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

• ClinicalTrials.gov Identifier: NCT05503797
• Recruitment Status: Recruiting
• First Posted: August 17, 2022
• Last Update Posted: May 3, 2024
• Sponsor: Fore Biotherapeutics
• Information provided by (Responsible Party): Fore Biotherapeutics

Tracking Information

• First Submitted Date: August 15, 2022
• First Posted Date: August 17, 2022
• Last Update Posted Date: May 3, 2024
• Actual Study Start Date: February 21, 2023
• Estimated Primary Completion Date: June 27, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 15, 2022)

Objective Response Rate (ORR) [ Time Frame: Up to approximately 4 years ]

ORR will be determined by standard tumor response criteria by blinded independent central review (BICR).

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: March 5, 2024)

• Duration of Response (DOR) [ Time Frame: Up to approximately 4 years ]
  DOR will be determined by standard tumor response criteria.
• ORR per Investigator Assessment [ Time Frame: Up to approximately 4 years ]
  ORR will be determined by standard tumor response criteria by BICR.
• DOR per Investigator Assessment [ Time Frame: Up to approximately 4 years ]
  DOR will be determined by standard tumor response criteria.
• Group A: CNS-DOR by BICR [ Time Frame: Up to approximately 4 years ]
• Percentage of Participants with DOR at 6 months, 12 months, and 18 months [ Time Frame: 6 months, 12 months and 18 months ]
• Time to Response by BICR [ Time Frame: Up to approximately 4 years ]
• Progression Free Survival (PFS) by BICR [ Time Frame: Up to approximately 4 years ]
• PFS per Investigator's Assessment [ Time Frame: Up to approximately 4 years ]
• Percentage of Participants with PFS at 6 months, 12 months and 18 months [ Time Frame: 6 months, 12 months and 18 months ]
• Overall Survival [ Time Frame: Up to approximately 4 years ]
• Disease Control Rate (DCR) [ Time Frame: Up to approximately 4 years ]
• Group A: CNS-ORR by BICR [ Time Frame: Up to approximately 4 years ]
• Number of Participants who Experience Treatment-emergent Adverse Events (TEAEs) [ Time Frame: Up to approximately 4 years ]
• Plasma Concentrations of Plixorafenib [ Time Frame: Up to approximately 4 years ]
• Plasma Concentrations of Plixorafenib Metabolites [ Time Frame: Up to approximately 4 years ]

Original Secondary Outcome Measures (submitted: August 15, 2022)

• Duration of Response (DOR) [ Time Frame: Up to approximately 4 years ]
  DOR will be determined by standard tumor response criteria.
• ORR per Investigator Assessment [ Time Frame: Up to approximately 4 years ]
  ORR will be determined by standard tumor response criteria by BICR.
• DOR per Investigator Assessment [ Time Frame: Up to approximately 4 years ]
  DOR will be determined by standard tumor response criteria.
• Group A: CNS-DOR by BICR [ Time Frame: Up to approximately 4 years ]
• Percentage of Participants with DOR at 6 months, 12 months, and 18 months [ Time Frame: 6 months, 12 months and 18 months ]
• Time to Response by BICR [ Time Frame: Up to approximately 4 years ]
• Progression Free Survival (PFS) by BICR [ Time Frame: Up to approximately 4 years ]
• PFS per Investigator's Assessment [ Time Frame: Up to approximately 4 years ]
• Percentage of Participants with PFS at 6 months, 12 months and 18 months [ Time Frame: 6 months, 12 months and 18 months ]
• Overall Survival [ Time Frame: Up to approximately 4 years ]
• Disease Control Rate (DCR) [ Time Frame: Up to approximately 4 years ]
• Group A: CNS-ORR by BICR [ Time Frame: Up to approximately 4 years ]
• Number of Participants who Experience Treatment-emergent Adverse Events (TEAEs) [ Time Frame: Up to approximately 4 years ]
• Plasma Concentrations of FORE8394 [ Time Frame: Up to approximately 4 years ]
• Plasma Concentrations of FORE8394 Metabolites [ Time Frame: Up to approximately 4 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Assess the Efficacy and Safety of FORE8394 in Participants With Cancer Harboring BRAF Alterations
• Official Title: 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
• Brief Summary: The objective of this study is to evaluate the efficacy of plixorafenib in participants with locally advanced or metastatic solid tumors, or recurrent or progressive primary central nervous system (CNS) tumors harboring BRAF fusions, or in participants with recurrent high-grade glioma (HGG) harboring BRAF V600E mutation. This will be conducted as two single arm open-label subprotocols (F8394-201A; F8394-201B) under one master protocol.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Cancer Harboring BRAF Alterations

Intervention

• Drug: Plixorafenib
  Oral tablets
  Other Name: FORE8394
• Drug: Cobicistat
  Oral tablets
  Other Name: TYBOST(R)

Study Arms

• Experimental: Group A
  Participants with unresectable, locally advanced or metastatic solid tumors or primary CNS tumors harboring BRAF fusions, will receive 900 mg of plixorafenib administered with 150 mg of cobicistat once daily (QD), continuously in 3-weeks cycles until disease progression, unacceptable toxicity, or other reason for withdrawal.
  Interventions:

  • Drug: Plixorafenib
  • Drug: Cobicistat
• Experimental: Group B
  Participants with recurrent primary CNS tumors harboring BRAF V600E mutations will receive 900 mg of plixorafenib administered with 150 mg of cobicistat QD, continuously in 3-week cycles until disease progression, unacceptable toxicity, or other reason for withdrawal.
  Interventions:

  • Drug: Plixorafenib
  • Drug: Cobicistat

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 15, 2022): 135
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: August 28, 2026
• Estimated Primary Completion Date: June 27, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria

Group 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 at CLIA or CLIA-equivalent laboratory or sponsor-designated central laboratory.
4. 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.
5. 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.
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 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:

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).
   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. Consult the Medical Lead to discuss and determine if participant is eligible for enrollment.

   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 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.
4. 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.
5. Measurable disease based upon RANO HGG for high-grade tumors or RANO LGG for the low grade tumors, as determined by the radiographic BICR.

6. 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
7. 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.

Exclusion Criteria:

Group 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 (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. 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. NOTE: There is no restriction on the number of lines of chemotherapy or immunotherapy.
6. Malignancy with co-occurring activating RAS mutation(s) at any time.
7. Uncontrolled intercurrent illness that would limit compliance with study requirements.
8. Current or planned participation in a study of an investigational agent or device.
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. 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:

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.
9. Progressively worsening in frequency or severity seizures indicative of rapid tumor progression, or seizures poorly controlled with available therapy.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 10 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Jessica Rine; 610-442-4517; jessica.rine@fore.bio

Contact: Geri Bardelli; 978-835-2310; geraldine.bardelli@fore.bio

• Listed Location Countries: Canada, France, Germany, Italy, Korea, Republic of, Spain, Sweden, United Kingdom, United States

Administrative Information

• NCT Number: NCT05503797
• Other Study ID Numbers: F8394-201; 2022-000627-20 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Fore is committed to sharing with qualified external researchers access to deidentified patient-level data and related study documents (eg. study protocol) from eligible studies following publication of the study results.
• Supporting Materials: Study Protocol
• Time Frame: Starting 6 months after publication of summary data and ending 36 months following article publication.
• Access Criteria: Qualified external researchers may submit a request to access deidentified patient-level data and related study documents (eg. study protocol). These requests will be reviewed and approved by an independent committee on the basis of scientific merit and may be subject to certain criteria, conditions, and exceptions. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

• Current Responsible Party: Fore Biotherapeutics
• Original Responsible Party: Same as current
• Current Study Sponsor: Fore Biotherapeutics
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Fore Biotherapeutics
• Verification Date: June 2023