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 Date07 Apr 2025

Sponsor / Collaborator

The Sidney Kimmel Comprehensive Cancer Center

[+2]

NCT06385119

/ CompletedPhase 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 following in two parts:
Part A
* 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.
Part B
* To examine the effect of a high-fat and a low-fat meal versus fasted state on the single dose PK of plixorafenib administered alone.
* To examine the effect of a low-fat meal versus fasted state on the single dose PK of plixorafenib administered with cobicistat.
* To determine the safety of plixorafenib administered alone or with cobicistat (low-fat meal only) in a single dose regimen.

Start Date24 Apr 2024

Sponsor / Collaborator

Fore Biotherapeutics, Inc.

NCT05503797

/ RecruitingPhase 2

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 With Cancer Harboring BRAF Alterations

The objective of this Master Protocol is to evaluate the efficacy and safety of plixorafenib in participants with locally advanced or metastatic solid tumors, or recurrent or progressive primary central nervous system (CNS) tumors harboring BRAF fusions, or in participants with rare BRAF V600-mutated solid tumors, melanoma, thyroid, or recurrent primary CNS tumors.

Start Date21 Feb 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

06 Jan 2025·Theranostics

Oncogenic non-V600 mutations evade the regulatory machinery of RAF including the Cdc37/Hsp90 chaperone and the 14-3-3 scaffold

Article

Author: Yap, Jiajun ; Jubri, Karlina Bte ; Wan, Xiaoyu ; Tan, Nazereth Chor Boon ; Hu, Jiancheng ; Chen, Junjun ; Ma, Yiying ; Yap, Yoon Sim ; Hu, Jingyi ; Faruk, Regina ; Li, Yifan ; Fu, Nai Yang ; Lim, Yiting ; Li, Quan ; Zhang, Ge ; Wang, Mei ; Yuan, Jimin ; Lam, Paula

The Ser/Thr kinase RAF, particularly BRAF isoform is a dominant target of oncogenic mutations and many mutations have been identified in various cancers. However, how these mutations except V600E evade the regulatory machinery of RAF protein and hence trigger its oncogenicity remains unclear. Methods: In this study, we used mutagenesis, peptide affinity assay, immunoprecipitation, immunoblot, and complementary split luciferase assay as well as mouse xenograft tumour model to investigate how the function of RAF is cooperatively regulated by Cdc37/Hsp90 chaperones and 14-3-3 scaffolds and how this regulatory machinery is evaded by prevalent non-V600 mutations. Results: We found that Cdc37/Hsp90 chaperones engaged with mature BRAF proteins promoted together with 14-3-3 scaffolds a switch of BRAF proteins from active open dimers into inactive close monomers. Most non-V600 mutations were enriched on or around the Cdc37/Hsp90-binding segments of BRAF, which impair association of CDc37/Hsp90 chaperones with BRAF and hence trap BRAF in active open conformation favouring dimerization. These BRAF mutants with high dimer propensity sustained a prolonged ERK signaling, and were effectively targeted by RAF dimer breaker plx8394 in vitro and in vivo. In contrast, CRAF and ARAF existed as immature monomers highly packaged with Cdc37/Hsp90 chaperones, which will be released upon dimerization driven by RAS-GTP binding with their N-terminus as well as 14-3-3 scaffold association with their C-terminus. Mature CRAF and ARAF dimers also sustained a prolonged ERK signaling as non-V600 BRAF mutants by virtue of absence of the C-terminal Cdc37/Hsp90-binding segment. Conclusions: Cdc37/Hsp90 chaperones and 14-3-3 scaffolds cooperatively facilitate the switch of RAF proteins from open active dimers to close inactive monomers. Non-V600 mutations disrupt this regulatory machinery, and trap RAF in dimers, which could be targeted by RAF dimer breakers.

10 Oct 2024·JOURNAL OF CHEMICAL AND ENGINEERING DATA

Beyond the Veil: Free Energy Profiles and Partition Coefficients for Antimelanoma Drugs in Self-Assembled Nanomicelles via COSMOmic and Atomistic Molecular Dynamics Simulations

Author: Pricl, Sabrina ; Cavalieri, Gabriele ; Marson, Domenico ; Laurini, Erik ; Fermeglia, Maurizio ; Mio, Andrea

This study investigates the encapsulation efficiency (EE) and mol. interactions between amphiphilic dendrimer nanomicelles (AD NMs) and six BRAF inhibitors (BRAFis) used in melanoma treatment: dabrafenib (DAB), vemurafenib (VEM), ponatinib (PON), AZ 628 (AZ), PLX8394 (PLX), and encorafenib (ENC).Exptl. determination of EE coupled with computational methods, including mol. dynamics and COSMOmic simulations, was employed to explore the drug encapsulation behavior.The results indicate efficient encapsulation of all BRAF inhibitors by AD NMs with different EE values.DAB, ENC, and PLX exhibit a higher EE (∼75%), while VEM, AZ, and PON show slightly lower encapsulation efficiency (∼60%).Mol. dynamics and COSMOmic simulations identify three binding positions (POS 1, POS 2, POS 3) within the nanocarrier, revealing preferential sites for each BRAFi.Hydrophobic interactions dominate in POS 1, while electrostatic forces play a crucial role in POS 2 and POS 3.Partition coefficient (logK) anal. shows that DAB, ENC, and PLX have higher affinity for the nanocarrier.This study combines exptl. and computational insights to improve understanding of BRAFi-AD NM interactions, essential for optimizing drug delivery systems and advancing the development of melanoma treatment.

01 Aug 2024·Life Science Alliance

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

Article

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

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.

News (Medical) associated with Plixorafenib

09 Jan 2025

·www.businesswire.com

FORE Biotherapeutics Highlights Recent Pipeline Achievements for its Targeted-Oncology Program and Provides Strategic Objectives for 2025

PHILADELPHIA--( BUSINESS WIRE )--FORE Biotherapeutics, a registration stage biotherapeutics company dedicated to developing targeted therapies to treat patients with cancer, today highlighted its recent pipeline achievements and provided its key strategic objectives for 2025. William Hinshaw, Chief Executive Officer of Fore Biotherapeutics, will detail progress and discuss anticipated milestones in a presentation at the 43 rd Annual J.P. Morgan Healthcare Conference. The presentation will take place on Tuesday, January 14, 2025, at 5:30 p.m. PT in San Francisco, CA. “ 2025 will be an exciting year at Fore, with multiple value-creating catalysts anticipated in the near-term across our trials. Our focus in 2025 will be continued execution of our differentiated monotherapy development of plixorafenib, which represents a multi-billion dollar opportunity, and the potential for expansion into developing plixorafenib as a combination agent. Plixorafenib’s unique mechanism of action supports the potential to reset the standard for patients with BRAF driven tumors, which have been underserved and underpenetrated due to the limitations of current agents. Plixorafenib is designed to inhibit not only the constitutively active BRAFV600 monomers targeted by first-generation RAF inhibitors, but also disrupt constitutively active dimeric BRAF class II mutants, fusions, splice variants and others, which differentiates it from current approved therapies. We are encouraged by the compelling safety and efficacy profile we have seen and the progress in our registrational trials,” said William Hinshaw, Chief Executive Officer of Fore. 2024 Achievements Strengthened Leadership Team: In 2024, Fore strengthened its leadership team with the appointment of William Hinshaw as Chief Executive Officer, Michael Byrnes as Chief Financial Officer and Payman Darouian, as Senior Vice President, Corporate Development, Strategy and Commercial. The new management team brings extensive experience from large pharmaceutical companies and multiple high-growth, publicly traded biotechnology companies adding to the strong existing capabilities of the team. Continued Execution of FORTE Master Protocol: The FORTE Master Protocol is a global clinical trial which includes baskets evaluating plixorafenib in distinct patient populations. The three monotherapy indications currently under evaluation are BRAF V600 Recurrent Primary Central Nervous System (CNS) Tumors, Rare BRAF V600 Mutated Solid Tumors and Solid Tumors with BRAF Fusions. Advanced Plixorafenib in BRAF V600 Recurrent Primary Central Nervous System Tumors: Continued enrollment in registration-intended basket in up to 50 patients with BRAF V600-mutated recurrent primary CNS tumors. This BOP2 design trial enrolls patients who are naïve to MAPK pathway inhibitor (MAPKi) treatment. Major efficacy endpoints include overall response rate (ORR) and duration of response (DOR). The study builds upon a previous clinical trial of plixorafenib in which six out of nine, or 67%, of MAPKi naïve adults with recurrent BRAF V600-mutated primary CNS tumors demonstrated a partial response (PR) with a median DOR (mDOR) of 13.9 months. Advanced Plixorafenib in Rare BRAF V600 Mutated Solid Tumors: Initiated enrollment in registration-intended basket in up to 75 patients with rare BRAF V600-mutated solid tumors. This BOP2 design trial enrolls patients who are naïve to MAPKi treatment. Major efficacy endpoints include ORR and DOR. The study builds upon a previous clinical trial of plixorafenib in which 42% of MAPKi naïve adults with BRAF V600-mutated solid tumors demonstrated a PR with a mDOR of 17.8 months. Advanced Plixorafenib in Solid Tumors with BRAF Fusions: Continued enrollment in registration-intended basket in up to 75 patients with BRAF fusion advanced solid tumors. This BOP2 design trial enrolls patients with tumors harboring BRAF fusions, excluding those with prior treatment with MAPK inhibitors as well as patients with colorectal or pancreatic ductal adenocarcinoma. The primary endpoint is ORR, as determined by RANO criteria or RECIST v1.1 for primary CNS tumors or other solid tumors, respectively. The study builds upon a previous clinical trial of plixorafenib that demonstrated promising single agent activity including one complete response with a DOR of 66.7+ months, one PR with a DOR of 9.2+ months, and seven stable disease, out of 14 adults evaluable for efficacy. Reported Supportive Nonclinical Data at AACR 2024: Fore reported nonclinical data at AACR 2024 demonstrating that plixorafenib in combination with binimetinib, a MEK inhibitor, is more potent than other BRAF and pan-RAF inhibitors combined with binimetinib, as well as the synergistic activity of plixorafenib with MEK inhibition across all BRAF alterations tested. Reported Supportive Safety and Efficacy Data at International Symposium on Pediatric Neuro-Oncology (ISPNO 2024): Fore reported safety and efficacy data at ISPNO 2024 building on the existing evidence of plixorafenib in children and adults with BRAF-altered recurrent primary CNS tumors. Reported Supportive Safety and Efficacy Data in Ovarian Cancer at 15 th Biennial Ovarian Cancer Research Symposium (OCRS): Fore reported safety and efficacy data at OCRS 2024, including durable partial responses in three out of three patients with BRAF V600-mutated ovarian cancer, who were all heavily pre-treated. 2025 Strategic Objectives and Anticipated Milestones Continued Execution of the FORTE Master Protocol with Interim Analyses in Three Monotherapy Indications Anticipated in 2025 BRAF V600 Primary Recurrent Central Nervous System Tumors: An interim efficacy analysis from the first 25 evaluable patients is anticipated to be conducted in the third quarter of 2025. Pending a positive recommendation from the data monitoring committee, topline data from this trial would be anticipated in the second half of 2026. The company anticipates that this trial, with sufficient demonstration of safety and efficacy, would enable the submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) under the Accelerated Approval pathway. Rare BRAF V600 Mutated Solid Tumors: An interim efficacy analysis from the first 25 evaluable patients is anticipated to be conducted in the fourth quarter of 2025. Advanced Solid Tumors with BRAF Fusions: An interim efficacy analysis from the first 25 evaluable patients is anticipated to be conducted in the fourth quarter of 2025. 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 FORTE, a global registrational basket trial to support three distinct indications. For more information, please visit www.fore.bio or follow us on X and LinkedIn .

Clinical ResultExecutive Change

19 Dec 2024

·www.businesswire.com

FORE Biotherapeutics to Present at the 43rd Annual J.P. Morgan Healthcare Conference

PHILADELPHIA--( BUSINESS WIRE )--FORE Biotherapeutics, a registration stage biotherapeutics company dedicated to developing targeted therapies to treat patients with cancer, today announced that William Hinshaw, Chief Executive Officer of Fore Biotherapeutics, will present at the 43 rd Annual J.P. Morgan Healthcare Conference. The presentation will take place on Tuesday, January 14, 2025, at 5:30 p.m. PT at the Westin St. Francis Hotel in San Francisco. Mr. Hinshaw will detail progress and anticipated milestones for Fore’s lead asset, plixorafenib, a novel, small-molecule, next generation, orally available selective inhibitor of mutated BRAF. Plixorafenib is currently being evaluated in a clinical trial with registrational intent in three distinct indications. 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 .

Phase 1

05 Dec 2024

·www.businesswire.com

FORE Biotherapeutics to Participate in the Wells Fargo Virtual Private Biotech Symposium

PHILADELPHIA--( BUSINESS WIRE )--FORE Biotherapeutics today announced that the Company will participate in the Wells Fargo Virtual Private Biotech Symposium on Thursday, December 12. William Hinshaw, Chief Executive Officer and Michael Byrnes, Chief Financial Officer, 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 .

Phase 1

100 Deals associated with Plixorafenib

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
BRAF mutation Solid Tumors	Phase 2	United States	Fore Biotherapeutics, Inc.	21 Feb 2023
BRAF mutation Solid Tumors	Phase 2	Australia	Fore Biotherapeutics, Inc.	21 Feb 2023
BRAF mutation Solid Tumors	Phase 2	Canada	Fore Biotherapeutics, Inc.	21 Feb 2023
BRAF mutation Solid Tumors	Phase 2	France	Fore Biotherapeutics, Inc.	21 Feb 2023
BRAF mutation Solid Tumors	Phase 2	Germany	Fore Biotherapeutics, Inc.	21 Feb 2023
BRAF mutation Solid Tumors	Phase 2	Italy	Fore Biotherapeutics, Inc.	21 Feb 2023
BRAF mutation Solid Tumors	Phase 2	Spain	Fore Biotherapeutics, Inc.	21 Feb 2023
BRAF mutation Solid Tumors	Phase 2	Sweden	Fore Biotherapeutics, Inc.	21 Feb 2023
BRAF mutation Solid Tumors	Phase 2	United Kingdom	Fore Biotherapeutics, Inc.	21 Feb 2023
BRAF V600 mutation-positive Melanoma	Phase 2	United States	Fore Biotherapeutics, Inc.	21 Feb 2023

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02428712 (CTNI-76, SNO2023)	Phase 1/2	Central Nervous System Neoplasms BRAF-altered \| BRAFV600+	113	Plixorafenib 900-3600 mg/day	shiinybnsv(gqolzdfjda) = exxnnfietk vrodzfvctu (ehmjdcpqcx )	Positive	10 Nov 2023
NCT02428712 (ASCO 12023 \| ASCO 22023) Manual	Phase 2	BRAF-mutation brain cancer \| HR-positive/HER2-low Solid Tumors BRAF	110	Plixorafenib±cobicistat	rquxitllur(qtqfjstqqd) = Dose-limiting toxicities were only observed at doses ≥1500 mg/day + cobi: 1500-1800 mg/day (4) and 2700-3600 mg/day (1). sqejblcpil (jtzjdgpkur )	Positive	31 May 2023
NCT02428712 (ASCO 12023 \| ASCO 22023) Manual	Phase 1/2	HR-positive/HER2-low Solid Tumors \| Central Nervous System Neoplasms	110	FORE8394	quptjgtcpm(qpzsqlmtmx) = xlmlrdjfqh cekuywytxk (qhrsrvqxmc ) View more	Positive	26 May 2023
NCT02428712 (ASCO 12023 \| ASCO 22023) Manual	Phase 1/2		110	FORE8394 (pts with MAPKi-naïve, V600 mutant tumors (excluding colorectal cancer [CRC]))	mhdxiwutyw(xukwnnnwkl) = ptzubgnint odgzodorwx (yuucerrpgg )	Positive	26 May 2023
NCT02428712 (ESMO2020)	Phase 1/2	Advanced cancer	69	PLX8394	owklaphvwn(udtvqajszg) = 4 pts ntnlwvbaav (wwpwmmdwua ) View more	Positive	18 Sep 2020
NCT02428712 (ASCO 12018 \| ASCO 22018) Manual	Phase 1/2	BRAF mutation Solid Tumors BRAF Mutation	31	PLX8394+cobicistat	hgwxcxanwx(mtgrsdevbx) = zqoexamdzp nscydrevlz (shelmcoclp )	Positive	04 Jun 2018
NCT02428712 (ASCO 12018 \| ASCO 22018) Manual	Phase 1/2	BRAF mutation Solid Tumors BRAF Mutation	31	PLX8394+cobicistat	vfcjegxtwj(jncaaqxibm) = luanyaomus aktwhadsdh (yparbjjukl ) View more	Positive	04 Jun 2018

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