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

Summary

This is an international, open-label phase II clinical trial for recurrent patients who have a glioma harboring a BRAF abnormality.

Alterations in the BRAF genomic sequence — including V600 and non-V600 mutations, in-frame deletions, and BRAF gene fusions — activate BRAF and promote tumor growth growth. FORE8394 is a is a next-generation orally available small-molecule selective inhibitor of mutated BRAF.

This study is evaluating the safety and efficacy of FORE8394 in:

Group A: Participants with solid tumors with or without CNS metastases or recurrent/progressive primary CNS tumors with BRAF fusions
Group B: Participants with recurrent primary CNS tumors with BRAF V600E mutations

Inclusion Criteria

Group A:

Age ≥10 years and weight ≥30 kg.
Histologic diagnosis of a solid tumor or primary CNS tumor.
Documentation of BRAF gene fusion in tumor 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 at less than 24 months from date of screening available with sufficient tumor for central next generation sequencing (NGS) testing and biomarker analyses, or >24 months if the participant has never received targeted therapy. 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 (at least 2 preferred). For participants with LGG, every effort should be made to provide 3 to 4 pre-baseline scans to the central imaging vendor whenever feasible.
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
1. Alopecia (Grade ≤2)
2. Sensory neuropathy (Grade ≤2)
3. 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.

Group B:

Age ≥10 years and weight ≥30 kg.
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).
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:
  1. Had prior treatment with radiotherapy and/or first-line chemotherapy or concurrent chemoradiation therapy OR
    1. 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.
  2. Is intolerant to available therapies OR
  3. The investigator has determined that treatment with standard therapy is not appropriate.
Documented BRAF V600E mutation in tumor or blood detected by an analytically validated test by NGS or polymerase chain reaction (PCR) methods and locally approved assays at CLIA or CLIA-equivalent laboratory approved by sponsor or sponsor-designated central test. Sponsor review of the report is required, and testing of BRAF alteration is required at sponsor's central laboratory.
An archival tissue sample at less than 24 months from date of screening available with sufficient tumor for central NGS testing* and biomarker analyses, or >24 month if the participant has never received a targeted therapy, 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 RANO HGG for high-grade tumors or RANO LGG for the low grade tumors, 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:
1. Alopecia (Grade ≤2)
2. Sensory neuropathy (Grade ≤2)
3. 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.

For the most up-to-date list of criteria, please visit clinicaltrials.gov.

Exclusion Criteria

Group 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 RAF/BRAF 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).
1. 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.
Prior treatment with a MEK inhibitor.
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.
Malignancy with co-occurring activating RAS mutation(s) at any time.
Uncontrolled intercurrent illness that would limit compliance with study requirements.
Current or planned participation in a study of an investigational agent or device.
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).
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 and 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.

Group B:

Prior treatment with BRAF, ERK, and/or MEK inhibitor(s).
Known or suspected neurofibromatosis-1 (NF-1) and/or Ras related gene alterations.
Uncontrolled intercurrent illness that would limit compliance with study requirements.
Active infection requiring systemic therapy.
Current or planned participation in a study of an investigational agent or device.
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).
Grade ≥ 2 changes in AST, ALT, gamma-glutamyl transaminase (GGT), or bilirubin attributed to prior immune checkpoint inhibitor treatment are exclusionary, even if resolved.
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.
Progressively worsening in frequency or severity seizures indicative of rapid tumor progression, or seizures poorly controlled with available therapy.

For the most up-to-date criteria, please visit clinicaltrials.gov.

Investigator(s)