A Study to Assess the Efficacy and Safety of FORE8394 in Participants With Cancer Harboring BRAF Alterations
- Conditions
- HGGLGGCancer Harboring BRAF AlterationsSolid Tumors
- 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
- 254
Not provided
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.
- 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.
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, 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, continuously in 3-week cycles until disease progression, unacceptable toxicity, or other reason for withdrawal. Subprotocol D Plixorafenib Participants with BRAF V600E-mutated advanced solid tumors will receive plixorafenib until disease progression, unacceptable toxicity, or other reason for withdrawal.
- 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) and by 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
Trial Locations
- Locations (59)
UCSF Helen Diller Family Comprehensive Cancer Center
🇺🇸San Francisco, California, United States
University of California Los Angeles Rheumatology
🇺🇸Westwood, Los Angeles, 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
Dana-Farber Cancer Institute
🇺🇸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
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