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

• Drug: Plixorafenib
• Drug: Cobicistat

Inclusion Criteria

Subprotocol A:

1. Male and female, ≥10 years of age, and weighing ≥30 kg.
2. Histologic diagnosisthe process of identifying a disease based on signs and symptoms, patient history and medical test results of a solid tumor or primary CNS tumor.
3. Documentation of BRAF gene fusion in tumor and/or bloodthe red bodily fluid that transports oxygen and other nutrients around the body detected by an analytically validated test by DNA sequencing or RNA (transcriptome) sequencing.
4. Have an archival tissuea group of cells that work together to perform a function sample available meeting protocol requirements.
5. Consent to provide scan(s) prior to baseline to assess change in tumor trajectory.
6. Received all available standard therapy, is intolerant to available therapies, or the investigator has determined that treatment with standard therapy is not appropriate.
7. All adverse events related to prior therapies (chemotherapya cancer treatment that uses drugs to kill or slow the growth of cancer cells, while minimising damage to healthy cells; radiotherapy; surgerytreatment involving removal of cancerous tissue and/or tumours and a margin of healthy tissue around it to reduce recurrence) must have resolved to Gradea description of how abnormal cancer cells and tissue look under a microscope when compared to healthy cells 1 or baseline.

Subprotocol B:

1. Male and female, ≥10 years of age, and weighing ≥30 kg.
2. Histological diagnosis of a primary CNS tumor, including but not limited to the following:
   1. Adults (≥18 years) with Grade 1-4 glioma or glioneuronal tumor (including glioblastoma, anaplastica term used to describe abnormal cancer cells that grow uncontrollably in the body and have little or no resemblence to regular cells astrocytoma, high grade astrocytoma with piloid features, pilocytic astrocytoma, gliosarcoma, anaplastic pleomorphicmany forms; cells that have different size, shape etc. xanthoastrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, not otherwise specified [NOS], ganglioglioma, or recurrent LGG). OR
   2. 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.
   3. 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.

   ii. Is intolerant to available therapies OR iii. The investigator has determined that treatment with standard therapy is not appropriate.

3. Documented BRAF V600E mutation in tumor and/or liquid biopsyremoval of a section of tissue to analyse for cancer cells detected by an analytically validated test at CLIA or CLIA-equivalent laboratory approved by sponsor or sponsor-designated central test.
4. An archival tissue sample available meeting protocol requirements, or fresh biopsy is required if the archival sample is not available for retrospective confirmation test.
5. Consent to provide scan(s) prior to baseline to assess change in tumor trajectory.
6. Measurable disease based upon specified response criteria, as determined by the radiographic BICR.
7. All adverse events related to prior therapies (eg, chemotherapy, radiotherapy, surgery) must have resolved to Grade 1 or baseline.
8. Participants who are receiving corticosteroid treatment must be on a stable or decreasing dosethe amount of medication taken of ≤8 mg/day of dexamethasone or equivalent corticosteroid treatment for 7 days prior to first dose of study treatments.

Subprotocol C:

1. Male and female, ≥10 years of age, and weighing ≥30 kg.
2. Histologic diagnosis of a rare BRAF V600E-mutated solid tumor that is unresectable, locally advanced or metastatic.
3. Measurable disease on CT, MRI, or physical exam
4. Documented BRAF V600E mutation in tumor and/or liquid biopsy detected by an analytically validated test.
5. Have an archival tissue sample available meeting protocol requirements.
6. Consent to provide scan(s) prior to baseline to assess change in tumor trajectory
7. Received all available standard therapy, is intolerant to available therapies, or the investigator has determined that treatment with standard therapy is not appropriate.
8. All adverse events related to prior therapies (chemotherapy; radiotherapy; surgery) must have resolved to Grade 1 or baseline.

Subprotocol D:

1. Male and female, ≥10 years of age, and weighing ≥30 kg.
2. Histologic diagnosis of a metastatic melanoma or thyroid cancera disease where abnormal cells split without control and spread to other nearby body tissue and/or organs harboring a BRAF V600E mutation.
3. Participants with cutaneous melanoma have previously received and not tolerated a BRAF inhibitor, while participants with thyroid cancer are MAPK inhibitor naïve.
4. Measurable disease on CT, MRI, or physical exam.
5. Evidence of BRAF V600E mutation in tumor and/or blood detected by genomic tests.
6. Consent to provide a tumor biopsy.
7. All adverse events related to prior therapies (chemotherapy; radiotherapy; surgery) must have resolved to Grade 1 or baseline.