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A Study to Assess the Efficacy and Safety of FORE8394 in Participants With Cancer Harboring BRAF Alterations
||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 study is to evaluate the efficacy of FORE8394 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 recurrent high-grade glioma (HGG) harboring BRAF V600E mutation. This will be conducted as two single arm open-label subprotocols (F8394-201A; F8394-201B) under one master protocol.
Group A: -Male and female, ≥10 years of age, and weighing ≥30 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. Group B: -Male and female, ≥10 years of age, and weighing ≥30 kg. -Histological diagnosis of a grade 3 or 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], or high grade ganglioglioma), or has a prior, histologically confirmed, diagnosis of a grade 2 glioma and now has radiographic or histopathological findings consistent with an HGG (World Health Organization [WHO] grade 3 or 4). Note: If a non anaplastic pleomorphic xanthoastrocytoma is re-resected at recurrence and found to have a ≥ Grade 2 histology, this would be considered eligible. -Have received at least one line of prior therapy including radiation. NOTE: Patients for whom radiotherapy is not considered standard of care may remain eligible for the study.
Group 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 (such as tovorafenib [formerly known as DAY 101, TAK 580, and MLN 2480], KIN-2787, BGB-3245, and CFT1946). Group 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.
Experimental: Group A Participants with unresectable, locally advanced or metastatic solid tumors or primary CNS tumors harboring BRAF fusions, will receive 900 mg of FORE8394 administered with 150 mg of cobicistat once daily (QD), continuously in 3-weeks cycles until disease progression, unacceptable toxicity, or other reason for withdrawal. Experimental: Group B Participants with recurrent primary CNS tumors harboring BRAF V600E mutations will receive 900 mg of FORE8394 administered with 150 mg of cobicistat QD, continuously in 3-week cycles until disease progression, unacceptable toxicity, or other reason for withdrawal. In total about 50 mL (about 3 ½ tablespoons) of blood will be taken at the first study visit, prior to taking the study drug. On the first day of taking study drug, about 80 mL of blood will be taken (about 5 ½ tablespoons). At most other visits, about 25 mL (about 1 ½ tablespoons) will be taken. The doctor may also need to take an additional biopsy (puncture with a needle) of tumor(s) for the study. For each subject, the study includes a Screening Period (up to 28 days), a Treatment Period (cycles of 3 weeks), End of Treatment assessment and Follow-up Period (every 3 months). This will involve a weekly visit to the study doctor for the first six weeks, every other week for the next four weeks, and then once every 3 weeks after that. After one year participating on the study, the visits may decrease in frequency. Tumor assessments (scans to assess disease) will continue to be collected until the disease has become worse (progressed), even if study treatment has stopped. At the end of treatment or after the disease becomes worse (whichever is later), the study doctor will continue to call subjects every three months to see how they are doing.