PO.CTP01.02 · 进行中的临床试验
FORTE: A phase 2 master protocol assessing plixorafenib for BRAF-altered cancers
作者与单位
摘要 Abstract
BACKGROUND
Plixorafenib (FORE8394; PLX8394) is a novel, oral, small-molecule BRAF inhibitor and paradox breaker highly selective for BRAF V600 monomers and BRAF-containing dimers, including fusions. Plixorafenib binding disrupts RAF dimerization and prevents paradoxical MAPK pathway activation, avoiding the need for combination with a MEK inhibitor. Plixorafenib demonstrated in vitro activity against V600 and non-V600 mutant BRAF proteins, and anti-tumor activity has been demonstrated in BRAF V600 and non-V600 nonclinical models.
In a phase 1/2a study, plixorafenib demonstrated promising safety and clinical activity across a range of doses tested in tumors with BRAF V600 mutations and BRAF fusions. The most common adverse events included predominantly grade 1-2 liver function test changes and grade 1 fatigue, nausea, diarrhea, and vomiting.
The ongoing FORTE basket study is assessing the safety and efficacy of plixorafenib as monotherapy in participants with BRAF-altered advanced solid tumors.
METHODS
The FORTE study is currently enrolling participants ≥10 years of age (to be expanded to ≥8 years upon N=6 pediatric patients and IDMC approval) into 4 baskets. Study details are shown in the Table. Eligible participants have received available therapies for advanced disease, have measurable disease, and have a Karnofsky (≥16 years) or Lansky (<16 years) Performance Score of ≥60 at study entry. All participants receive plixorafenib continuous dosing once daily within 30 minutes following a meal. Prior MAPK inhibitor therapy is excluded unless otherwise specified below.
As of January 2026, the trial is recruiting participants in 11 countries globally, with 64 sites currently activated. To date, over 100 patients are enrolled. Clinical trial registry number: NCT05503797.
Table Sub-Protocol A Sub-Protocol B Sub-Protocol C Sub-Protocol D Participant Population Advanced solid and primary CNS tumors harboring BRAF fusions BRAF V600-mutated recurrent primary CNS tumors Rare 1 BRAF V600-mutated advanced solid tumors BRAF V600-mutated selected solid tumors 2 Planned Enrollment Approximately 100 Approximately 50 Approximately 75 Approximately 15-30 Design Single-arm, open-label BOP2 design Single-arm, open-label design Planned Efficacy Interim Analyses N=25
N=50 N=25 (completed) N=25
N=50 None Primary Endpoint ORR 3 PK Key Additional Endpoints DOR, DCR, PFS, OS, PK, Safety Safety, ORR, DOR, DCR, PFS, OS Key Exploratory Endpoint Longitudinal ctDNA assessments 4 1 BRAF V600-mutated tumors occurring in ≤40,000 US patients annually (eg, ovarian/gynecologic cancers, cholangiocarcinoma, small intestinal and other gastrointestinal cancers other than colorectal adenocarcinoma, neuroendocrine cancers).
2 Including advanced cutaneous melanoma, MAPK inhibitor-naïve thyroid cancer, and other solid tumors with ≤1 prior MAPK inhibitor.
3 Response assessed by BICR using either RECIST v1.1 for solid tumors or RANO HGG or LGG for primary CNS tumors. ORR for primary CNS tumors using RANO 2.0 is an exploratory endpoint. Tumors assessed at cycle 1 day 1, every 9 weeks for 48 weeks, then every 12 weeks.
4 Plasma ctDNA assessments for all patients; plasma and CSF assessments for patients with primary CNS tumors.
BICR, blinded independent central review; BOP2, Bayesian optimal phase 2; CSF, cerebrospinal fluid; ctDNA, circulating tumor DNA; DCR, disease control rate; DOR, duration of response; HGG, high-grade glioma; LGG, low-grade glioma; MAPK, mitogen-activated protein kinase; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetics; RANO, Response Assessment in Neuro-oncology; RECIST, Response Evaluation Criteria in Solid Tumors.
利益披露 Disclosure
E. Fontana,
Fore Biotherapeutics Travel, Other, Funding to Institution.
ESMO Other, Personal.
Repare Therapeutics; CARIS Life Science; Seagen; Sapience; BicycleTx Ltd; Erasca Travel.
Astellas; Pfizer; BicycleTx Ltd; BMS; Erasca; BeOne; Bayer Other, Participation on a Data Safety Monitoring Board or Advisory Board.
European Organisation for Research and Treatment of Cancer (EORTC); GITCG secretary (2021-2023) ASCO Annual Meeting Scientific Programme Committee GI cancers; g., Board of Directors, non-salaried role).
Colorectal and Anal Track (2024-2026) ESMO Lecturer g., Board of Directors, non-salaried role).
Acerta Pha; ADC Therapeutics; Alterome; Amgen; Apollo therapeutics; Arcus Bioscience; Array Biopharma; Artios Pharma; Astellas; Astex; AstraZeneca; Aveo Pharmaceuticals; Basilea Pharmaceutical; Bayer Other, Funding to Institution.
BeiGene; Bicycle Therapeutics; Bioinvent; BioNTech SE; BluePrint; BMS; Boehringer Ingelheim; Calithera; Carrick Therapeutics; Casi Therapeutics; Cellcentric; Clovis Oncology; Crescendo Biologics; Other, Funding to Institution.
Cronos Bio; CytomX Therapeutics; Daiichi Sankyo; Deciphera; ED Therapeutics; EliLilly; Elipsees; Erasca; Exelixis; G1 Therapeutics; Genentech; Gilead Science; GSK; H3 Biomedicine; HUTCHMED; Other, Funding to Institution.
Immunocore; Immunomedics; Incyte; Instil Bio; Iovance; Janssen; Jiangsu Hengrui Medicine; Keros Therapeutics; Lupin Limited; Macrogenics; Menarini; Merck KGaA; Mereo Biopharma; Other, Funding to Institution.
Merus; Millenium Pharmaceuticals; MSD; Nerviano Medica; Nurix Therapeutics; Oncologie; Oxford Vacmedix; Pfizer; Plexxikon; PMV Pharma; Pyxis Oncology; Relay Therapeutics; Repair Therapeutics; Other, Funding to Institution.
Ribon Therapeutics; Roche; Sapience Pharma; Seagen; Servier; SK plc; Synthon Biopharmaceuticals; Taiho Pharmaceutical; Takeda; Tesaro; Turning Point Therapeutics Other, Funding to Institution.
M. I. de la Fuente,
GCAR ), Other, Clinical trial support to Institution.
Servier ), Other, Consulting, Participation on a Data Safety Monitoring Board or Advisory Board, Clinical trial support to Institution.
Fore Biotherapeutics ), Other, Consulting, Participation on a Data Safety Monitoring Board or Advisory Board, Clinical trial support to Institution, Drug provided for pre-clinical work.
Caris ).
Rigel Other, Consulting, Participation on a Data Safety Monitoring Board or Advisory Board.
An-Heart Other, Consulting, Participation on a Data Safety Monitoring Board or Advisory Board.
Medscape Other, Payment or honoraria for lectures, presentations, speakers bureaus, abstract writing or educational events.
Society for Neuro-Oncology g., Board of Directors, non-salaried role).
MSKCC Other, Clinical trial support to Institution.
Peloton Other, Clinical trial support to Institution.
E. Sherman,
Fore Biotherapeutics ), Other, Consulting.
Regeneron ).
Eisai Other, Participation on a Data Safety Monitoring Board or Advisory Board.
Lilly Other, Participation on a Data Safety Monitoring Board or Advisory Board.
R. Yaeger,
Mirati Therapeutics Independent Contractor, ).
Revolution Medicines Independent Contractor, ).
Eli Lilly Independent Contractor, ).
Merck Independent Contractor.
Erasca Independent Contractor.
Parabilis Medicines Independent Contractor, ).
Alterome Independent Contractor.
Bayer Independent Contractor.
Pfizer ).
Boundless Bio Independent Contractor, ).
Daiichi Sankyo ).
CytoDyn Independent Contractor.
M. Ameratunga,
Roche ), Other, Support for the present abstract. Payments to institution.
Novotech ), Other, Payments to institution.
Beigene Aus ), Other, Payments to institution.
Senz Oncology ), Other, Payments to institution.
Alpha-9 Theranostics ), Other, Payments to institution.
Servier Laboratories ), Other, Payments to institution.
Medpace ), Other, Payments to institution.
Pharmaceutical Research Associates ), Other, Payments to institution.
Iqvia ), Other, Payments to institution.
Antengene ), Other, Payments to institution.
AACR ), Other, Grant - CIA.
Monash Partners Comprehensive Cancer Consortium ), Other, Grant - CIA.
Victorian Rare Cancers Clinical Trial Alliance g., Board of Directors, non-salaried role).
V. Gambardella,
Jansen Travel.
Boehringer Other, Participation on a Data Safety Monitoring Board or Advisory Board.
Genentech; Merck Serono; Roche; Beigene; Bayer; Servier; Lilly; Novartis; Takeda; Astelas; Fibrogen; Amcure; Natera; Sierra Oncology; AstraZeneca; Medimmune; BMS; MSD Other, Institutional Funding.
J. Rine,
Fore Biotherapeutics Employment.
S. Shahab,
Fore Biotherapeutics Employment, Stock, Stock Option, Travel.
M. Winkler,
Fore Biotherapeutics Employment.
M. Monga,
Fore Biotherapeutics Employment, Stock, Stock Option.
D. Modest,
Servier; Amgen ).
Amgen; Merck; J & J, Servier; MSD; BMS; Takeda; Taiho; AstraZeneca; Regeneron; Bicara; Rottapharm; Abbvie; Onkowissen; Cor2ED; IKF GmbH; Aio Studien gGmbH; Incyte; Pierre Fabre; 21 up; Medscape Other, Consulting, Payment or honoraria for lectures, presentations, speakers bureaus, abstract writing or educational events.
Amgen; Servier; Takeda Travel.
J. Yachnin,
Other Other, I participate in several DMC boards in our ongoing phase I studies.
M. Touat,
Sanofi ).
Amgen ).
Servier Other, Consulting, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, Participation on a Data Safety Monitoring Board or Advisory Board.
Novocure Other, Consulting, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, Participation on a Data Safety Monitoring Board or Advisory Board.
Resilience Other, Consulting.
NH TherAguix Other, Consulting.
GSK Other, Consulting.
Ono Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events.
G. de Velasco,
Pfizer; Ipsen; MSD; BMS; Janssen; Arcus Biosciences; EISAI; Genmab Other, Consulting.
Pfizer; Roche; Ipsen; Merck; MSD; BMS; Astellas; Bayer; Janssen; Novartis; Pierre Fabre; AstraZeneca; EISAI Other, Payment or honoraria for lectures, presentations, speakers bureaus, abstract writing or educational events.
J. Rodon,
European Society for Medical Oncology; American Society of Medical Oncology; Dava Oncology; STOP Cancer Travel, Other, non-financial support.
Ellipses Pharma; Lonctura; Amgen; Merus; MonteRosa; Bridgebio; Debio; Bristol Myers Squibb; BioHybrid Solutions Travel, Other, Consulting, (including serving on the scientific advisory board).
Vall d'Hebron Institute of Oncology; AstraZeneca; Boxer Capital LLC; Ecor1; Tang Advisors, LLC; Guidepoint Other, Consulting.
Blueprint Medicines; Merck Sharp & Dohme; Hummingbird; AstraZeneca; 280 Bio; Vall d'Hebron Institute of Oncology/Cancer Core Europe; Bristol Myers Squibb Other, Research funding.
Cancer Core Europe; Pfizer; Kelun-Biotech; Roche Pharmaceuticals; 280 Bio; Bicycle Therapeutics; ForeBio; Ideaya; Amgen; Tango Therapeutics; Bristol Myers Squibb; MonteRosa; Debio; Beigene; Relay; Other, investigator in clinical trials.
Novartis; Scorpion Therapeutics; Incyte; Parabilis Pharmaceuticals; Tyra; Nuvectis Pharma; Adcentrix; Vividion; AstraZenneca; Alnylam; Immuneering Corp; Alterome; Exelixis; Ensem; Bridgebio; Cogent; Other, investigator in clinical trials.
Biohaven; Insilico Medicines; Ipsen; Eli Lilly; Seed; Zai Labs Other, investigator in clinical trials.
K. C. Schreck,
Fore Biotherapeutics Other, Payments made to institution for clinical trial funding.
Springworks Therapeutics Other, Institutional funding.
Nurix Other, Consulting.
Advarra Participation on a Data Safety Monitoring Board or Advisory Board.
Society for Neuro-Oncology g., Board of Directors, non-salaried role).