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

Inclusion Criteria

Subprotocol A:

1. Male and female, ≥10 years of age, and weighing ≥30 kg.

2. Histologic diagnosis of a solid tumor or primary CNS tumor.

3. Documentation of BRAF gene fusion in tumor and/or blood detected by an analyticallyvalidated test by DNA sequencing or RNA (transcriptome) sequencing.

4. Have an archival tissue 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, orthe investigator has determined that treatment with standard therapy is notappropriate.

7. All adverse events related to prior therapies (chemotherapy; radiotherapy; surgery)must have resolved to Grade 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 thefollowing:

3. Adults (≥18 years) with Grade 1-4 glioma or glioneuronal tumor (includingglioblastoma, anaplastic astrocytoma, high grade astrocytoma with piloidfeatures, pilocytic astrocytoma, gliosarcoma, anaplastic pleomorphicxanthoastrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma,not otherwise specified [NOS], ganglioglioma, or recurrent LGG). OR

4. Pediatric patients (10-17 years of age) with a Grade 3 or 4 glioma orglioneuronal tumor, including those with a prior, histologically confirmed,diagnosis of a low-grade glioma or glioneuronal tumor and now have radiographicor histopathological findings consistent with WHO [2021] Grade 3 or 4 primaryCNS tumor.

5. Participants must have unresectable, locally advanced or metastatic diseasethat: i. Had prior treatment with radiotherapy and/or first-line chemotherapy orconcurrent chemoradiation therapy OR

• Note: Participants who have a WHO Grade 3 or 4 glioma for whom chemotherapyand/or radiotherapy is not considered standard of care may remain eligible forthe study. ii. Is intolerant to available therapies OR iii. The investigator has determinedthat treatment with standard therapy is not appropriate.

3. Documented BRAF V600E mutation in tumor and/or liquid biopsy detected by ananalytically validated test at CLIA or CLIA-equivalent laboratory approved bysponsor or sponsor-designated central test.

4. An archival tissue sample available meeting protocol requirements, or fresh biopsyis required if the archival sample is not available for retrospective confirmationtest.

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 theradiographic 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 ordecreasing dose of ≤8 mg/day of dexamethasone or equivalent corticosteroid treatmentfor 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 ananalytically 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, orthe investigator has determined that treatment with standard therapy is notappropriate.

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 cancer harboring a BRAFV600E mutation.

3. Participants with cutaneous melanoma have previously received and not tolerated aBRAF 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.

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 areindicative of a prior treatment effect instead of a driver mutation.

3. Prior treatment with RAF/BRAF inhibitors active for Class 2 BRAF alterations foradvanced unresectable or metastatic disease.

4. Prior treatment with a MEK inhibitor.

5. Tyrosine kinase inhibitor(s) and/or targeted therapies are allowed (other thanBRAF/MAPK pathway inhibitors per Exclusion Criteria 3 and 4) and will be restrictedto no more than the number of lines of therapy that are consistent with standardtreatment guidelines.

6. Malignancy with co-occurring activating RAS mutation(s) at any time.

7. Uncontrolled intercurrent illness that would limit compliance with studyrequirements.

8. HIV infection with exceptions; discuss with treating physician.

9. Have impairment of gastrointestinal (GI) function or GI disease that maysignificantly alter the absorption of oral plixorafenib or cobicistat (such asulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorptionsyndrome, and small bowel resection).

10. Current active liver disease from any cause, including a positive test at screeningfor HBV (HBsAg), or HCV (HCV antibody, confirmed by HCV RNA PCR).

11. Grade ≥2 changes in AST, ALT, GGT, or bilirubin attributed to prior immunecheckpoint inhibitor treatment are exclusionary, even if resolved.

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 studyrequirements.

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 theabsorption of oral plixorafenib or cobicistat (such as ulcerative diseases,uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowelresection).

7. Grade ≥ 2 changes in AST, ALT, gamma-glutamyl transaminase (GGT), or bilirubinattributed to prior immune checkpoint inhibitor treatment are exclusionary, even ifresolved.

Subprotocol C:

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), orNSCLC.

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 activatingmutations that lead to constitutive hormone receptor activation (AR-V7, ESR1).

7. Uncontrolled intercurrent illness that would limit compliance with studyrequirements.

8. Active infection requiring systemic therapy.

9. HIV infection with exceptions; discuss with treating physician.

Subprotocol D:

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 pathwaytargeted therapies.

3. Participant has CNS metastases.

4. Uncontrolled intercurrent illness that would limit compliance with studyrequirements.

5. Active infection requiring systemic therapy.

6. HIV infection with exceptions; discuss with treating physician.