Feasibility of CSF (Cerebrospinal Fluid) and Plasma ctDNA (Circulating Tumor Deoxyribonucleic) in BRAF (V-raf Murine Sarcoma Viral Oncogene Homolog B1)-Altered Glioma During Treatment With Plixorafenib

Evaluating the sensitivity and feasibility of using ctDNA assays optimized for detecting very low ctDNA counts from cerebrospinal fluid (CSF) and plasma. The investigators will evaluate the sensitivity of ctDNA from plasma and CSF at baseline (defined as Cycle1 Day1 (C1D1) pre-treatment) and over time in response to treatment with plixorafenib co-administered with cobicistat in BRAF-V600E mutant glioma refractory to prior therapies.

Start Date15 Nov 2024

Sponsor / Collaborator

The Sidney Kimmel Comprehensive Cancer Center

[+2]

NCT06385119 / RecruitingPhase 1

A Phase 1, Open-Label, 2-Part, Single Dose, Crossover Study to Examine the Effect of Food and Cobicistat Administration on the Pharmacokinetics and Safety of Plixorafenib in Healthy Participants.

The primary goal of this phase 1 study is to evaluate the effect of food and cobicistat on the pharmacokinetics of plixerafenib in healthy volunteers. Healthy male and female participants between the ages of 18 and 55 will be enrolled into this study. This study is looking to examine:
The effect of food on the single dose PK of plixorafenib administered with cobicistat.
The effect of cobicistat administration on the single dose PK of plixorafenib.
The safety of plixorafenib administered alone and with cobicistat in a single dose regimen in healthy participants.

Start Date24 Apr 2024

Sponsor / Collaborator

Fore Biotherapeutics, Inc.

CTIS2024-513578-23-00 / Recruiting

A Phase 2 Master Protocol to assess the efficacy and safety of FORE8394,an inhibitor of BRAF class 1 and class 2 alterations, in participants withcancer harboring BRAF alterations - F8394-201

Start Date11 Jul 2023

Sponsor / Collaborator

Fore Biotherapeutics, Inc.

100 Clinical Results associated with Plixorafenib

100 Translational Medicine associated with Plixorafenib

100 Patents (Medical) associated with Plixorafenib

Literatures (Medical) associated with Plixorafenib

01 Aug 2024·Pathology - Research and Practice

Exosomal miR-19a derived from melanoma cell promotes the vemurafenib resistance of malignant melanoma through directly targeting LRIG1 to reactivate AKT and MAPK pathway

Article

Author: Luan, Wenkang ; Ruan, Hongru ; Lu, Xu ; Rao, Min ; Shen, Xuanlin ; Peng, Huiyong

Exosomes derived from neighboring v-raf murine sarcoma viral oncogene homolog B1 inhibitor (BRAFi)-resistant melanoma cells mediate the formation of resistance in melanoma cells sensitive to BRAFi. The function and molecular mechanisms of exosomal miRNA in BRAFi resistance of melanoma have not been studied. We found that the expression of miR-19a in BRAFi resistant melanoma cells was significantly higher than that in sensitive cells, and miR-19a contributes to the resistance of melanoma cells to BRAFi by targeting immunoglobulin-like domains protein 1 (LRIG1). miR-19a was highly enriched in exosomes secreted from BRAFi resistant melanoma cells, and these exosomal miR-19a promote the spread of BRAFi resistant. The reactivation of Protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) pathways is the main reason for the BRAFi resistant of melanoma cells. We demonstrated that exosomal miR-19a derived from melanoma cell promotes the formation and spread of BRAFi resistant in melanoma through targeting LRIG1 to reactivate AKT and MAPK pathway. Therefore, miR-19a may serve as a potential therapeutic target in melanoma patients with acquired drug resistance.

01 Aug 2024·Life Science Alliance

Off-targets of BRAF inhibitors disrupt endothelial signaling and vascular barrier function

Article

Author: Zadorozhna, Yuliia ; Nawrocki, Arkadiusz ; Zila, Nina ; Bromberger, Sophie ; Røssel Larsen, Martin ; Springer, Alexander ; Schossleitner, Klaudia ; Holzner, Silvio ; Ressler, Julia Maria

Targeted therapies against mutant BRAF are effectively used in combination with MEK inhibitors (MEKi) to treat advanced melanoma. However, treatment success is affected by resistance and adverse events (AEs). Approved BRAF inhibitors (BRAFi) show high levels of target promiscuity, which can contribute to these effects. The blood vessel lining is in direct contact with high plasma concentrations of BRAFi, but effects of the inhibitors in this cell type are unknown. Hence, we aimed to characterize responses to approved BRAFi for melanoma in the vascular endothelium. We showed that clinically approved BRAFi induced a paradoxical activation of endothelial MAPK signaling. Moreover, phosphoproteomics revealed distinct sets of off-targets per inhibitor. Endothelial barrier function and junction integrity were impaired upon treatment with vemurafenib and the next-generation dimerization inhibitor PLX8394, but not with dabrafenib or encorafenib. Together, these findings provide insights into the surprisingly distinct side effects of BRAFi on endothelial signaling and functionality. Better understanding of off-target effects could help to identify molecular mechanisms behind AEs and guide the continued development of therapies for BRAF-mutant melanoma.

01 Dec 2023·Oncogene

Inhibition of TGF-β signaling, invasion, and growth of cutaneous squamous cell carcinoma by PLX8394

Article

Author: Kähäri, Veli-Matti ; Siljamäki, Elina ; Rappu, Pekka ; Suwal, Ujjwal ; Heino, Jyrki ; Riihilä, Pilvi ; Nissinen, Liisa ; Kallajoki, Markku

AbstractCutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer. The prognosis of patients with metastatic cSCC is poor emphasizing the need for new therapies. We have previously reported that the activation of Ras/MEK/ERK1/2 and transforming growth factor β (TGF-β)/Smad2 signaling in transformed keratinocytes and cSCC cells leads to increased accumulation of laminin-332 and accelerated invasion. Here, we show that the next-generation B-Raf inhibitor PLX8394 blocks TGF-β signaling in ras-transformed metastatic epidermal keratinocytes (RT3 cells) harboring wild-type B-Raf and hyperactive Ras. PLX8394 decreased phosphorylation of TGF-β receptor II and Smad2, as well as p38 activity, MMP-1 and MMP-13 synthesis, and laminin-332 accumulation. PLX8394 significantly inhibited the growth of human cSCC tumors and in vivo collagen degradation in xenograft model. In conclusion, our data indicate that PLX8394 inhibits several serine-threonine kinases in malignantly transformed human keratinocytes and cSCC cells and inhibits cSCC invasion and tumor growth in vitro and in vivo. We identify PLX8394 as a potential therapeutic compound for advanced human cSCC.

News (Medical) associated with Plixorafenib

07 Nov 2024

·www.businesswire.com

FORE Biotherapeutics to Participate in Upcoming November Conferences

PHILADELPHIA--( BUSINESS WIRE )--FORE Biotherapeutics today announced that the Company will participate at the following investor conferences: Stifel 2024 Healthcare Conference. The Company will attend on Monday, November 18, and will provide a corporate presentation at 2:25 p.m. – 2:55 p.m. ET. Jefferies London Healthcare Conference. The Company will attend and participate in one-on-one meetings on Wednesday, November 20, and Thursday, November 21. Management will host and participate in one-on-one meetings. Please contact Argot Partners to schedule one-on-one meetings with the management team. About FORE Biotherapeutics Fore is a registration stage targeted oncology company dedicated to developing innovative treatments that provide better outcomes for patients with the hardest-to-treat cancers. The Company’s lead asset plixorafenib (FORE8394; formerly PLX8394) is a V600 and non-V600 BRAF inhibitor rationally designed with a first-in-class mechanism to address treatment gaps from 1 st and 2 nd generation BRAF inhibitors. Plixorafenib has demonstrated single-agent efficacy signals across a variety of tumor types with a manageable safety profile in a Phase 1/2a clinical trial of over 100 patients and is currently enrolling patients in a clinical trial with registrational intent in three distinct indications. For more information, please visit www.fore.bio or follow us on X and LinkedIn .

04 Sep 2024

·www.businesswire.com

FORE Biotherapeutics to Participate in Upcoming Investor Conferences

PHILADELPHIA--( BUSINESS WIRE )--FORE Biotherapeutics today announced that the Company, will participate at the following investor conferences: Cantor 2024 Global Healthcare Conference. The Company will attend and participate in one-on-one meetings on Wednesday, September 18. UBS 2024 Virtual Biotechnology Private Company Symposium. The Company will attend on Thursday, September 19, and will provide a corporate presentation from 10:00 a.m. – 10:25 a.m. ET. Bank of America Healthcare Trailblazers Private Company Conference. The Company will attend and participate in one-on-one meetings on Wednesday, September 25. RBC Capital Markets 2024 Virtual Biotechnology Private Company Conference. The Company will attend on Tuesday, October 1, and will sit for a fireside chat from 10:40 a.m. – 11:10 a.m. ET. Management will host and participate in one-on-one meetings. Please contact Argot Partners to schedule one-on-one meetings with the management team. About FORE Biotherapeutics Fore Bio is a precision oncology company dedicated to developing innovative treatments that provide better outcomes for patients with the hardest-to-treat cancers. The Company’s lead asset plixorafenib (FORE8394; formerly PLX8394) is a V600 and non-V600 BRAF inhibitor with manageable clinical safety and early efficacy signals in an ongoing Phase 1/2a clinical trial. The Fore Bio research and development team is optimizing drug development by identifying existing compounds with known clinical profiles and a clear path through clinical development to advance new medicines for patients without treatment options. For more information, please visit www.fore.bio or follow us on X (formerly Twitter) and LinkedIn .

09 Apr 2024

·www.biospace.com

FORE Biotherapeutics to Present Nonclinical Data at the 2024 AACR Annual Meeting Supporting Superior Potency for Plixorafenib Compared with BRAF or Pan-Raf Inhibitors, When Combined with MEK Inhibition

PHILADELPHIA--(BUSINESS WIRE)-- FORE Biotherapeutics today announced new nonclinical data related to plixorafenib (FORE8394; formerly PLX8394), the company's novel, investigational, small-molecule, next-generation, orally available selective inhibitor of BRAF alterations, will be presented at the AACR Annual Meeting 2024, taking place April 5-10, 2024, in San Diego and virtually. The data show nonclinical synergistic activity of plixorafenib when combined with MEK inhibition across all BRAF alterations tested. In cells with BRAF V600 or non-V600 mutations or BRAF fusions, the combination of plixorafenib and binimetinib is most potent of the BRAF and pan-RAF inhibitors tested. In plixorafenib resistant cells, these cells can be resensitized with the addition of binimetinib. To date, plixorafenib has demonstrated encouraging efficacy and safety data from the phase 1/2a study; these nonclinical data help build the foundation for potential future development of plixorafenib in combination with a MEK inhibitor. Poster Abstract number: 4609 Poster Title: The paradox-breaker BRAF inhibitor plixorafenib (PLX8394; FORE8394) synergizes with MEK inhibitors (MEKi) in BRAF V600 and non-V600 alterations, with higher potency compared to early generation BRAFi and pan-RAFi Presentation Session Date/Time: April 9, 2024, 9:00 AM - 12:30 PM Poster Session About Plixorafenib Plixorafenib is an investigational, novel, small-molecule, next-generation, orally available selective inhibitor of mutated BRAF. It was designed to target a wide range of BRAF alterations while sparing wild-type forms of RAF. Nonclinical and clinical studies have shown that its unique mechanism of action effectively inhibits not only the constitutively active BRAF V600 monomers targeted by first- and second-generation RAF inhibitors but also disrupts constitutively active dimeric BRAF class 2 mutants, fusions, splice variants and others. Unlike earlier-generation BRAF inhibitors, plixorafenib does not induce paradoxical activation of the RAF/MEK/ERK pathway. As a “paradox breaker”, plixorafenib could therefore address acquired resistance to current RAF inhibitors and, additionally, may yield improved safety and more durable efficacy than first-generation RAF inhibitors. Plixorafenib is currently being evaluated in two clinical trials in patients with advanced solid tumors with activating BRAF alterations. Interim clinical data from a Phase 1/2a trial presented at ESMO 2022, ASCO 2023 and SNO 2023 provided evidence of durable anti-tumor activity in patients with BRAF-mutated cancers with a 42% overall response rate and a median duration of response of 17.8 months in MAPK inhibitor-naïve participants with V600-mutated advanced solid tumors. Of the 9 patients with primary central nervous system tumors, 6 had confirmed response (ORR 67%) with a median duration of response of 13.9 months. In addition to the Phase 1/2a trial, plixorafenib is currently being investigated in the ongoing, potentially registrational Phase 2 FORTE study. About FORE Biotherapeutics Fore Bio is a precision oncology company dedicated to developing innovative treatments that provide better outcomes for patients with the hardest-to-treat cancers. The Company’s lead asset plixorafenib (FORE8394; formerly PLX8394) is a V600 and non-V600 BRAF inhibitor with manageable clinical safety and early efficacy signals in an ongoing Phase 1/2a clinical trial. The Fore Bio research and development team is optimizing drug development by identifying existing compounds with known clinical profiles and a clear path through clinical development to advance new medicines for patients without treatment options. For more information, please visit or follow us on X (formerly Twitter) and LinkedIn.

Clinical ResultAACRPhase 2Phase 1

100 Deals associated with Plixorafenib

External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB16038

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
BRAF mutation Solid Tumors	Phase 2	SE	Fore Biotherapeutics, Inc.	21 Feb 2023
BRAF mutation Solid Tumors	Phase 2	IT	Fore Biotherapeutics, Inc.	21 Feb 2023
BRAF mutation Solid Tumors	Phase 2	FR	Fore Biotherapeutics, Inc.	21 Feb 2023
BRAF mutation Solid Tumors	Phase 2	ES	Fore Biotherapeutics, Inc.	21 Feb 2023
BRAF mutation Solid Tumors	Phase 2	GB	Fore Biotherapeutics, Inc.	21 Feb 2023
BRAF mutation Solid Tumors	Phase 2	CA	Fore Biotherapeutics, Inc.	21 Feb 2023
BRAF mutation Solid Tumors	Phase 2	DE	Fore Biotherapeutics, Inc.	21 Feb 2023
BRAF mutation Solid Tumors	Phase 2	KR	Fore Biotherapeutics, Inc.	21 Feb 2023
Solid tumor	Phase 2	US	Fore Biotherapeutics, Inc.	01 Apr 2015
Leukemia	Phase 2	-	Daiichi Sankyo Co., Ltd.	-

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02428712 (ASCO2023) Manual	Phase 2	BRAF-mutation brain cancer \| HR-positive/HER2-low Solid Tumors BRAF	110	Plixorafenib±cobicistat	(qvqbcxrltc) = Dose-limiting toxicities were only observed at doses ≥1500 mg/day + cobi: 1500-1800 mg/day (4) and 2700-3600 mg/day (1). smrqwxtzvp (wbviixduyx )	Positive	31 May 2023
NCT02428712 (ASCO2023) Manual	Phase 1/2	HR-positive/HER2-low Solid Tumors \| Central Nervous System Neoplasms	110	FORE8394	(rnbhdqzqpu) = csckuesdoq ovqsiwursr (zklixnjtbf ) View more	Positive	26 May 2023
NCT02428712 (ASCO2023) Manual	Phase 1/2		110	FORE8394 (pts with MAPKi-naïve, V600 mutant tumors (excluding colorectal cancer [CRC]))	(pgpzltkwtd) = pqjndiynbl bpvpckjyxy (agjxyihpno )	Positive	26 May 2023
NCT02428712 (ESMO2020)	Phase 1/2	Advanced cancer	69	PLX8394	(grywqnxmmk) = 4 pts azkmalwwxy (ywjbssdxfd ) View more	Positive	18 Sep 2020
NCT02428712 (ASCO2018) Manual	Phase 1/2	BRAF mutation Solid Tumors BRAF Mutation	31	PLX8394+cobicistat	(ouzurcexpp) = pfakcpgcca ibzxkbcfev (amswejytmz )	Positive	04 Jun 2018
NCT02428712 (ASCO2018) Manual	Phase 1/2	BRAF mutation Solid Tumors BRAF Mutation	31	PLX8394+cobicistat	(gtthakohnx) = deeliwwfzj szjncakpxq (meiyfluwkv ) View more	Positive	04 Jun 2018

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