A Study to Assess the Efficacy and Safety of FORE8394 in Participants With Cancer Harboring BRAF Alterations
- Conditions
- Cancer Harboring BRAF AlterationsHGGLGGSolid TumorsMelanoma BRAF V600E/K MutatedThyroid Cancer
- Interventions
- Registration Number
- NCT05503797
- Lead Sponsor
- Fore Biotherapeutics
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 135
Not provided
Subprotocol A:
- Participants with known co-occurring NF1 alteration and/or RAS-related mutations.
- Participants with evidence of subclonal mutations or heterogeneity that are indicative of a prior treatment effect instead of a driver mutation.
- 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.
- 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).
- Current active liver disease from any cause, including a positive test at screening for HBV (HBsAg), or HCV (HCV antibody, confirmed by HCV RNA PCR).
- 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 or cobicistat (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, thyroid cancer (ATC and PTC), or NSCLC.
- Participant has CNS metastases.
- Prior treatment with BRAF, ERK, and/or MEK inhibitor(s).
- 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.
- Participants with known acquired driver mutations, including from prior MAPK pathway targeted therapies.
- Participant has 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Subprotocol A Plixorafenib 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. Subprotocol B Plixorafenib Participants with recurrent primary CNS tumors harboring BRAF V600E mutations will receive plixorafenib administered with cobicistat, continuously in 3-week cycles until disease progression, unacceptable toxicity, or other reason for withdrawal. Subprotocol B Cobicistat Participants with recurrent primary CNS tumors harboring BRAF V600E mutations will receive plixorafenib administered with cobicistat, continuously in 3-week cycles until disease progression, unacceptable toxicity, or other reason for withdrawal. Subprotocol C Plixorafenib Participants with advanced, rare, non-CNS solid tumors harboring BRAF V600E mutations will receive plixorafenib administered with cobicistat, continuously in 3-week cycles until disease progression, unacceptable toxicity, or other reason for withdrawal. Subprotocol C Cobicistat Participants with advanced, rare, non-CNS solid tumors harboring BRAF V600E mutations will receive plixorafenib administered with cobicistat, continuously in 3-week cycles until disease progression, unacceptable toxicity, or other reason for withdrawal. Subprotocol D Plixorafenib Participants with BRAF V600E-mutated cutaneous melanoma and BRAF V600E-mutated thyroid cancer (MAPK inhibitor naïve) will be randomized to receive plixorafenib with or without cobicistat. Subprotocol D Cobicistat Participants with BRAF V600E-mutated cutaneous melanoma and BRAF V600E-mutated thyroid cancer (MAPK inhibitor naïve) will be randomized to receive plixorafenib with or without cobicistat.
- Primary Outcome Measures
Name Time Method Objective Response Rate (ORR) (Subprotocols A, B and C) Up to approximately 4 years ORR will be determined by standard tumor response criteria by blinded independent central review (BICR).
Pharmacokinetics (Subprotocol D) Up to approximately 4 years Systemic exposure of plixorafenib measured by Cmax and AUC
- Secondary Outcome Measures
Name Time Method Duration of Response (DOR) by BICR (Subprotocols A, B and C) Up to approximately 4 years DOR will be determined by standard tumor response criteria per BICR (subprotocols A-C)
ORR per Investigator Assessment Up to approximately 4 years ORR will be determined by standard tumor response criteria by Investigator Assessment.
DOR per Investigator Assessment Up to approximately 4 years DOR will be determined by standard tumor response criteria.
Percentage of Participants with DOR at 6 months, 12 months, and 18 months 6 months, 12 months and 18 months Time to Response by BICR (Subprotocols A, B and C) Up to approximately 4 years Progression Free Survival (PFS) by BICR (Subprotocols A, B and C) Up to approximately 4 years PFS per Investigator's Assessment Up to approximately 4 years Overall Survival Up to approximately 4 years Percentage of Participants with PFS at 6 months, 12 months and 24 months 6 months, 12 months and 24 months BICR (Subprotocols A, B and C) Investigator Assessment (Subprotocols A, B, C and D)
Disease Control Rate (DCR) Up to approximately 4 years Number of Participants who Experience Treatment-emergent Adverse Events (TEAEs) Up to approximately 4 years Plasma Concentrations of Plixorafenib Up to approximately 4 years Plasma Concentrations of Plixorafenib Metabolites Up to approximately 4 years Subprotocol A: CNS-DOR by BICR Up to approximately 4 years Subprotocol A: CNS-ORR by BICR Up to approximately 4 years Subgroup analyses for efficacy endpoints in low-grade and high-grade primary CNS tumors will be reported. Up to approximately 4 years
Trial Locations
- Locations (55)
UCSF Helen Diller Family Comprehensive Cancer Center
🇺🇸San Francisco, California, United States
University of California Los Angeles Rheumatology
🇺🇸Westwood, California, United States
University of Miami Hospital and Clinics
🇺🇸Miami, Florida, United States
The John Hopkins Hospital
🇺🇸Baltimore, Maryland, United States
Maryland Oncology Hematology- Columbia
🇺🇸Rockville, Maryland, United States
Tufts Medical Center
🇺🇸Boston, Massachusetts, United States
St. Luke's Hospital
🇺🇸Duluth, Minnesota, United States
Mosaic Life Care at Saint Joseph - Medical Center
🇺🇸Saint Joseph, Missouri, United States
Nebraska Cancer Specialists - Midwest Cancer Center - Legacy
🇺🇸Omaha, Nebraska, United States
Overlook Medical Center
🇺🇸Summit, New Jersey, United States
Columbia University Irving Medical Center
🇺🇸New York, New York, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Nationwide Children's Hospital
🇺🇸Columbus, Ohio, United States
Taylor Cancer Research Center
🇺🇸Maumee, Ohio, United States
Toledo Clinic Cancer Center
🇺🇸Toledo, Ohio, United States
Thomas Jefferson University
🇺🇸Philadelphia, Pennsylvania, United States
Lifespan Cancer Institute - Rhode Island Hospital
🇺🇸Providence, Rhode Island, United States
Baylor Scott & White Research Institute
🇺🇸Dallas, Texas, United States
Baylor Scott & White Medical Center
🇺🇸Temple, Texas, United States
University of Washington School of Medicine
🇺🇸Seattle, Washington, United States
West Virginia University Health Sciences Campus
🇺🇸Morgantown, West Virginia, United States
Newcastle Private Hospital
🇦🇺New Lambton Heights, New South Wales, Australia
The Alfred
🇦🇺Melbourne, Victoria, Australia
Sydney Children's Hospital Network - Randwick
🇦🇺Randwick, Australia
Sunny brook Health Sciences Centre- Bayview Campus
🇨🇦Toronto, Ontario, Canada
Centre Hospitalier Universitaire Sainte-Justine
🇨🇦Montréal, Quebec, Canada
Institut Bergonie
🇫🇷Bordeaux Cedex, Aquitaine, France
Hôpital Nord de Marseille
🇫🇷Marseille, Bouches-du-Rhône, France
Hôpital Morvan
🇫🇷Brest, Finistère, France
Hôpital Universitaire Pitié Salpêtrière
🇫🇷Paris, Ile-de-France, France
Institut de Cancerologie de l'Ouest- Angers
🇫🇷Angers, Pays De La Loire, France
Gustave Roussy
🇫🇷Villejuif, Val-de-Marne, France
Institut Universitaire du Cancer de Toulouse Oncopole
🇫🇷Toulouse, France
Universitätsklinikum Heidelberg
🇩🇪Heidelberg, Baden-Württemberg, Germany
Krankenhaus Nordwest
🇩🇪Frankfurt, Hessen, Germany
Charité - Universitätsmedizin Berlin
🇩🇪Berlin, Germany
Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" - IRST
🇮🇹Meldola, Forli-Cesena, Italy
Istituto Nazionale Tumori IRCCS Fondazione G. Pascale
🇮🇹Napoli, Naples, Italy
Istituto Europeo di Oncologia
🇮🇹Milano, Italy
Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) - Ospedale San Raffaele
🇮🇹Milan, Italy
Catholic University of Korea Saint Vincent's Hospital
🇰🇷Suwon-si, Gyeonggi-do, Korea, Republic of
Seoul National University Hospital
🇰🇷Seoul, Seoul Teugbyeoisi, Korea, Republic of
Dong-A University Hospital
🇰🇷Busan, Gyeongsangnam-do, Korea, Republic of
Chonnam National University Hwasun Hospital
🇰🇷Hwasun, Jeollanam-do, Korea, Republic of
Severance Hospital
🇰🇷Seoul, Seoul Teugbyeolsi, Korea, Republic of
Hospital Clinico Universitarlo de Santiago
🇪🇸Santiago De Compostela, A Coruña, Spain
Hospital Clinico Universitarlo de Valencia
🇪🇸València, Valencia, Spain
Hospital Universitari Vall d'Hebron
🇪🇸Barcelona, Spain
Hospital Infantil Universitario Niño Jesús
🇪🇸Madrid, Spain
Hospital Universitario 12 de Octubre
🇪🇸Madrid, Spain
Hospital Universitario Virgen del Rocío
🇪🇸Sevilla, Spain
Skånes Universitetssjukhus
🇸🇪Lund, Skåne Län, Sweden
Karolinska Universitetssjukhuset
🇸🇪Solna, Stockholms Län, Sweden
The Christie NHS Foundation Trust
🇬🇧Manchester, England, United Kingdom
Sarah Cannon Research Institute
🇬🇧London, United Kingdom