Molecular Basket Trial In Multiple Malignancies With Common Target Pathway Aberrancies: A Phase II Trial of GSK2256098 and Trametinib in Patients With Advanced Pancreatic Cancer

This is a phase 2 study (the second phase in testing a new drug or combination to see how effect the drug or combination is) of investigational drugs GSK2256098 and Trametinib.
The purpose of the study is to evaluate the antitumor activity of GSK2256098 and Trametinib in patients with advanced pancreatic cancer.

开始日期2016-04-01

申办/合作机构

University Health Network

[+1]

NCT02551653 / Completed临床1期

A Microdose Study to Evaluate the Biodistribution of [11C]-GSK2256098 in the Lungs and Heart of Healthy Subjects and Idiopathic Pulmonary Arterial Hypertension (PAH) Patients Using Positron Emission Tomography (PET)

Pulmonary arterial hypertension (PAH) involves the narrowing of blood vessels connected to and within the lungs. Focal adhesion kinase (FAK) is a focal adhesion-associated protein kinase involved in cellular adhesion and spreading processes which leads to stiffening and thickening of blood vessels in lungs. This further increases the blood pressure within the lungs and impairs their blood flow. This study aims to demonstrate biodistribution of FAK inhibitor, GSK2256098, in cardiopulmonary sites i.e. heart and lung tissues. The uptake of 11C-radiolabelled GSK2256098 within the lung and / or heart of healthy subjects and idiopathic pulmonary arterial hypertension (iPAH) patients will be assessed using Positron Emission Tomography (PET). Based on study results the decision as to whether a follow-on phase 2 trial should be initiated to investigate the therapeutic utility of GSK2256098 in iPAH will be decided. Sufficient number of subjects will be screened (up to 30 days prior to scan) to enrol 12 healthy subjects and 12 PAH patients in the study. Enrolled subjects will receive a microdose of [11C]-GSK2256098 on a scanning day which will be followed by the follow-up visit (2-4 weeks post-last dose).

开始日期2015-11-17

申办/合作机构

GSK Plc

NCT02523014 / Recruiting临床2期IIT

Phase II Trial of SMO/ AKT/ NF2/CDK Inhibitors in Progressive Meningiomas With SMO/ AKT/ NF2/CDK Pathway Mutations

This phase II trial studies how well vismodegib, focal adhesion kinase (FAK) inhibitor GSK2256098, and capivasertib work in treating patients with meningioma that is growing, spreading, or getting worse (progressive). Vismodegib, FAK inhibitor GSK2256098, capivasertib, and abemaciclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

开始日期2015-08-01

申办/合作机构

Alliance Foundation Trials LLC

[+4]

100 项与 GSK-2256098 相关的临床结果

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100 项与 GSK-2256098 相关的转化医学

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100 项与 GSK-2256098 相关的专利（医药）

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项与 GSK-2256098 相关的文献（医药）

2024-12-01·BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

Modeling of FAK-PROTAC candidates from GSK2256098 analogs for targeted protein degradation

Article

作者: Lee, Keun Woo ; Parate, Shraddha ; Jung, Tae Sung ; Kumar, Vikas ; Ro, Hyeon-Su

Protein inhibition via the traditional drug-designing approach has been shown to be an effective method for developing numerous small-molecule-based therapeutics. In the last decade, small inhibitors-guided protein degradation has arisen as an alternative method with the potential to fulfill the drug requirement for undruggable targets. Focal adhesion kinase (FAK) is a crucial modulator of the growth and spread of tumors, apart from it also acts as a scaffold for signaling of other proteins. FAK inhibitors have thus far had unsatisfactory results in clinical trials for cancer applications. Unlike prior attempts to control FAK expression, which were restricted to kinase domain inhibition with limited success in clinical research, protein degradation has the potential to concurrently disrupt FAK's kinase and scaffolding function. Recently, several FAK degraders were reported based on FAK Type I inhibitors using complex chemical synthesis approaches. Interestingly, recently a ternary complex was published revealing the binding mode of the FAK-PROTAC-E3 complex. This complex opens an avenue for the development of rational PROTAC design against FAK protein. Therefore, in the present study, we selected the most active Type I FAK inhibitor GSK2256098. The binding mode of the inhibitor prompted us to identify the most suitable analog for PROTAC design. We have identified a high-affinity analog that is suitable for PTOTAC design through the application of molecular docking (MD) and molecular dynamics simulations (MDS). Further based on the ternary FAK-PROTAC-E3 complex we build a binary complex FAK-Hit-E3-VHL between both proteins. Using the structure-based approach ten different potential FAK PROTACs candidates were designed. The stability of the complexes was analyzed using MDS and binding free energies were used to predict the binding affinity. Finally, based on desirable intermolecular interactions with the target and E3 ligase ProTAC4 was selected as the best candidate when compared with known FAK PROTAC GSK215.

2023-01-20·Journal of clinical oncology : official journal of the American Society of Clinical Oncology

Alliance A071401: Phase II Trial of Focal Adhesion Kinase Inhibition in Meningiomas With Somatic NF2 Mutations

Article

作者: Senecal, Francis M. ; Barker, Frederick G. ; Martinez-Lage, Maria ; De La Fuente, Macarena ; Dunn, Ian F. ; Kunschner-Ronan, Lara J. ; Brown, Paul D. ; Shonka, Nicole ; Schiff, David ; Iafrate, A. John ; Twohy, Erin L. ; Knopp, Michael ; Vora, Shivangi ; Brastianos, Priscilla K. ; Carrillo, Jose ; Iwamoto, Fabio ; Lennerz, Jochen ; Santagata, Sandro ; Kaufmann, Timothy J. ; Giannini, Caterina ; Cachia, David ; Carrero, Xiomara W. ; Cohen, Adam L. ; Taylor, Jennie W. ; Chaudhary, Rekha ; Gerstner, Elizabeth R. ; Monga, Varun ; Chowdhary, Sajeel A. ; Bettegowda, Chetan ; Cahill, Daniel P. ; Sarkaria, Jann ; Morrison, Tara ; Welch, Mary R. ; Galanis, Evanthia ; Piccioni, David E. ; Damek, Denise ; Thomas, Alissa A. ; Ansstas, George ; Kaley, Thomas ; Jaeckle, Kurt A. ; Geyer, Susan ; Anderson, Mark D. ; Jeyapalan, Suriya ; Kumthekar, Priya ; Fadul, Camilo E.

PURPOSE:

Patients with progressive or recurrent meningiomas have limited systemic therapy options. Focal adhesion kinase (FAK) inhibition has a synthetic lethal relationship with NF2 loss. Given the predominance of NF2 mutations in meningiomas, we evaluated the efficacy of GSK2256098, a FAK inhibitor, as part of the first genomically driven phase II study in recurrent or progressive grade 1-3 meningiomas.

PATIENTS AND METHODS:

Eligible patients whose tumors screened positively for NF2 mutations were treated with GSK2256098, 750 mg orally twice daily, until progressive disease. Efficacy was evaluated using two coprimary end points: progression-free survival at 6 months (PFS6) and response rate by Macdonald criteria, where PFS6 was evaluated separately within grade-based subgroups: grade 1 versus 2/3 meningiomas. Per study design, the FAK inhibitor would be considered promising in this patient population if either end point met the corresponding decision criteria for efficacy.

RESULTS:

Of 322 patients screened for all mutation cohorts of the study, 36 eligible and evaluable patients with NF2 mutations were enrolled and treated: 12 grade 1 and 24 grade 2/3 patients. Across all grades, one patient had a partial response and 24 had stable disease as their best response to treatment. In grade 1 patients, the observed PFS6 rate was 83% (10/12 patients; 95% CI, 52 to 98). In grade 2/3 patients, the observed PFS6 rate was 33% (8/24 patients; 95% CI, 16 to 55). The study met the PFS6 efficacy end point both for the grade 1 and the grade 2/3 cohorts. Treatment was well tolerated; seven patients had a maximum grade 3 adverse event that was at least possibly related to treatment with no grade 4 or 5 events.

CONCLUSION:

GSK2256098 was well tolerated and resulted in an improved PFS6 rate in patients with recurrent or progressive NF2-mutated meningiomas, compared with historical controls. The criteria for promising activity were met, and FAK inhibition warrants further evaluation for this patient population.

2022-12-01·Journal of gastrointestinal oncology

A phase II trial of GSK2256098 and trametinib in patients with advanced pancreatic ductal adenocarcinoma

Article

作者: Goodwin, Rachel ; Hedley, David ; Jang, Gun Ho ; Ali, Saara ; Dhani, Neesha ; Wang, Lisa ; Zhang, Tong ; Aung, Kyaw L ; Fischer, Sandra E ; Siu, Lillian L ; Welch, Stephen ; Lovell, Sophia ; Gallinger, Steven ; Ramachandran, Makilpriya ; Knox, Jennifer J ; McWhirter, Elaine ; Stockley, Tracy L ; Makepeace, Barbara ; Bedard, Philippe L ; Malpage, Anne ; Stayner, Lee-Anne

Background:

Mitogen-activated protein kinase kinase (MEK) is activated by mutated KRAS in >90% of pancreatic ductal adenocarcinoma (PDAC). MEK and focal adhesion kinase (FAK) are frequently co-activated in PDAC providing a rationale for combining trametinib, an oral allosteric MEK1/2 inhibitor, with GSK2256098, an oral FAK inhibitor.

Methods:

Advanced PDAC patients whose disease progressed after first line palliative chemotherapy were treated with GSK2256098 250 mg twice daily and trametinib 0.5 mg once daily orally. The primary endpoint was clinical benefit (CB; complete response, partial response, or stable disease ≥24 weeks). Twenty-four patients were planned to enroll using a 2-stage minimax design (P₀=0.15, P₁=0.40; alpha =0.05, power 0.86). The combination would be considered inactive if 2/12 or fewer patients achieved CB at the end of stage 1, and would be considered active if >7/24 response-evaluable patients achieved CB by the end of stage 2. Serial blood samples were collected for circulating tumor DNA (ctDNA) mutation profiling.

Results:

Sixteen patients were enrolled and 11 were response evaluable. Of those 11, 10 had progressive disease as best tumor response and one had stable disease for 4 months. No treatment related grade ≥3 adverse events (AEs) were observed. The median progression free survival (PFS) was 1.6 (95% CI: 1.5-1.8) months and the median overall survival (OS) was 3.6 (95% CI: 2.7-not reached) months. One response-inevaluable patient achieved clinical stability for 5 months with reduction in CA19-9 and ctDNA levels with a MAP2K1 treatment resistance mutation detected in ctDNA at clinical progression.

Conclusions:

The combination of GSK2256098 and trametinib was well tolerated but was not active in unselected advanced PDAC.

项与 GSK-2256098 相关的新闻（医药）

2023-05-08

·PRNewswire

Global Pancreatic Cancer Competitive Landscape Report 2023: Comprehensive Insights about 250+ Companies and 300+ Drugs

DUBLIN, May 8, 2023 /PRNewswire/ -- The "Pancreatic Cancer - Competitive landscape, 2023" report has been added to ResearchAndMarkets.com's offering. This "Pancreatic Cancer- Competitive landscape, 2023" report provides comprehensive insights about 250+ companies and 300+ drugs in Pancreatic Cancer Competitive landscape. It covers the therapeutics assessment by product type, stage, route of administration, and molecule type. It further highlights the inactive pipeline products in this space. In March 2023, Adaptimmune Therapeutics plc. and TCR Therapeutics Inc. (NASDAQ: TCRR), announced entry into a definitive agreement under which Adaptimmune will combine with TCR in an all-stock transaction to create a preeminent cell therapy company focused on treating solid tumors. The combination provides extensive benefits for clinical development and product delivery supported by complementary technology platforms. As a result, and following the closing of the transaction, it is anticipated that the combined company's cash runway will extend into 2026. In February 2023, Akamis Bio, announced an expansion of its ongoing partnership with the Parker Institute for Cancer Immunotherapy (PICI) to include a clinical collaboration with the Cancer Research Institute (CRI) that will focus on advancing novel treatments for pancreatic cancer. As part of the Akamis Bio, PICI, and CRI partnership, NG-350A, an immuno-stimulatory tumor gene therapy driving intratumoral expression of a CD40 agonist monoclonal antibody, will be evaluated in combination with standard-of-care chemotherapy and the CTLA-4 inhibitor ipilimumab (YERVOY). In February 2023, Gritstone bio, Inc. announced that it has entered into a clinical trial agreement with the National Cancer Institute (NCI), an institute of the National Institutes of Health, to evaluate an autologous T cell therapy expressing a T cell receptor targeting mutated KRAS in combination with Gritstone's KRAS-directed vaccine candidate, SLATE-KRAS, in a Phase 1 study. Under the terms of the agreement, NCI will identify patients with metastatic cancer that are eligible for adoptive cell transfer based on the presence of a G12V or G12D KRAS mutation (KRASmut). In February 2023, Keymed Biosciences Inc., jointly announced a global exclusive license agreement with AstraZeneca for CMG901, a potential first-in-class Claudin 18.2 antibody drug conjugate (ADC). Under the license agreement, AstraZeneca will be responsible for the research, development, manufacture and commercialization of CMG901 globally. CMG901 is currently in a Phase I clinical trial for the treatment of Claudin 18.2-positive solid tumors. In January 2023, AIM ImmunoTech Inc. announced it has entered into an external sponsored collaborative clinical research agreement with Erasmus MC and AstraZeneca. Under the agreement, Erasmus MC is planning to perform an investigator-initiated clinical study, entitled "Combining anti-PD-L1 immune checkpoint inhibitor durvalumab with TLR-3 agonist rintatolimod in patients with metastatic pancreatic ductal adenocarcinoma for therapy effect. DURIPANC Study," in which it will use both Study Drugs provided by AstraZeneca and AIM ImmunoTech. Pancreatic Cancer Analytical Perspective In-depth Commercial Assessment: Pancreatic Cancer Collaboration Analysis by Companies The Report provides in-depth commercial assessment of drugs that have been included, which comprises collaboration, agreement, licensing and acquisition - deals values trends. The sub-segmentation is described in the report which provide company-company collaboration (licensing/partnering), company academic collaboration and acquisition analysis in tabulated form. Key Questions Answered Current Treatment Scenario and Emerging Therapies: How many companies are developing Pancreatic Cancer drugs? How many Pancreatic Cancer drugs are developed by each company? How many emerging drugs are in mid-stage, and late-stage of development for the treatment of Pancreatic Cancer? What are the key collaborations (Industry-Industry, Industry-Academia), Mergers and acquisitions, licensing activities related to the Pancreatic Cancer therapeutics? What are the recent trends, drug types and novel technologies developed to overcome the limitation of existing therapies? What are the clinical studies going on for Pancreatic Cancer and their status? What are the key designations that have been granted to the emerging and approved drugs? Key Players Panbela Therapeutics ERYtech Pharma Jiangsu HengRui Medicine Co., Ltd. FibroGen Novartis AG AB Science TME Pharma AG Intensity Therapeutics Silenseed LTD SynerGene Therapeutics Elevation oncology Salspera LLC Redx Pharma Plc AIM ImmunoTech Inc. Rain Oncology Jazz Pharmaceuticals Invyte Corporation Immodulon Therapeutics Ltd GSK plc Merck Sharp & Dohme LLC Roche Helsinn Healthcare SA Argenus Inc. Actuate Therapeutics OSE Immunotherapeutics Incyte Corporation Galera Therapeutics CSPC ZhongQi Pharmaceutical Technology Astellas Pharma Global Development, Inc. NanOlogy Theriva Biologics AstraZeneca Berg, LLC Agenus ABVC BioPharma, Inc. Boehringer Ingelheim Alligator Bioscience CARsgenTherapeutics Co.,Ltd Purple Biotech Ltd. Lisata Therapeutics Chongqing Precision Biotech Co., Ltd Cybrexa Therapeutics Bold Therapeutics BioNTech SE Bristol-Myers Squibb DEKA Biosciences Senhwa Biosciences Cue Biopharma Carisma Therapeutics Inc Key Products Olaptesed pegol INT230-6 SBP-101 Masitinib NIS793 siG12D LODER SGT-53 Seribantumab Salmonella-IL2 RXC004 Rintatolimod RAIN-32 Lurbinectedin Retifanlimab IMM-101 GSK2256098 Belzutifan Atezolizumab Anamorelin AGEN1423 Elraglusib OSE2101 Epacadostat GC4711 Docetaxel Zolbetuximab NanoPac VCN-01 Danvatirsen BPM31510 Botensilimab ABV-1703 BI 907828 Mitazalimab CT041 CM24 CEND-1 CEA-targeted CAR-T cells CBX-12 BOLD-100 BNT141 BMS-813160 DK210 CX-5461 CUE-102 CT-0508 For more information about this report visit About ResearchAndMarkets.com ResearchAndMarkets.com is the world's leading source for international market research reports and market data. We provide you with the latest data on international and regional markets, key industries, the top companies, new products and the latest trends. Media Contact: Research and Markets Laura Wood, Senior Manager [email protected] For E.S.T Office Hours Call +1-917-300-0470 For U.S./CAN Toll Free Call +1-800-526-8630 For GMT Office Hours Call +353-1-416-8900 U.S. Fax: 646-607-1907 Fax (outside U.S.): +353-1-481-1716 Logo: SOURCE Research and Markets

免疫疗法引进/卖出疫苗临床1期抗体药物偶联物

100 项与 GSK-2256098 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB16106

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
脑膜瘤	临床2期	美国	-	2021-09-11
腺癌	临床2期	加拿大	GSK Plc	2016-04-01
胰腺癌	临床2期	加拿大	GSK Plc	2016-04-01
特发性肺动脉高压	临床1期	英国	GSK Plc	2015-11-17
晚期恶性实体瘤	临床1期	法国	GSK Plc	2013-11-18
晚期恶性实体瘤	临床1期	英国	GSK Plc	2013-11-18
复发性胶质母细胞瘤	临床1期	澳大利亚	GSK Plc	2010-07-27
复发性胶质母细胞瘤	临床1期	法国	GSK Plc	2010-07-27
复发性胶质母细胞瘤	临床1期	英国	GSK Plc	2010-07-27
间皮瘤	临床1期	法国	GSK Plc	-

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临床结果

适应症

分期

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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


NCT02523014 (Alliance A071401, ASCO2020) 人工标引	临床2期	脑膜瘤 NF2 Mutation	36	GSK-2256098 (Grade I meningiomas)	廠簾廠壓獵範築膚製夢(範積艱積製艱廠鑰壓衊) = 淵窪獵醖夢醖獵醖鏇鑰艱夢襯觸簾獵鏇壓壓餘 (壓蓋範鏇鏇廠餘齋範憲, 52 ~ 98)	积极	2020-05-25
				GSK-2256098 (Grade II/III meningiomas)	廠簾廠壓獵範築膚製夢(範積艱積製艱廠鑰壓衊) = 積鹹憲鹹夢網鹽廠餘願艱夢襯觸簾獵鏇壓壓餘 (壓蓋範鏇鏇廠餘齋範憲, 16 ~ 55)
NCT02551653 (CTgov)	临床1期	特发性肺动脉高压	10	GSK2256098 (PAH Participants)	蓋膚夢觸艱顧範網廠糧(網糧鬱觸構遞積窪蓋鹹) = 願醖網壓繭蓋膚鹹憲襯壓範顧膚願繭夢鬱願淵 (夢鑰襯顧衊壓艱獵遞網, 積範餘膚簾廠鏇蓋觸衊 ~ 構餘簾顧糧範繭壓繭顧) 更多	-	2018-08-17
				GSK2256098 (Healthy Volunteers)	蓋膚夢觸艱顧範網廠糧(網糧鬱觸構遞積窪蓋鹹) = 齋積繭網夢膚艱艱範顧壓範顧膚願繭夢鬱願淵 (夢鑰襯顧衊壓艱獵遞網, 廠繭齋鑰衊醖構顧鬱鹽 ~ 築繭鏇蓋觸淵齋觸遞襯) 更多
NCT02428270 (ASCO_GI2018) 人工标引	临床2期	晚期胰腺导管腺癌二线	16	trametinib+GSK2256098	顧顧蓋鹹襯窪鹹襯窪鹽(選鬱窪衊夢獵衊鏇夢餘) = 構憲網積範齋遞淵壓積膚顧積鬱膚夢獵鏇衊鬱 (選夢蓋夢繭襯鏇積夢艱, 1.5 ~ 1.8) 更多	不佳	2018-01-19
NCT01938443 (ASCO2015) 人工标引	临床1期	HR阳性/HER2低表达实体瘤	24	GSK2256098+trametinib (total population)	廠積顧鑰衊膚獵選夢憲(繭餘餘夢淵衊築築鏇製) = 醖構齋鹹艱襯夢範憲糧夢鑰鹹廠壓鹹鹽築獵積 (艱艱築顧壓餘醖膚網醖 )	积极	2015-05-20
				GSK2256098+trametinib (mesothelioma pts)	顧繭襯獵鏇遞夢糧簾繭(壓醖衊壓夢鏇淵淵憲衊) = 壓願艱觸憲簾廠範醖廠遞觸積鏇廠鬱繭廠鏇夢 (襯構獵簾鏇獵膚醖鏇廠 )