A Phase 2 Master Protocol to Assess the Efficacy and Safety of FORE8394, an Inhibitor of BRAF Class 1 and Class 2 Alterations, in Participants With Cancer Harboring BRAF Alterations

Overview

Plixorafenib (PLX-8394; FORE-8394) is an investigational oral BRAF inhibitor being studied in cancers with BRAF mutations or fusions. Human efficacy and safety results are available from an early-phase, single-arm trial; a phase 2 study is evaluating it further. (fore.bio)

Mechanism of action

Plixorafenib inhibits signaling from BRAF V600 mutants and disrupts BRAF-containing dimers, including those formed by some non-V600 mutants and BRAF fusions. In laboratory studies, it did not disrupt CRAF homodimers. It is described as a paradox breaker because it was designed to avoid the unintended MAPK-pathway activation seen with some earlier BRAF inhibitors. (pmc.ncbi.nlm.nih.gov)

Efficacy

In a phase 1/2a study, 13 of 43 adults (30%) with BRAF V600-mutated tumors other than colorectal cancer had a confirmed response. In a separate analysis of 13 patients with BRAF V600-mutated colorectal cancer who had not previously received MAPK-targeted therapy, one (8%) had a confirmed partial response and eight (62%) had disease control. These are small, nonrandomized groups, so the results do not establish how plixorafenib compares with other treatments. (fore.bio)

Safety

Among 113 treated patients in the phase 1/2a study, common treatment-emergent events included elevated liver enzymes, fatigue, nausea and diarrhea. Elevated ALT occurred in 43% of patients, including grade 3–4 elevations in approximately 9%. Five patients discontinued treatment because of an adverse event; one discontinuation was attributed to a treatment-related event. (fore.bio)

Further reading

• BRAF-dimer mechanism study
• Phase 1/2a results poster
• 2026 colorectal cancer trial abstract
• Phase 2 study record

Last updated: Sep 2026

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 analytically validated 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, or the investigator has determined that treatment with standard therapy is not appropriate.

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 the following:

1. 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

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 biopsy 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 dose 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 cancer 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.

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 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.

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. 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.

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), 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.

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 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.