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Trial record 1 of 1 for:    F8394-201
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A Study to Assess the Efficacy and Safety of FORE8394 in Participants With Cancer Harboring BRAF Alterations

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ClinicalTrials.gov Identifier: NCT05503797
Recruitment Status : Recruiting
First Posted : August 17, 2022
Last Update Posted : May 21, 2024
Sponsor:
Information provided by (Responsible Party):
Fore Biotherapeutics

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.

Condition or disease Intervention/treatment Phase
Cancer Harboring BRAF Alterations Drug: Plixorafenib Drug: Cobicistat Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 135 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : February 21, 2023
Estimated Primary Completion Date : June 27, 2025
Estimated Study Completion Date : August 28, 2026

Resource links provided by the National Library of Medicine

Drug Information available for: Cobicistat

Arm Intervention/treatment
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.
Drug: Plixorafenib
Oral tablets
Other Name: FORE8394

Drug: Cobicistat
Oral tablets
Other Name: TYBOST(R)

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.
Drug: Plixorafenib
Oral tablets
Other Name: FORE8394

Drug: Cobicistat
Oral tablets
Other Name: TYBOST(R)




Primary Outcome Measures :
  1. 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).


Secondary Outcome Measures :
  1. Duration of Response (DOR) [ Time Frame: Up to approximately 4 years ]
    DOR will be determined by standard tumor response criteria.

  2. ORR per Investigator Assessment [ Time Frame: Up to approximately 4 years ]
    ORR will be determined by standard tumor response criteria by BICR.

  3. DOR per Investigator Assessment [ Time Frame: Up to approximately 4 years ]
    DOR will be determined by standard tumor response criteria.

  4. Group A: CNS-DOR by BICR [ Time Frame: Up to approximately 4 years ]
  5. Percentage of Participants with DOR at 6 months, 12 months, and 18 months [ Time Frame: 6 months, 12 months and 18 months ]
  6. Time to Response by BICR [ Time Frame: Up to approximately 4 years ]
  7. Progression Free Survival (PFS) by BICR [ Time Frame: Up to approximately 4 years ]
  8. PFS per Investigator's Assessment [ Time Frame: Up to approximately 4 years ]
  9. Percentage of Participants with PFS at 6 months, 12 months and 18 months [ Time Frame: 6 months, 12 months and 18 months ]
  10. Overall Survival [ Time Frame: Up to approximately 4 years ]
  11. Disease Control Rate (DCR) [ Time Frame: Up to approximately 4 years ]
  12. Group A: CNS-ORR by BICR [ Time Frame: Up to approximately 4 years ]
  13. Number of Participants who Experience Treatment-emergent Adverse Events (TEAEs) [ Time Frame: Up to approximately 4 years ]
  14. Plasma Concentrations of Plixorafenib [ Time Frame: Up to approximately 4 years ]
  15. Plasma Concentrations of Plixorafenib Metabolites [ Time Frame: Up to approximately 4 years ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   10 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05503797


Contacts
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Contact: Jessica Rine 610-442-4517 jessica.rine@fore.bio
Contact: Geri Bardelli 978-835-2310 geraldine.bardelli@fore.bio

Locations
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Sponsors and Collaborators
Fore Biotherapeutics
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Responsible Party: Fore Biotherapeutics
ClinicalTrials.gov Identifier: NCT05503797    
Other Study ID Numbers: F8394-201
2022-000627-20 ( EudraCT Number )
First Posted: August 17, 2022    Key Record Dates
Last Update Posted: May 21, 2024
Last Verified: May 2024
Individual Participant Data (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.

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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
Keywords provided by Fore Biotherapeutics:
BRAF alterations
BRAF Fusions
BRAF V600E
BRAF Class 1
BRAF Class 2
Additional relevant MeSH terms:
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Cobicistat
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action