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

Subprotocol 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 at CLIA or CLIA-equivalent laboratory or sponsor-designated central laboratory.
• Have an archival tissue sample available meeting protocol requirements. If an archival tissue sample is not available, a newly obtained (before treatment) tumor biopsy may be submitted instead.
• 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 except for
  • Alopecia (Grade ≤2)
  • Sensory neuropathy (Grade ≤2)
  • Other adverse events that have resolved to Grade ≤2 that, according to the clinical judgment of the investigator, do not constitute a safety risk to the participant. Subprotocol B:
• Male and female, ≥10 years of age, and weighing ≥30 kg.
• Histological diagnosis of a primary CNS tumor, including but not limited to the following:
  • 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 (10-17 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: i. Had prior treatment with radiotherapy and/or first-line chemotherapy or concurrent chemoradiation therapy OR
  • 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. Consult the Medical Lead to discuss and determine if participant is eligible for enrollment. ii. Is intolerant to available therapies OR iii. The investigator has determined that treatment with standard therapy is not appropriate.
• Documented BRAF V600E mutation in tumor and/or blood 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. Tissue obtained most proximal to initiating this subprotocol is preferred.
• 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 except for:
  • Alopecia (Grade ≤2)
  • Sensory neuropathy (Grade ≤2)
  • Other adverse events that have resolved to Grade ≤2 that, according to the clinical judgment of the investigator, do not constitute a safety risk to the participant
• 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, ≥10 years of age, and weighing ≥30 kg.
• Histologic diagnosis of a rare BRAF V600E-mutated solid tumor that is unresectable, locally advanced or metastatic.
• Documented BRAF V600E mutation in tumor and/or blood detected by an analytically validated test at CLIA or CLIA-equivalent laboratory approved by sponsor or sponsor-designated central test.
• Have an archival tissue sample available meeting protocol requirements. If an archival tissue sample is not available, a newly obtained (before treatment) tumor biopsy may be submitted instead.
• 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 except for
  • Alopecia (Grade ≤2)
  • Sensory neuropathy (Grade ≤2)
  • Other adverse events that have resolved to Grade ≤2 that, according to the clinical judgment of the investigator, do not constitute a safety risk to the participant. Subprotocol D:
• Male and female, ≥10 years of age, and weighing ≥30 kg.
• Histologic diagnosis of a metastatic melanoma or thyroid cancer harboring a BRAF V600E mutation.
• Consent to provide a tumor biopsy.
• All adverse events related to prior therapies (chemotherapy; radiotherapy; surgery) must have resolved to Grade 1 or baseline except for
  • Alopecia (Grade ≤2)
  • Sensory neuropathy (Grade ≤2)
  • Other adverse events that have resolved to Grade ≤2 that, according to the clinical judgment of the investigator, do not constitute a safety risk to the participant.

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 MAPK inhibitors active for Class 2 BRAF alterations for advanced unresectable or metastatic disease (including but not limited to tovorafenib [formerly known as DAY 101, TAK 580, and MLN 2480], KIN-2787, BGB-3245, and CFT1946).
  • Note: Participants with pediatric-type LGGs (molecular classification by WHO2021; diagnosed at ≤25 years of age) who had received prior treatment(s) with RAF/BRAF inhibitors are eligible for enrollment, provided there was no evidence of tumor progression on that therapy or within 4 weeks of discontinuation, based upon radiographic assessment.

5. Malignancy with co-occurring activating RAS mutation(s) at any time.
6. Uncontrolled intercurrent illness that would limit compliance with study requirements.
7. Current or planned participation in a study of an investigational agent or device.
8. 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).
9. Are currently receiving (within 7 days of Cycle 1 Day 1) or are planning to receive during participation:
   • Agents that are known strong inducers or inhibitors of CYP3A4 . Restrictions include foods or herbal medications, including grapefruit juice, grapefruit/grapefruit related citrus fruits (eg, Seville oranges, pomelos), and St. John's Wort. Subprotocol B:
10. Prior treatment with BRAF, ERK, and/or MEK inhibitor(s).
11. Known or suspected neurofibromatosis-1 (NF-1) and/or Ras related gene alterations.
12. Uncontrolled intercurrent illness that would limit compliance with study requirements.
13. Active infection requiring systemic therapy.
14. Current or planned participation in a study of an investigational agent or device.
15. 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, small bowel resection).
16. Grade ≥ 2 changes in AST, ALT, gamma-glutamyl transaminase (GGT), or bilirubin attributed to prior immune checkpoint inhibitor treatment are exclusionary, even if resolved.
17. Are currently receiving (within 7 days of Cycle 1 Day 1) or are planning to receive during participation:
    • Agents that are known strong inducers or inhibitors of CYP3A4 (other than cobicistat). Restrictions include foods or herbal medications, including grapefruit juice, grapefruit/grapefruit related citrus fruits (eg, Seville oranges, pomelos), and St. John's Wort.
    • Agents that are contraindicated with cobicistat Note: For participants with no other option except agents with potential drug interactions with cobicistat, but which are not contraindicated, the dose of that agent must be altered or the regimen must follow the cobicistat prescribing information and be approved by the medical monitor. Subprotocol C:
18. Diagnosis of colorectal adenocarcinoma or pancreatic ductal adenocarcinoma (neuroendocrine or acinar tumors are eligible).
19. Participant has CNS metastases. If participants have symptoms that could be indicative of CNS metastases or tumors that are at high risk of CNS metastases, CNS imaging is required prior to the first dose of plixorafenib (MRI with contrast preferred).
20. Prior treatment with BRAF, ERK, and/or MEK inhibitor(s).
21. Known or suspected neurofibromatosis-1 (NF-1) and/or RAS related gene alterations.
22. Uncontrolled intercurrent illness that would limit compliance with study requirements.
23. Active infection requiring systemic therapy.
24. Current or planned participation in a study of an investigational agent or device.
25. 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, small bowel resection).
26. Grade ≥ 2 changes in AST, ALT, gamma-glutamyl transaminase (GGT), or bilirubin attributed to prior immune checkpoint inhibitor treatment are exclusionary, even if resolved.
27. Are currently receiving (within 7 days of Cycle 1 Day 1) or are planning to receive during participation:
    • Agents that are known strong inducers or inhibitors of CYP3A4 (other than cobicistat). Restrictions include foods or herbal medications, including grapefruit juice, grapefruit/grapefruit related citrus fruits (eg, Seville oranges, pomelos), and St. John's Wort.
    • Agents that are contraindicated with cobicistat Note: For participants with no other option except agents with potential drug interactions with cobicistat, but which are not contraindicated, the dose of that agent must be altered or the regimen must follow the cobicistat prescribing information and be approved by the medical monitor. Subprotocol D:
28. Known or suspected neurofibromatosis-1 (NF-1) and/or RAS related gene alterations.
29. Participant has CNS metastases.
30. Uncontrolled intercurrent illness that would limit compliance with study requirements.
31. Active infection requiring systemic therapy.
32. Current or planned participation in a study of an investigational agent or device.
33. 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, small bowel resection).
34. Grade ≥ 2 changes in AST, ALT, gamma-glutamyl transaminase (GGT), or bilirubin attributed to prior immune checkpoint inhibitor treatment are exclusionary, even if resolved.
35. Are currently receiving (within 7 days of Cycle 1 Day 1) or are planning to receive during participation:
    • Agents that are known strong inducers or inhibitors of CYP3A4 (other than cobicistat). Restrictions include foods or herbal medications, including grapefruit juice, grapefruit/grapefruit related citrus fruits (eg, Seville oranges, pomelos), and St. John's Wort.
    • Agents that are contraindicated with cobicistat Note: For participants with no other option except agents with potential drug interactions with cobicistat, but which are not contraindicated, the dose of that agent must be altered or the regimen must follow the cobicistat prescribing information and be approved by the medical monitor.