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

Exclusion Criteria

Subprotocol A:

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 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.

4. 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. NOTE: There is no restriction on the number of lines of chemotherapy or immunotherapy.

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:

   1. 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:

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. Current or planned participation in a study of an investigational agent or device.

6. 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).

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.

8. Are currently receiving (within 7 days of Cycle 1 Day 1) or are planning to receive during participation:

   1. 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.
   2. 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:

1. Diagnosis of colorectal adenocarcinoma or pancreatic ductal adenocarcinoma (neuroendocrine or acinar tumors are eligible).

2. 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).

3. Prior treatment with BRAF, ERK, and/or MEK inhibitor(s).

4. Known or suspected neurofibromatosis-1 (NF-1) and/or RAS related gene alterations.

5. Uncontrolled intercurrent illness that would limit compliance with study requirements.

6. Active infection requiring systemic therapy.

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, small bowel resection).

9. Grade ≥ 2 changes in AST, ALT, gamma-glutamyl transaminase (GGT), or bilirubin attributed to prior immune checkpoint inhibitor treatment are exclusionary, even if resolved.

10. Are currently receiving (within 7 days of Cycle 1 Day 1) or are planning to receive during participation:

    1. 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.
    2. 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:

1. Known or suspected neurofibromatosis-1 (NF-1) and/or RAS related gene alterations.

2. Participant has CNS metastases.

3. Uncontrolled intercurrent illness that would limit compliance with study requirements.

4. Active infection requiring systemic therapy.

5. Current or planned participation in a study of an investigational agent or device.

6. 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).

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.

8. Are currently receiving (within 7 days of Cycle 1 Day 1) or are planning to receive during participation:

   1. 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.
   2. 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.