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.

Start Date01 Apr 2016

Sponsor / Collaborator

University Health Network

[+1]

NCT02551653 / CompletedPhase 1

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).

Start Date17 Nov 2015

Sponsor / Collaborator

GSK Plc

NCT02523014 / RecruitingPhase 2IIT

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.

Start Date01 Aug 2015

Sponsor / Collaborator

Alliance Foundation Trials LLC

[+4]

100 Clinical Results associated with GSK-2256098

100 Translational Medicine associated with GSK-2256098

100 Patents (Medical) associated with GSK-2256098

Literatures (Medical) associated with GSK-2256098

01 Dec 2024·BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

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

Article

Author: 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.

20 Jan 2023·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

Author: Senecal, Francis M. ; Martinez-Lage, Maria ; Barker, Frederick G. ; De La Fuente, Macarena ; Dunn, Ian F. ; Brown, Paul D. ; Kunschner-Ronan, Lara J. ; Shonka, Nicole ; Iafrate, A. John ; Schiff, David ; Knopp, Michael ; Twohy, Erin L. ; Vora, Shivangi ; Brastianos, Priscilla K. ; Carrillo, Jose ; Iwamoto, Fabio ; Lennerz, Jochen ; Santagata, Sandro ; Kaufmann, Timothy J. ; Giannini, Caterina ; Cachia, David ; Carrero, Xiomara W. ; Taylor, Jennie W. ; Cohen, Adam L. ; Gerstner, Elizabeth R. ; Chaudhary, Rekha ; Monga, Varun ; Chowdhary, Sajeel A. ; Cahill, Daniel P. ; Bettegowda, Chetan ; Sarkaria, Jann ; Welch, Mary R. ; Morrison, Tara ; 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.

01 Dec 2022·Journal of gastrointestinal oncology

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

Article

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

News (Medical) associated with GSK-2256098

08 May 2023

·www.prnewswire.com

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

ImmunotherapyLicense out/inVaccinePhase 1ADC

100 Deals associated with GSK-2256098

External Link

KEGG	Wiki	ATC	Drug Bank
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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Meningioma	Phase 2	US	-	11 Sep 2021
Adenocarcinoma	Phase 2	CA	GSK Plc	01 Apr 2016
Pancreatic Cancer	Phase 2	CA	GSK Plc	01 Apr 2016
Idiopathic pulmonary arterial hypertension	Phase 1	GB	GSK Plc	17 Nov 2015
Advanced Malignant Solid Neoplasm	Phase 1	FR	GSK Plc	18 Nov 2013
Advanced Malignant Solid Neoplasm	Phase 1	GB	GSK Plc	18 Nov 2013
Solid tumor	Phase 1	AU	GSK Plc	27 Jul 2010
Mesothelioma	Phase 1	FR	GSK Plc	-
Mesothelioma	Phase 1	GB	GSK Plc	-

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02523014 (Alliance A071401, ASCO2020) Manual	Phase 2	Meningioma NF2 Mutation	36	GSK-2256098 (Grade I meningiomas)	eqctazgehe(krrhjvsckh) = yjzrwewjwd petlulvscp (znlcqkddvi, 52 - 98)	Positive	25 May 2020
				GSK-2256098 (Grade II/III meningiomas)	eqctazgehe(krrhjvsckh) = ibbsvygskh petlulvscp (znlcqkddvi, 16 - 55)
NCT02551653 (CTgov)	Phase 1	Idiopathic pulmonary arterial hypertension	10	GSK2256098 (PAH Participants)	jnidmksazx(fydomfptai) = ylfxwablkn bolvacegjn (orcvhqxlhn, celrkhgfon - vgwyebbqhv) View more	-	17 Aug 2018
				GSK2256098 (Healthy Volunteers)	jnidmksazx(fydomfptai) = iyytjjcvfc bolvacegjn (orcvhqxlhn, qcjesjpvdj - xuehxwbusq) View more
NCT02428270 (ASCO_GI2018) Manual	Phase 2	Advanced Pancreatic Ductal Adenocarcinoma Second line	16	trametinib+GSK2256098	aubykmfwov(qzoneqskiy) = jyyihjfgjm nczsaxjcml (aifceajqhm, 1.5 - 1.8) View more	Negative	19 Jan 2018
NCT01938443 (ASCO2015) Manual	Phase 1	HR-positive/HER2-low Solid Tumors	24	GSK2256098+trametinib (total population)	uhydkqclyw(yxqrrzayzb) = qraahmvsot upnilkmror (vmmrjchlqg )	Positive	20 May 2015
				GSK2256098+trametinib (mesothelioma pts)	yxjeqanxym(aeviicrmiy) = eujocvhrmt rikwrzsjuo (wnyjqndhbw )
NCT01138033 (ASCO2012)	Phase 1	HR-positive/HER2-low Solid Tumors	57	GSK2256098	njpmctkydf(fproofssfp) = mzpybybarh jgpoyraexe (ijhftoqpja ) View more	-	20 May 2012

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