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

Study Overview
=================
Brief Summary
-----------------
The objective of this study is to evaluate the efficacy of FORE8394 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.

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

Conditions
-----------------
Cancer Harboring BRAF Alterations

Intervention / Treatment
-----------------
* Drug: FORE8394
* Drug: Cobicistat


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Group A: Male and female, ≥10 years of age, and weighing ≥30 kg. Histologic diagnosis of a solid tumor or primary CNS tumor. Documentation of BRAF gene fusion in tumor and/or blood detected by an analytically validated test by DNA sequencing or RNA (transcriptome) sequencing. Have an archival tissue sample available with sufficient tumor for central next generation sequencing (NGS) testing and biomarker analyses. 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 at least 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 Alopecia (Grade ≤2) Sensory neuropathy (Grade ≤2) 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: Male and female, ≥10 years of age, and weighing ≥30 kg. Histological diagnosis of a grade 3 or 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], or high grade ganglioglioma), or has a prior, histologically confirmed, diagnosis of a grade 2 glioma and now has radiographic or histopathological findings consistent with an HGG (World Health Organization [WHO][2021] grade 3 or 4). Note: If a non anaplastic pleomorphic xanthoastrocytoma is re-resected at recurrence and found to have a ≥ Grade 2 histology, this would be considered eligible. Have received at least one line of prior therapy including radiation. NOTE: Patients for whom radiotherapy is not considered standard of care may remain eligible for the study. Documented BRAF V600E mutation in tumor and/or blood (if individual test has sufficient analytical coverage) detected by an analytically validated test by NGS or polymerase chain reaction (PCR) methods. An archival tissue sample at less than 24 months from date of screening or >24 months 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 basket trial is preferred. Measurable disease based upon RANO HGG 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: Alopecia (Grade ≤2) Sensory neuropathy (Grade ≤2) 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. 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 (such as tovorafenib [formerly known as DAY 101, TAK 580, and MLN 2480], KIN-2787, BGB-3245, and CFT1946). 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 FORE8394 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: 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. 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 FORE8394 or cobicistat (such as ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection). Are currently receiving (within 7 days of Cycle 1 Day 1) or are planning to receive during participation: 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. Agents that are contraindicated with cobicistat i) 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.

Ages Eligible for Study
-----------------
Minimum Age: 10 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>Participants with unresectable, locally advanced or metastatic solid tumors or primary CNS tumors harboring BRAF fusions, will receive 900 mg of FORE8394 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: FORE8394<br>* Oral tablets<br>Drug: Cobicistat<br>* Oral tablets<br>* Other names: TYBOST(R);|
| Experimental: Group B<br>Participants with recurrent primary CNS tumors harboring BRAF V600E mutations will receive 900 mg of FORE8394 administered with 150 mg of cobicistat QD, continuously in 3-week cycles until disease progression, unacceptable toxicity, or other reason for withdrawal. | Drug: FORE8394<br>* Oral tablets<br>Drug: Cobicistat<br>* Oral tablets<br>* Other names: TYBOST(R);|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR will be determined by standard tumor response criteria by blinded independent central review (BICR). | Up to approximately 4 years | 

Secondary Outcome Measures

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

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
BRAF Fusions, BRAF alterations, BRAF V600E, BRAF Class 1, BRAF Class 2