Cancer Harboring BRAF AlterationsPhase 2NCT05503797
A Study to Assess the Efficacy and Safety of FORE8394 in Participants With Cancer Harboring BRAF Alterations
A Phase 2 study testing Plixorafenib in people with Cancer Harboring BRAF Alterations and HGG, run by Fore Biotherapeutics at 70 sites in 12 countries.
Trial summary
The objective of this Master Protocol is to evaluate the efficacy and safety of plixorafenib in participants with BRAF altered (BRAF V600E or BRAF fusions) locally advanced or metastatic solid tumors, or recurrent or progressive primary central nervous system (CNS) tumors, including rare BRAF V600E-mutated solid… Read more about this study
- Who is it for?
- Ages 8 years and older
- Conditions the study is for
- Cancer Harboring BRAF Alterations, HGG, LGG
- What is being tested?
- Plixorafenib
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 254 participants
- Where
- 70 sitesin 12 countries
- Study dates
- 21 Feb 2023to 28 Dec 2028
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 8 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Subprotocol A:
- Male and female, ≥8 years of age, and weighing ≥25 kg.
- Histologic diagnosis of a solid tumor or primary CNS tumor.
- Documentation of BRAF gene fusion in tumor and/or blood detected by an analytically validated test by DNA sequencing or RNA (transcriptome) sequencing.
- Have an archival tissue sample available meeting protocol requirements.
- Consent to provide scan(s) prior to baseline to assess change in tumor trajectory.
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- Received all available standard therapy, is intolerant to available therapies, or the investigator has determined that treatment with standard therapy is not appropriate.
- All adverse events related to prior therapies (chemotherapy; radiotherapy; surgery) must have resolved to Grade 1 or baseline.
- Subprotocol B:
- Male and female, ≥8 years of age, and weighing ≥25 kg.
- Histological diagnosis of a primary CNS tumor, including but not limited to the following:
- Adults (≥18 years) with Grade 1-4 glioma or glioneuronal tumor (including glioblastoma, anaplastic astrocytoma, high grade astrocytoma with piloid features, pilocytic astrocytoma, gliosarcoma, anaplastic pleomorphic xanthoastrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, not otherwise specified [NOS], ganglioglioma, or recurrent LGG). OR
- Pediatric patients (8-17 years of age) with a Grade 3 or 4 glioma or glioneuronal tumor, including those with a prior, histologically confirmed, diagnosis of a low-grade glioma or glioneuronal tumor and now have radiographic or histopathological findings consistent with WHO [2021] Grade 3 or 4 primary CNS tumor.
- Participants must have unresectable, locally advanced or metastatic disease that:
- Had prior treatment with radiotherapy and/or first-line chemotherapy or concurrent chemoradiation therapy OR
- Note: Participants who have a WHO Grade 3 or 4 glioma for whom chemotherapy and/or radiotherapy is not considered standard of care may remain eligible for the study.
- Is intolerant to available therapies OR iii. The investigator has determined that treatment with standard therapy is not appropriate.
- Documented BRAF V600E mutation in tumor and/or liquid biopsy detected by an analytically validated test at CLIA or CLIA-equivalent laboratory approved by sponsor or sponsor-designated central test.
- An archival tissue sample available meeting protocol requirements, or fresh biopsy is required if the archival sample is not available for retrospective confirmation test.
- Consent to provide scan(s) prior to baseline to assess change in tumor trajectory.
- Measurable disease based upon specified response criteria, as determined by the radiographic BICR.
- All adverse events related to prior therapies (eg, chemotherapy, radiotherapy, surgery) must have resolved to Grade 1 or baseline.
- Participants who are receiving corticosteroid treatment must be on a stable or decreasing dose of ≤8 mg/day of dexamethasone or equivalent corticosteroid treatment for 7 days prior to first dose of study treatments.
- Subprotocol C:
- Male and female, ≥8 years of age, and weighing ≥25 kg.
- Histologic diagnosis of a rare BRAF V600E-mutated solid tumor that is unresectable, locally advanced or metastatic.
- Measurable disease on CT, MRI, or physical exam
- Documented BRAF V600E mutation in tumor and/or liquid biopsy detected by an analytically validated test.
- Have an archival tissue sample available meeting protocol requirements.
- Consent to provide scan(s) prior to baseline to assess change in tumor trajectory
- Received all available standard therapy, is intolerant to available therapies, or the investigator has determined that treatment with standard therapy is not appropriate.
- Subprotocol D:
- Male and female, ≥8 years of age, and weighing ≥25 kg.
- Histologic diagnosis of a solid tumor harboring a BRAF V600E mutation and not eligible for other subprotocols.
- Measurable disease on CT, MRI, or physical exam.
- Evidence of BRAF V600E mutation in tumor and/or blood detected by genomic tests.
- Consent to provide a tumor biopsy.
- Willingness to comply with the ECG substudy procedures.
- All adverse events related to prior therapies (chemotherapy; radiotherapy; surgery) must have resolved to Grade 1 or baseline.
Who cannot join
- Subprotocol A:
- Prior treatment with RAF/BRAF inhibitors active for Class 2 BRAF alterations for advanced unresectable or metastatic disease.
- Prior treatment with a MEK inhibitor.
- Tyrosine kinase inhibitor(s) and/or targeted therapies are allowed (other than BRAF/MAPK pathway inhibitors per Exclusion Criteria 3 and 4) and will be restricted to no more than the number of lines of therapy that are consistent with standard treatment guidelines.
- Malignancy with co-occurring activating RAS mutation(s) at any time.
- Uncontrolled intercurrent illness that would limit compliance with study requirements.
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- HIV infection with exceptions; discuss with treating physician.
- Have impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral plixorafenib or cobicistat (such as ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, and small bowel resection).
- Grade ≥2 changes in AST, ALT, GGT, or bilirubin attributed to prior immune checkpoint inhibitor treatment are exclusionary, even if resolved.
- Subprotocol B:
- Prior treatment with BRAF, ERK, and/or MEK inhibitor(s).
- Known or suspected neurofibromatosis-1 (NF-1) and/or RAS related gene alterations.
- Uncontrolled intercurrent illness that would limit compliance with study requirements.
- Active infection requiring systemic therapy.
- HIV infection with exceptions; discuss with treating physician.
- Have impairment of GI function or GI disease that may significantly alter the absorption of oral plixorafenib (such as ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection).
- Grade ≥ 2 changes in AST, ALT, gamma-glutamyl transaminase (GGT), or bilirubin attributed to prior immune checkpoint inhibitor treatment are exclusionary, even if resolved.
- Subprotocol C:
- Diagnosis of colorectal adenocarcinoma or pancreatic ductal adenocarcinoma (neuroendocrine or acinar tumors are eligible).
- Diagnosis of BRAF V600E-mutated cutaneous melanoma, papillary thyroid cancer, or NSCLC.
- Participant has CNS metastases.
- Prior treatment with BRAF, ERK, and/or MEK inhibitor(s), unless otherwise specified for specific tumor types (i.e. low grade serous or borderline ovarian cancer).
- Known or suspected neurofibromatosis-1 (NF-1) and/or RAS related gene alterations.
- Participants with prostate, breast, or gynecologic cancers with known activating mutations that lead to constitutive hormone receptor activation (AR-V7, ESR1).
- Uncontrolled intercurrent illness that would limit compliance with study requirements.
- Active infection requiring systemic therapy.
- HIV infection with exceptions; discuss with treating physician.
- Subprotocol D:
- Known or suspected neurofibromatosis-1 (NF-1) and/or RAS related gene alterations or other co-occurring driver mutations.
- Participant has a non-CNS solid tumor with CNS metastases.
- Uncontrolled intercurrent illness that would limit compliance with study requirements.
- Active infection requiring systemic therapy.
- HIV infection with exceptions; discuss with treating physician.
- Use or anticipate the need for medications with known risk for QT-prolonging potential and Torsades de Pointes.
- History of acute or chronic cardiovascular disease or surgery, hypertension, with systolic blood pressure >160mm HG, history of QTc abnormalities, or clinical significantly ECG abnormalities (for participants in the ECG substudy).
Trial locations and contacts
70 sites in 12 countries. Contact the study team or a site near you to ask about taking part.
70 sites in 12 countries
United States30 sites, 29 recruiting
- Recruiting
The John Hopkins Hospital
Baltimore, Maryland, 21287
- Recruiting
Precision NextGen Oncology & Research Center
Beverly Hills, California, 90210
- Recruiting
Tufts Medical Center
Boston, Massachusetts, 02111
- Recruiting
Massachusetts General Hospital
Boston, Massachusetts, 02214
- Not yet recruiting
Dana-Farber Cancer Institute
Boston, Massachusetts, 02215
- Recruiting
Nationwide Children's Hospital
Colombus, Ohio, 43205
- Recruiting
The Ohio State University Comprehensive Cancer Center (OSUCCC) - The James Cancer Hospital and Solove Research Institute
Columbus, Ohio, 43221
- Recruiting
Baylor Scott & White Research Institute
Dallas, Texas, 75246
- Recruiting
St. Luke's Hospital
Duluth, Minnesota, 55805
- Recruiting
University of Texas MD Anderson Cancer Center
Houston, Texas, 77030
- Recruiting
Taylor Cancer Research Center
Maumee, Ohio, 43537
- Recruiting
University of Miami Hospital and Clinics
Miami, Florida, 33136
- Recruiting
West Virginia University Health Sciences Campus
Morgantown, West Virginia, 26506
- Recruiting
SCRI - TriStar Medical Group Children's Specialists
Nashville, Tennessee, 37203
- Recruiting
SCRI Oncology Partners
Nashville, Tennessee, 37203
- Recruiting
Columbia University Irving Medical Center
New York, New York, 10032
- Recruiting
Memorial Sloan Kettering Cancer Center
New York, New York, 10065
- Recruiting
Norwalk Hospital
Norwalk, Connecticut, 06856
- Recruiting
Nebraska Cancer Specialists - Midwest Cancer Center - Legacy
Omaha, Nebraska, 68130
- Recruiting
Thomas Jefferson University
Philadelphia, Pennsylvania, 19107
- Recruiting
Lifespan Cancer Institute - Rhode Island Hospital
Providence, Rhode Island, 02903
- Recruiting
Maryland Oncology Hematology- Columbia
Rockville, Maryland, 20850
- Recruiting
Mosaic Life Care at Saint Joseph - Medical Center
Saint Joseph, Missouri, 64506
- Recruiting
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, California, 94143
- Recruiting
University of Washington School of Medicine
Seattle, Washington, 98109
- Recruiting
Overlook Medical Center
Summit, New Jersey, 07901
- Recruiting
Baylor Scott & White Medical Center
Temple, Texas, 43205
- Completed
Toledo Clinic Cancer Center
Toledo, Ohio, 43623
- Recruiting
University of California Los Angeles Rheumatology
Westwood, Los Angeles, California, 90095-6984
- Recruiting
Atrium Health Wake Forest Baptist - Comprehensive Cancer Center
Winston-Salem, North Carolina, 27157
France7 sites, 7 recruiting
- Recruiting
Institut de Cancerologie de l'Ouest- Angers
Angers, Pays de la Loire Region, 49055
- Recruiting
Institut Bergonie
Bordeaux, Aquitaine, 33000
- Recruiting
Hôpital Morvan
Brest, Finistère, 29200
- Recruiting
Hôpital Nord de Marseille
Marseille, Bouches-du-Rhône, 13005
- Recruiting
Hôpital Universitaire Pitié Salpêtrière
Paris, Île-de-France Region, 75013
- Recruiting
Institut Universitaire du Cancer de Toulouse Oncopole
Toulouse, 31059
- Recruiting
Gustave Roussy
Villejuif, Val-de-Marne, 94805
South Korea6 sites, 6 recruiting
- Recruiting
Chonnam National University Hwasun Hospital
Hwasun, Jeollanam-do, 58128
- Recruiting
Dong-A University Hospital
Pusan, Gyeongsangnam-do, 602-812
- Recruiting
Seoul National University Hospital
Seoul, Seoul Teugbyeoisi, 03080
- Recruiting
Severance Hospital
Seoul, Seoul Teugbyeolsi, 03722
- Recruiting
Catholic University of Korea Saint Vincent's Hospital
Suwon, Gyeonggi-do, 16247
- Recruiting
Seoul National University Hospital
Suwon, Gyeonggido, 443-721
Spain6 sites, 6 recruiting
- Recruiting
Hospital Universitari Vall d'Hebron
Barcelona, Barcelona, 08035
- Recruiting
Hospital Infantil Universitario Niño Jesús
Madrid, Madrid, 28009
- Recruiting
Hospital Universitario 12 de Octubre
Madrid, Madrid, 28041
- Recruiting
Hospital Clinico Universitarlo de Santiago
Santiago de Compostela, A Coruña, 15706
- Recruiting
Hospital Universitario Virgen del Rocío
Seville, Sevilla, 41013
- Recruiting
Hospital Clinico Universitarlo de Valencia
Valencia, Valencia, 46010
Australia5 sites, 5 recruiting
- Recruiting
Flinders Medical Centre
Bedford Park, South Australia, 5042
- Recruiting
The Alfred
Melbourne, Victoria, 3004
- Recruiting
Newcastle Private Hospital
New Lambton Heights, New South Wales, 2305
- Recruiting
Orange Health Service
Orange, New South Wales, 2800
- Recruiting
Sydney Children's Hospital Network - Randwick
Randwick, New South Wales, 2031
Italy4 sites, 4 recruiting
- Recruiting
Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" - IRST
Meldola, Forli-Cesena, 47014
- Recruiting
Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) - Ospedale San Raffaele
Milan, 20132
- Recruiting
Istituto Europeo di Oncologia
Milan, 20141
- Recruiting
Istituto Nazionale Tumori IRCCS Fondazione G. Pascale
Naples, Naples, 80131
Germany3 sites, 2 recruiting
- Recruiting
Charité - Universitätsmedizin Berlin
Berlin, 13353
- Active, not recruiting
Krankenhaus Nordwest
Frankfurt am Main, Hesse, 60488
- Recruiting
Universitätsklinikum Heidelberg
Heidelberg, Baden-Wurttemberg, 69120
Canada2 sites, 2 recruiting
- Recruiting
Centre Hospitalier Universitaire Sainte-Justine
Montreal, Quebec, H3T 1C5
- Recruiting
Sunny brook Health Sciences Centre- Bayview Campus
Toronto, Ontario, M4N 3M5
Norway2 sites, 2 recruiting
- Recruiting
Haukeland Univeritetssjukehus
Bergen, Hordaland, 5021
- Recruiting
Oslo Universitetssykehus-Radiumhospitalet
Oslo, Oslo, 0379
Sweden2 sites, 2 recruiting
- Recruiting
Skånes Universitetssjukhus
Lund, Skåne County, 221 85
- Recruiting
Karolinska Universitetssjukhuset
Solna, Stockholm County, 171 64
United Kingdom2 sites, 2 recruiting
- Recruiting
Sarah Cannon Research Institute
London, W1G 6AD
- Recruiting
The Christie NHS Foundation Trust
Manchester, England, M20 4BX
Netherlands1 site, 1 recruiting
- Recruiting
Erasmus Medisch Centrum
Rotterdam, South Holland, 3015 GD
About this study
Official title: 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 BRAF altered (BRAF V600E or BRAF fusions) locally advanced or metastatic solid tumors, or recurrent or progressive primary central nervous system (CNS) tumors, including rare BRAF V600E-mutated solid tumors, including anaplastic thyroid, ovarian, cholangiocarcinoma or other rare cancers.
- Conditions
- Cancer Harboring BRAF Alterations, HGG, LGG, Solid Tumors
- Being tested
- Plixorafenib
- Keywords
- BRAF alterations, BRAF Fusions, BRAF V600E, BRAF Class 1, BRAF Class 2, High grade glioma, low grade glioma, HGG, LGG, Solid tumors, Biliary tract cancer, Ovarian cancer, Fallopian tube cancer, Primary peritoneal cancer, Anaplastic thyroid cancer, Cholangiocarcinoma, Bladder cancer, Uterine cancer, Hepatocellular carcinoma, Gastrointestinal stromal tumor (GIST)
- Medical subject headings
- Glioma, Biliary Tract Neoplasms, Ovarian Neoplasms, Fallopian Tube Neoplasms, Thyroid Carcinoma, Anaplastic, Cholangiocarcinoma, Urinary Bladder Neoplasms, Uterine Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PlixorafenibDrug
Also called FORE8394, PLX8394, PLX-8394
Oral tablets
| Study group | Role | What they receive |
|---|---|---|
| Subprotocol A | Experimental | Participants with unresectable, locally advanced or metastatic solid tumors or primary CNS tumors harboring BRAF fusions will receive plixorafenib which will be increased as tolerated, continuously in 3-week cycles until disease progression, unacceptable toxicity, or other reason for withdrawal. Receives: Drug: Plixorafenib |
| Subprotocol B | Experimental | Participants with recurrent primary CNS tumors harboring BRAF V600E mutations will receive plixorafenib, continuously in 3-week cycles until disease progression, unacceptable toxicity, or other reason for withdrawal. Receives: Drug: Plixorafenib |
| Subprotocol C | Experimental | Participants with advanced, rare, non-CNS solid tumors harboring BRAF V600E mutations will receive plixorafenib, continuously in 3-week cycles until disease progression, unacceptable toxicity, or other reason for withdrawal. Receives: Drug: Plixorafenib |
| Subprotocol D | Experimental | Participants with BRAF V600E-mutated advanced solid tumors will receive plixorafenib until disease progression, unacceptable toxicity, or other reason for withdrawal. Receives: Drug: Plixorafenib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Objective Response Rate (ORR) (Subprotocols A, B and C)
ORR will be determined by standard tumor response criteria by blinded independent central review (BICR).
Measured: Up to approximately 4 years
Pharmacokinetics (Subprotocol D)
Systemic exposure of plixorafenib measured by Cmax and AUC
Measured: Up to approximately 4 years
Secondary outcomes (13)
Duration of Response (DOR) by BICR (Subprotocols A, B and C)
DOR will be determined by standard tumor response criteria per BICR (subprotocols A-C)
Measured: Up to approximately 4 years
ORR per Investigator Assessment
ORR will be determined by standard tumor response criteria by Investigator Assessment.
Measured: Up to approximately 4 years
DOR per Investigator Assessment
DOR will be determined by standard tumor response criteria.
Measured: Up to approximately 4 years
Percentage of Participants with DOR at 6 months, 12 months, and 18 months
Measured: 6 months, 12 months and 18 months
Time to Response by BICR (Subprotocols A, B and C)
Measured: Up to approximately 4 years
Progression Free Survival (PFS) by BICR (Subprotocols A, B and C)
Measured: Up to approximately 4 years
PFS per Investigator's Assessment
Measured: Up to approximately 4 years
Overall Survival
Measured: Up to approximately 4 years
Percentage of Participants with PFS at 6 months, 12 months and 24 months
BICR (Subprotocols A, B and C) and by Investigator Assessment (Subprotocols A, B, C and D)
Measured: 6 months, 12 months and 24 months
Disease Control Rate (DCR)
Measured: Up to approximately 4 years
Number of Participants who Experience Treatment-emergent Adverse Events (TEAEs)
Measured: Up to approximately 4 years
Plasma Concentrations of Plixorafenib
Measured: Up to approximately 4 years
Plasma Concentrations of Plixorafenib Metabolites
Measured: Up to approximately 4 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Aug 2022
- Study start21 Feb 2023
- Primary completion31 Dec 2027 (estimated)
- Study completion28 Dec 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Cancer Harboring BRAF AlterationsStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Model description
- All four open-label single-arm subprotocols will enroll patients independently of one another, in parallel.
- Masking
- None (open label)
- Enrolment
- 254 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Fore Biotherapeutics
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05503797
- Sponsor's protocol ID
- F8394-201
- Other IDs
- 2024-513578-23-00, 2022-000627-20
- Status last verified
- Jun 2026
- First submitted
- 15 Aug 2022
- Last updated
- 27 Jul 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Fore is committed to sharing with qualified external researchers access to deidentified patient-level data and related study documents (eg. study protocol) from eligible studies following publication of the study results.