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

Eligibility Criteria

• 1. Participants with known co-occurring NF1 alteration and/or RAS-related mutations.
• 2. Participants with evidence of subclonal mutations or heterogeneity that are indicative of a prior treatment effect instead of a driver mutation.
• 3. Prior treatment with RAF/BRAF inhibitors active for Class 2 BRAF alterations for advanced unresectable or metastatic disease.
• 4. Prior treatment with a MEK inhibitor.
• 5. 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.
• 6. Malignancy with co-occurring activating RAS mutation(s) at any time.
• 7. Uncontrolled intercurrent illness that would limit compliance with study requirements.
• 8. HIV infection with exceptions; discuss with treating physician.
• 9. 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).
• 10. 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).
• 11. Grade ≥2 changes in AST, ALT, GGT, or bilirubin attributed to prior immune checkpoint inhibitor treatment are exclusionary, even if resolved.
• 1. Prior treatment with BRAF, ERK, and/or MEK inhibitor(s).
• 2. Known or suspected neurofibromatosis-1 (NF-1) and/or RAS related gene alterations.
• 3. Uncontrolled intercurrent illness that would limit compliance with study requirements.
• 4. Active infection requiring systemic therapy.
• 5. HIV infection with exceptions; discuss with treating physician.
• 6. 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).
• 7. Grade ≥ 2 changes in AST, ALT, gamma-glutamyl transaminase (GGT), or bilirubin attributed to prior immune checkpoint inhibitor treatment are exclusionary, even if resolved.
• 1. Diagnosis of colorectal adenocarcinoma or pancreatic ductal adenocarcinoma (neuroendocrine or acinar tumors are eligible).
• 2. Diagnosis of BRAF V600E-mutated cutaneous melanoma, thyroid cancer (ATC and PTC), or NSCLC.
• 3. Participant has CNS metastases.
• 4. Prior treatment with BRAF, ERK, and/or MEK inhibitor(s).
• 5. Known or suspected neurofibromatosis-1 (NF-1) and/or RAS related gene alterations.
• 6. Participants with prostate, breast, or gynecologic cancers with known activating mutations that lead to constitutive hormone receptor activation (AR-V7, ESR1).
• 7. Uncontrolled intercurrent illness that would limit compliance with study requirements.
• 8. Active infection requiring systemic therapy.
• 9. HIV infection with exceptions; discuss with treating physician.
• 1. Known or suspected neurofibromatosis-1 (NF-1) and/or RAS related gene alterations.
• 2. Participants with known acquired driver mutations, including from prior MAPK pathway targeted therapies.
• 3. Participant has CNS metastases.
• 4. Uncontrolled intercurrent illness that would limit compliance with study requirements.
• 5. Active infection requiring systemic therapy.
• 6. HIV infection with exceptions; discuss with treating physician.