 Annual General Meeting of shareholders on May 4, 2023. Jonathan Gear, Chief Executive Officer, Clarivate said: "I'm very pleased to announce the appointment of Gordon who has been a trusted and valued member of our Executive Leadership Team since he came to Clarivate from CPA Global as part of our acquisition in 2020. In this newly created role, he will be responsible for accelerating the growth of our IP segment empowering customers to establish, protect and manage their IP. Based on my experience working with him over the last eight months and the work we've done this year to align the organization, I'm confident that he will be instrumental to how we capitalize on product and service innovation to deliver organic growth. This is the first of our presidential appointments and we look forward to providing updates on further appointments in due course." Samson joined Clarivate in October 2020 with the acquisition of CPA Global, having joined CPA Global in 2014 as Chief Operating Officer. During the last three years with Clarivate, Samson has made significant contributions, helping transform the Company's APAC region and bringing together the Company's entire product portfolio to offer customers a full range of enriched data, insights, analytics and workflow solutions. He has a long and successful track record of driving organizational transformation and growth in the IP industry and beyond, having held senior executive roles with both operating and P&L accountability for more than 20 years. Andy Snyder, Chairman of the Board, Clarivate commented: "We look forward to Dr. Saha joining our Board. He will bring a great deal of experience in the pharmaceutical and biotech industries and his guidance will provide valuable insights and perspective, especially as we continue to execute on our growth strategy in the Life Sciences & Healthcare segment." Dr. Saha is a physician-scientist, pharmaceutical executive, and biotech entrepreneur dedicated to discovering and developing novel life-changing medicines. He is notable for leading the development and demonstrating human effectiveness of two innovative cancer drugs, an ERK kinase inhibitor (Ulixertinib) and an oncolytic immunotherapy (C. novyi-NT). He is currently CEO of Centessa Pharmaceuticals (NASDAQ: CNTA), a global pharma company. Prior to Centessa, Dr. Saha was a Senior Vice President of R&D and Global Head of Translational Medicine for all disease areas at Bristol Myers Squibb. Other past roles include Venture Partner at Atlas Venture, a VC firm in Cambridge MA, Chief Executive Officer at Delinia, Chief Medical Officer of Synlogic, a management consultant at McKinsey & Company, and head of the New Indications Discovery Unit at Novartis. He is an associate member and Global Clinical Scholar at Harvard Medical School, holds an MD and PhD in medicine and cancer genetics from The Johns Hopkins School of Medicine, an MSc in biophysics from the University of Oxford and a BSc in biochemistry from Caltech. About Clarivate Clarivate™ is a leading global information services provider. We connect people and organizations to intelligence they can trust to transform their perspective, their work and our world. Our subscription and technology-based solutions are coupled with deep domain expertise and cover the areas of Academia & Government, Life Sciences & Healthcare and Intellectual Property. For more information, please visit clarivate.com. Investor Relations Contact Mark Donohue, Head of Investor Relations, [email protected], +1 (215) 243 2202 Media Contact Amy Bourke-Waite, Senior Director, Corporate Communications, [email protected] SOURCE Clarivate Plc

高管变更

2022-11-02

·药渡Daily

德琪医药ATG-017获FDA批准I期临床，治疗晚期实体瘤！

2022年11月1日，德琪医药宣布，ERK1/2小分子抑制剂ATG-017的1期临床试验申请（IND）已获美国食品药品监督管理局（FDA）批准，用于治疗晚期实体瘤。随后，德琪医药将在美国启动1期ERASER研究的联合治疗部分，以评估ATG-017联合纳武利尤单抗用于治疗晚期实体瘤的安全性、药代动力学和初步疗效。来源：德琪医药官网该项由德琪医药与百时美施贵宝合作的旨在评估ATG-017联合纳武利尤单抗的临床合作是基于已有的临床前数据，其中部分数据已于2021年11月在第36届肿瘤免疫治疗学会（SITC）年会及会前环节中公布。数据显示，ERK1/2抑制剂（ATG-017）联合免疫检查点抑制剂（ICI，PD-L1单抗，阿特朱单抗）发挥了协同作用，在ICI耐药的小鼠体内模型中产生了更好的疗效，达到肿瘤由“冷”至“热”的转化。此外，据Clinicaltrails.gov网站信息显示，2020年3月12日德琪医药登记了一项临床研究（NCT04305249），这是一项开放、多中心I期研究（代号：ERASER），主要评估ATG-107单药治疗晚期实体瘤和恶性血液瘤患者的安全性、药代动力学和初步疗效。目前该单药治疗爬坡正在澳大利亚顺利开展，并将继续参与联合治疗部分的研究。除澳大利亚和美国外，德琪医药还计划在中国开展这项国际多中心研究。目前在药物临床试验登记与信息公示平台暂未检索到ATG-017的临床试验登记号。关于ERK1/2细胞外信号调节蛋白激酶1/2（ERK1/2）是一类丝氨酸/苏氨酸蛋白激酶，是MEK1/2唯一已知的底物，位于RAS-RAF-MEK-ERK（MAPK）通路的下游，其作用是作为RAS-MAPK信号转导级联通路的终端激酶。该级联通路调节细胞增殖等多种细胞进程。RAS-MAPK通路失调发于30%以上的癌症患者，最为常见的变化为多个肿瘤类型的RAS或BRAF基因突变。ERK抑制剂可同时靶向RAS和BRAF突变疾病。目前，已有多种靶向RAS、RAF和MEK的小分子抑制剂被批准用于癌症治疗，然后，长期治疗中产生的获得性耐药降低了这些药物的疗效。近年来，选择性抑制ERK1/2被认为是一种潜在的癌症治疗策略，它不仅可以有效阻断MAPK通路，还可以克服RAS、RAF和MEK上游突变引起的耐药性。ERK1/2的关键调控通路来源：Fu et al. J Med Chem. 2022, 65(20): 13561-13573关于ATG-017ATG-017（AZD0364，Tizaterkib）是一款作用于细胞外信号调节激酶1和2（ERK1/2）的可逆型、ATP竞争性的强效、选择性口服小分子抑制剂，是以阿斯利康已有的先导化合物7为基础，进行构效关系（SAR）优化后得到的激酶选择性更强、药代动力学性质更佳的ATG-107。ATG-107对ERK2的IC50值为0.6 nM，水溶性468 uM，在体外大鼠和人肝细胞中均较稳定，渗透性（Caco-2 Papp）为26.7*10-6 cm/s，是高渗化合物，大鼠和犬灌胃给药后的生物利用度分别为30%和100%，具有较好的药代动力学性质。据文献报道，基于临床前试验数据推测的人体清除率范围是0.5-6 ml/min/kg，预测人体首次给药剂量为20-110 mg，一天两次。根据此前研究报道，在多个体内异种移植瘤模型中，ATG-017展现了对ERK1/2依赖性信号生物标志物的剂量和时间依赖性调节，从而使得BRAF敏感型和KRAS突变敏感型异种移植瘤的肿瘤消退。此外，ATG-01与MEK1/2抑制剂selumetinib (AZD6244和ARRY142886)的联合给药可以更深入、更持久地抑制RAS/MAPK信号通路，这是单药治疗无法实现的。ATG-017和selumetinib联合给药也会在KRAS突变的异种移植瘤模型中出现显著的肿瘤消退。因此，ERK1/2抑制剂和MEK1/2抑制剂的联合给药是靶向KRAS突变肿瘤的一种可行的临床方法。体外研究中，ATG-017对MAPK信号通路的直接下游底物具有高细胞活性（如在BRAFV600E突变的A375细胞中，抑制phospho-p90RSK，IC50= 5.73 nM）。ATG-107浓度为1 uM时，在包含353种激酶的激酶库中对其中9种激酶（MEK1, COT, BRAF, MEK2, c-RAF, ERK7, CDK2, CDK5 and ARK5）的抑制作用大于50%。A: AZD0364（ATG-017）的结构式B: AZD0364（ATG-017）与ERK2的结合位点来源：Vikki Flemington. et al. Mol Cancer Ther. 2021, 20(2): 238-249.“RAS/MAPK通路是癌症发生的一个重要驱动因素。ATG-017靶向ERK1/2不仅能阻止肿瘤细胞的生长，还能与其他MAPK激酶抑制剂协同作用，更有效地阻断RAS-MAPK信号传导，同时克服患者对RAF及MEK抑制剂产生耐药。”德琪医药创始人、董事长兼首席执行官梅建明博士说，“我们认为ATG-017拥有强大的临床潜力和广阔的应用前景。不单是针对实体瘤与血液瘤的单药疗法，德琪团队也正深入挖掘ATG-017与公司其他在研产品的协同性，以期获得更好的抗癌效果。”权益合作ATG-017由阿斯利康公司发现及早期研究，德琪医药拥有开发、生产及商业化该产品的全球独家权益。2019年11月6日，德琪医药宣布与英国阿斯利康公司达成一项全球性的独家授权协议，推进创新药物ATG-017（AZD0364）在全球的临床开发，生产和商业化。阿斯利康公司在此次交易前已终止了全球范围内其他关于ATG-017的授权协议，包括与辅仁药业的授权协议。2021年12月13日，德琪医药宣布与百时美施贵宝公司达成了一项临床合作协议，将共同开展一项旨在评估ATG-017联合百时美施贵宝的PD-1检查点抑制剂欧狄沃®（纳武利尤单抗）用于治疗晚期实体瘤的安全性、药代动力学和初步疗效的开放性1/2期临床研究。根据该协议，德琪医药将负责该临床试验的开展，并提供资金支持。百时美施贵宝公司将提供联合疗法的剂量爬坡和剂量扩展研究中所需的欧狄沃®。竞争格局目前关于靶向ERK药物的研究尚处在早期临床阶段，全球范围内仅有BioMed Valley Discoveries公司的BVD-523、Merck公司的MK-8353与Genentech的GDC-0994披露临床数据。全球范围内到目前为止没尚无任何一款已获批上市的ERK1/2抑制剂。BVD-523BVD-523（Ulixertinib，VRT752271）是由BioMed Valley Discoveries公司研发的可逆型、ATP竞争性ERK1/2抑制剂，其对ERK1的Ki < 0. 3 nM，对ERK2的Ki = 0. 04 nM。2017年12月15日，Cancer Discov杂志公布了ERK1/2抑制剂BVD-523的I期临床试验（NCT01781429）数据。结果提示2期临床试验推荐剂量为600 mg BID给药，最常见治疗相关不良反应包括腹泻(48%)、疲劳(42%)、恶心(41%)和痤疮性皮炎(31%)。在部分患者中，BVD-523治疗确实获得了部分缓解或疾病稳定状态，且疗效似不受肿瘤类型的影响。BVD-523具有可接受的安全性和良好的药代动力学性质。MK-8353MK-8353是通过改善SCH772984的PK 而优化得到的（ERK1：IC50= 20 nM；ERK2：IC50 = 7 nM）。SCH772984是由Merck公司通过基于亲和力的质谱高通量平台筛选、鉴定并通过结构优化得到的ATP 竞争性的ERK1/2抑制剂。2018年2月22日，JCI Insight杂志公布了ERK1/2抑制剂MK-8353的I期临床试验（NCT01358331）数据。在所有剂量中MK-8353总体安全性和耐受性良好，并且未发生严重不良事件（SAE）。在400毫克和800毫克剂量组中观察到剂量限制性毒性。在可评价治疗缓解的15名晚期实体瘤患者中，3名患者具有部分缓解，他们全部患有BRAFV600突变型黑色素瘤。GDC-0994GDC-0994是由Genentech公司研发的口服的选择性ERK1/2抑制剂，其对ERK1和ERK2的IC50分别为6. 1和3. 1 nmol/L。2020年3月15日，CCR杂志公布了新型ERK1/2抑制剂GDC-0994的I期临床试验（NCT01875705）数据。47名跨癌种的难治性晚期实体瘤患者，接受了该药物治疗。20名患者在接受治疗前后，均进行PET-CT检测，从PET-CT上可以反应肿瘤的代谢活性，其中11名患者肿瘤代谢活性明显下降，其中就包括4名胰腺癌患者。而从普通CT上看，45名患者中有15人肿瘤控制稳定。最难能可贵的是：2名BRAF突变的难治性肠癌患者，接受该药物治疗后，肿瘤明显缩小，缩小幅度超过30%，给这种极端难治的晚期肠癌患者带来了新的希望。CC-90003CC-90003是不可逆的共价结合的选择性ERK1/2 抑制剂，主要用于治疗KRAS突变的肿瘤，2015年进入1期临床研究。但是由于在1期临床试验中，其最大耐受剂量（MTD）结果不令人满意，目前已经暂停了其临床试验（NCT02313012）。此外，据药渡数据的不完全统计，目前临床阶段上二十多款ERK1/2抑制剂药物正在推进中，进展最快的项目也仅处于2期阶段。国内进展最快的是海和医药的BPI-27336、和记黄埔的HMPL-295S1和捷思英达的JSI-1187，相关ERK1/2抑制剂所处临床阶段多为1期。德琪医药的ATG-017因拥有同类最佳的潜力，且该品种还与免疫检查点抑制剂和其它靶向 RAS/MAPK通路的抑制剂具有很高的联用潜力，有望在竞争中先拔头筹。参考来源各公司官网；Leilei Fu. et al. Targeting Extracellular Signal-Regulated Protein Kinase 1/2 (ERK1/2) in Cancer: An Update on Pharmacological Small-Molecule Inhibitors [J]. J Med Chem. 2022, 65(20): 13561-13573.Richard A. Ward. et al. Discovery of a Potent and Selective Oral Inhibitor of ERK1/2 (AZD0364) That Is Efficacious in Both Monotherapy and Combination Therapy in Models of Nonsmall Cell Lung Cancer (NSCLC) [J]. J Med Chem. 2019 62(24):11004-11018.Vikki Flemington. et al. AZD0364 is a potent and selective ERK1/2 inhibitor which enhances anti-tumour activity in KRAS mutant tumour models when combined with the MEK inhibitorSelumetinib [J]. Mol Cancer Ther. 2021, 20(2): 238-249.Andrea Varga. et al. A First-in-Human Phase I Study to Evaluate the ERK1/2 Inhibitor GDC-0994 in Patients with Advanced Solid Tumors [J]. Clin Cancer Res. 2020, 26(6):1229-1236.

免疫疗法小分子药物抗体合作

2022-09-12

·PRNewswire

BioMed Valley Discoveries Announces First Patient Dosed in Phase II Combination Trial with Ulixertinib (BVD-523), its First-in-Class and Best-in-Class ERK Inhibitor, in Combination with Hydroxychloroquine

KANSAS CITY, Mo., Sept. 12, 2022 /PRNewswire/ -- BioMed Valley Discoveries (BVD) announced that the first patient has been dosed in a phase II clinical trial of ulixertinib (BVD-523) in combination with hydroxychloroquine (HCQ). Ulixertinib is a first-in-class and best-in-class ERK inhibitor, with this clinical trial focusing on patients with advanced gastrointestinal malignancies and mutations in the MAPK pathway. This study builds upon the finding of the phase I study of the combination, which was completed at Huntsman Cancer Institute at the University of Utah. "Combining an ERK inhibitor with an autophagy inhibitor is anticipated to take advantage of the finding that tumors may become addicted to autophagy for survival in context of MAPK inhibition" said Brent Kreider, Ph.D., President of BioMed Valley Discoveries. "Given the favorable safety profile and efficacy seen with ulixertinib monotherapy, we believe that the combination with hydroxychloroquine has the potential to provide significant benefit to patients with advanced gastrointestinal malignancies." The Phase II efforts build on a successful Phase Ib evaluating ulixertinib monotherapy as a novel targeted cancer treatment in cohorts of patients with genetic alterations that result in aberrant MAPK pathway signaling. Results from phase Ib demonstrated ulixertinib has an acceptable safety profile and early evidence of clinical activity against a wide range of RAS/MAPK pathway-driven cancers, including atypical alterations in BRAF. In addition to targeting the terminal node of the RAS/MAPK pathway, ulixertinib's highly selective kinase inhibition profile is expected to provide potential impact across a number of tumor types in both monotherapy and combination. Previous efforts have also established a recommended phase 2 dose in combination with palbociclib, with additional combination efforts ongoing. About ulixertinib (BVD-523): Ulixertinib is a first-in class and best-in class small molecule inhibitor of extracellular signal-regulated kinase (ERK) family kinases (ERK1 and ERK2) that is being developed as a novel anti-cancer drug. ERK kinases are downstream components of the mitogen-activated protein kinase (MAPK) signaling cascade (RAS-RAF-MEK-ERK). Ulixertinib has demonstrated promising early efficacy for patients with tumors harboring alterations in the MAPK pathway. About the study: This is an open-label, multicenter, prospective phase II basket trial assessing the efficacy of ulixertinib in combination with hydroxychloroquine in patients with advanced gastrointestinal malignancies. All patients recruited must have a mitogen-activated protein kinase (MAPK) activating mutation to be deemed eligible for trial participation. Each disease-based basket will open to enrollment in two-stages and includes pancreatic, colorectal, esophageal, gastric and cholangiocarcinomas . (Clinicaltrials.gov Number NCT05221320). About BioMed Valley Discoveries (BVD): BioMed Valley Discoveries is a clinical stage biotechnology company focused on addressing unmet medical needs in a variety of therapeutic and diagnostic areas. In addition to the ERK inhibitor, BVD's portfolio includes an oncolytic bacteria that has completed enrollment for a Phase I study, and two early-stage antibodies targeting the tumor microenvironment. Operating since 2007, BioMed Valley Discoveries was established by Jim Stowers Jr., founder of the asset management firm American Century Investments, and his wife Virginia, to advance new medical innovations to improve the lives of patients with difficult-to-treat diseases. BVD is owned by a supporting organization of the Stowers Institute for Medical Research, a non-profit, basic biomedical research organization. Since 2000, the endowment of the Stowers Institute has received over $1.7 billion in dividend payments from American Century. The Institute has invested a portion of its endowment in BVD, whose profits accrue to the benefit of the Institute. For more information, visit . Media Contact Joe Chiodo, Head of Media Relations 724-462-8529 [email protected] SOURCE BioMed Valley Discoveries

抗体合作First in Class小分子药物

100 项与优立替尼相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11038	-	-	DB13930

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
胃肠道肿瘤	临床2期	美国	BioMed Valley Discoveries, Inc.	2022-05-26
晚期淋巴瘤	临床2期	美国	National Cancer Institute	2019-07-24
浆细胞骨髓瘤难治	临床2期	美国	National Cancer Institute	2019-07-24
难治性淋巴瘤	临床2期	美国	National Cancer Institute	2019-07-24
晚期恶性实体瘤	临床2期	美国	National Cancer Institute	2018-11-14
晚期恶性实体瘤	临床2期	波多黎各	National Cancer Institute	2018-11-14
室管膜瘤	临床2期	美国	National Cancer Institute	2018-11-14
室管膜瘤	临床2期	波多黎各	National Cancer Institute	2018-11-14
肝母细胞瘤	临床2期	美国	National Cancer Institute	2018-11-14
肝母细胞瘤	临床2期	波多黎各	National Cancer Institute	2018-11-14

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04488003 (CTgov)	临床2期	晚期恶性实体瘤	104	Ulixertinib	鹹遞壓憲襯簾範醖蓋膚(窪鹹選鏇選鏇衊製範膚) = 膚餘選鑰鏇糧選壓糧製艱簾餘衊獵夢襯選壓鏇 (淵鑰網觸夢夢壓衊窪構, 構鑰構憲觸顧積鏇餘憲 ~ 顧顧願積糧鹹顧鑰壓製) 更多	-	2024-06-04
NCT03698994 (CTgov)	临床2期	难治性软组织肉瘤 \| 复发性髓母细胞瘤 \| 室管膜瘤 ... 更多	20	Pharmacokinetic Study+Ulixertinib	齋膚遞範構範鹽淵夢齋(蓋鹹蓋憲顧鬱糧壓簾觸) = 艱夢簾窪壓餘鏇鏇壓蓋積蓋遞築繭積繭獵齋齋 (衊顧鹽鹽遞壓選憲築繭, 願鹹衊廠積願觸齋鹽襯 ~ 窪夢糧淵餘鹽構選簾製) 更多	-	2023-05-16
NCT02608229 (Pubmed) 人工标引	临床1期	转移性胰腺腺癌	18	Albumin-Bound Paclitaxel+Gemcitabine+Ulixertinib	蓋廠積鹽製願選餘繭構(顧鏇築艱蓋遞網壓選觸) = ulixertinib 450 mg BID 顧餘鑰遞網齋簾製窪廠 (醖醖艱夢簾選選願遞網 )	积极	2022-11-25
NCT02465060 (EAY131-Z1L, AACR2022) 人工标引	临床1期	肿瘤 BRAF Fusion	35	BVD-523FB	製淵鑰鏇獵醖廠壓簾襯(獵顧網築遞顧醖壓窪選) = 窪餘憲夢壓構觸壓廠網衊糧遞壓壓壓淵蓋網選 (築積願獵壓窪鹹獵鹽餘 ) 更多	积极	2022-06-15
NCT03698994 (ASCO2022) 人工标引	临床2期	肿瘤 MAPK Mutation	20	overall	齋遞廠壓膚衊鑰觸製構(糧衊範築簾蓋糧顧廠積) = 築顧鹽壓蓋選範顧鏇廠構淵願製積齋鬱齋範壓 (鏇糧襯夢醖鹹範願構夢, 17 ~ 58) 更多	积极	2022-06-02
NCT03698994 (ASCO2022) 人工标引	临床2期	肿瘤 MAPK Mutation	20	Ulixertinib 260 mg/m2 (DL1)	鹽願淵窪觸顧網願蓋鏇(窪窪艱積鑰鬱夢鏇網願) = 繭觸鹽鏇蓋鏇繭糧醖窪餘淵鑰窪願糧夢鹽糧廠 (範艱願遞願窪遞蓋鏇顧 )	积极	2022-06-02
NCT04566393 (ULI-EAP-100, ASCO2022) 人工标引	N/A	HR阳性/HER2低表达实体瘤 MAPK Mutation	48	ulixertinib	壓憲鬱膚顧築獵淵醖襯(壓遞獵醖選醖願鹽齋夢) = 鹹獵顧製廠餘積壓糧簾繭膚鑰餘醖積繭範遞蓋 (齋觸築選範鹹襯鏇遞觸 ) 更多	积极	2022-06-02
NCT03417739 (CTgov)	临床2期	葡萄膜黑色素瘤	13	BVD-523	積獵衊選艱醖膚餘糧鹽(遞遞簾鑰淵艱選構簾鬱) = 襯鹹範淵廠衊鹽壓鬱廠簾繭鬱憲夢衊夢夢淵繭 (獵憲顧繭鏇鹹願膚選廠, 簾艱顧遞獵襯膚齋選願 ~ 糧築餘鏇膚廠夢願糧糧) 更多	-	2021-11-11
NCT03454035 (ASCO2021)	临床1期	HR阳性/HER2低表达实体瘤	26	Ulixertinib 300mg BID + Palbociclib 75mg daily	鑰蓋範築簾願顧鹽選壓(壓繭膚淵膚鹽顧獵簾淵) = 簾夢鹽觸醖壓積壓艱觸鏇齋壓襯鬱壓夢餘積壓 (範糧壓觸網憲膚淵醖網, 1.87 ~ notdetermined)	-	2021-05-28
NCT01781429 (Pubmed \| Invest New Drugs)	临床1期	晚期癌症	135	Ulixertinib	壓鏇繭遞膚鑰窪鬱蓋壓(範蓋獵窪鏇顧齋築遞餘) = The most common dAEs included acneiform rash (45/135, 33%), maculopapular rash (36/135, 27%), and pruritus (34/135, 25%). Grade 3 dAEs were observed in 19% (25/135) of patients; no grade 4 or 5 dAEs were seen. 顧築憲窪鹹築願鹹鹹襯 (築構構糧鹹鑰獵糧鬱鬱 )	-	2021-01-03
NCT03417739 (ASCO2020)	临床2期	葡萄膜黑色素瘤	25	Ulixertinib (BVD-523)	網繭廠壓簾網淵夢網繭(積簾壓鑰醖構膚鏇衊窪) = Grade 3 and 4 toxicities associated with therapy were consistent with BVD-523 and other ERK inhibitors and included LFT elevation, hyponatremia, pruritis, amylase elevation, anemia and rash. 願選衊願獵壓觸簾範網 (願淵簾膚獵製餘窪獵顧 )	不佳	2020-05-25