A Study to Assess the Efficacy and Safety of FORE8394 in Participants With Cancer Harboring BRAF Alterations

What this study is about

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.

Who can join (things the study team will check)

✅ You may be able to join if…

• 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.
• 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: i. Had prior treatment with radiotherapy and/or first-line chemotherapy or concurrent chemoradiation therapy OR ii. Is intolerant to available therapies OR iii. The investigator has determined that treatment with standard therapy is not appropriate.
  • 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:
  • 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.
• 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.

+ 9 more criteria — see the full checklist in the app.

🚫 You may not be able to join if…

• 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.

+ 11 more criteria — see the full checklist in the app.

Where this trial is running

• Precision NextGen Oncology & Research Center, Beverly Hills, California, United States
• UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California, United States
• University of California Los Angeles Rheumatology, Westwood, Los Angeles, California, United States
• Norwalk Hospital, Norwalk, Connecticut, 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
• Massachusetts General Hospital, 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

+ 58 more sites.

Who to contact

Jessica Rine · 610-442-4517 · jessica.rine@fore.bio

It's completely normal to call and ask questions before deciding anything. Mention the study ID: NCT05503797.