Trial Review

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT05503797




Registration number
NCT05503797
Ethics application status
Date submitted
15/08/2022
Date registered
17/08/2022
Date last updated
14/05/2025

Titles & IDs
Public title
A Study to Assess the Efficacy and Safety of FORE8394 in Participants With Cancer Harboring BRAF Alterations
Scientific 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
Secondary ID [1] 0 0
2022-000627-20
Secondary ID [2] 0 0
F8394-201
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cancer Harboring BRAF Alterations 0 0
HGG 0 0
LGG 0 0
Solid Tumors 0 0
Melanoma BRAF V600E/K Mutated 0 0
Thyroid Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Thyroid

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Plixorafenib
Treatment: Drugs - Cobicistat

Experimental: Subprotocol A - Participants with unresectable, locally advanced or metastatic solid tumors or primary CNS tumors harboring BRAF fusions will receive plixorafenib which will be increased as tolerated, continuously in 3-week cycles until disease progression, unacceptable toxicity, or other reason for withdrawal.

Experimental: Subprotocol B - Participants with recurrent primary CNS tumors harboring BRAF V600E mutations will receive plixorafenib administered with cobicistat, continuously in 3-week cycles until disease progression, unacceptable toxicity, or other reason for withdrawal.

Experimental: Subprotocol C - Participants with advanced, rare, non-CNS solid tumors harboring BRAF V600E mutations will receive plixorafenib administered with cobicistat, continuously in 3-week cycles until disease progression, unacceptable toxicity, or other reason for withdrawal.

Experimental: Subprotocol D - Participants with BRAF V600E-mutated cutaneous melanoma and BRAF V600E-mutated thyroid cancer (MAPK inhibitor naïve) will be randomized to receive plixorafenib with or without cobicistat.


Treatment: Drugs: Plixorafenib
Oral tablets

Treatment: Drugs: Cobicistat
Oral tablets
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Objective Response Rate (ORR) (Subprotocols A, B and C)
Timepoint [1] 0 0
Up to approximately 4 years
Primary outcome [2] 0 0
Pharmacokinetics (Subprotocol D)
Timepoint [2] 0 0
Up to approximately 4 years
Secondary outcome [1] 0 0
Duration of Response (DOR) by BICR (Subprotocols A, B and C)
Timepoint [1] 0 0
Up to approximately 4 years
Secondary outcome [2] 0 0
ORR per Investigator Assessment
Timepoint [2] 0 0
Up to approximately 4 years
Secondary outcome [3] 0 0
DOR per Investigator Assessment
Timepoint [3] 0 0
Up to approximately 4 years
Secondary outcome [4] 0 0
Percentage of Participants with DOR at 6 months, 12 months, and 18 months
Timepoint [4] 0 0
6 months, 12 months and 18 months
Secondary outcome [5] 0 0
Time to Response by BICR (Subprotocols A, B and C)
Timepoint [5] 0 0
Up to approximately 4 years
Secondary outcome [6] 0 0
Progression Free Survival (PFS) by BICR (Subprotocols A, B and C)
Timepoint [6] 0 0
Up to approximately 4 years
Secondary outcome [7] 0 0
PFS per Investigator's Assessment
Timepoint [7] 0 0
Up to approximately 4 years
Secondary outcome [8] 0 0
Overall Survival
Timepoint [8] 0 0
Up to approximately 4 years
Secondary outcome [9] 0 0
Percentage of Participants with PFS at 6 months, 12 months and 24 months
Timepoint [9] 0 0
6 months, 12 months and 24 months
Secondary outcome [10] 0 0
Disease Control Rate (DCR)
Timepoint [10] 0 0
Up to approximately 4 years
Secondary outcome [11] 0 0
Number of Participants who Experience Treatment-emergent Adverse Events (TEAEs)
Timepoint [11] 0 0
Up to approximately 4 years
Secondary outcome [12] 0 0
Plasma Concentrations of Plixorafenib
Timepoint [12] 0 0
Up to approximately 4 years
Secondary outcome [13] 0 0
Plasma Concentrations of Plixorafenib Metabolites
Timepoint [13] 0 0
Up to approximately 4 years
Secondary outcome [14] 0 0
Subprotocol A: CNS-DOR by BICR
Timepoint [14] 0 0
Up to approximately 4 years
Secondary outcome [15] 0 0
Subprotocol A: CNS-ORR by BICR
Timepoint [15] 0 0
Up to approximately 4 years
Secondary outcome [16] 0 0
Subgroup analyses for efficacy endpoints in low-grade and high-grade primary CNS tumors will be reported.
Timepoint [16] 0 0
Up to approximately 4 years

Eligibility
Key inclusion criteria
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.
Minimum age
10 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
21/02/2023
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
28/12/2026
Actual
Sample size
Target
250
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 0 0
Newcastle Private Hospital - New Lambton Heights
Recruitment hospital [2] 0 0
The Alfred - Melbourne
Recruitment hospital [3] 0 0
Sydney Children's Hospital Network - Randwick - Randwick
Recruitment postcode(s) [1] 0 0
2305 - New Lambton Heights
Recruitment postcode(s) [2] 0 0
3004 - Melbourne
Recruitment postcode(s) [3] 0 0
2031 - Randwick
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Florida
Country [3] 0 0
United States of America
State/province [3] 0 0
Maryland
Country [4] 0 0
United States of America
State/province [4] 0 0
Massachusetts
Country [5] 0 0
United States of America
State/province [5] 0 0
Minnesota
Country [6] 0 0
United States of America
State/province [6] 0 0
Missouri
Country [7] 0 0
United States of America
State/province [7] 0 0
Nebraska
Country [8] 0 0
United States of America
State/province [8] 0 0
New Jersey
Country [9] 0 0
United States of America
State/province [9] 0 0
New York
Country [10] 0 0
United States of America
State/province [10] 0 0
Ohio
Country [11] 0 0
United States of America
State/province [11] 0 0
Pennsylvania
Country [12] 0 0
United States of America
State/province [12] 0 0
Rhode Island
Country [13] 0 0
United States of America
State/province [13] 0 0
Texas
Country [14] 0 0
United States of America
State/province [14] 0 0
Washington
Country [15] 0 0
United States of America
State/province [15] 0 0
West Virginia
Country [16] 0 0
Canada
State/province [16] 0 0
Ontario
Country [17] 0 0
Canada
State/province [17] 0 0
Quebec
Country [18] 0 0
France
State/province [18] 0 0
Aquitaine
Country [19] 0 0
France
State/province [19] 0 0
Bouches-du-Rhône
Country [20] 0 0
France
State/province [20] 0 0
Finistère
Country [21] 0 0
France
State/province [21] 0 0
Ile-de-France
Country [22] 0 0
France
State/province [22] 0 0
Pays De La Loire
Country [23] 0 0
France
State/province [23] 0 0
Val-de-Marne
Country [24] 0 0
France
State/province [24] 0 0
Toulouse
Country [25] 0 0
Germany
State/province [25] 0 0
Baden-Württemberg
Country [26] 0 0
Germany
State/province [26] 0 0
Hessen
Country [27] 0 0
Germany
State/province [27] 0 0
Berlin
Country [28] 0 0
Italy
State/province [28] 0 0
Forli-Cesena
Country [29] 0 0
Italy
State/province [29] 0 0
Naples
Country [30] 0 0
Italy
State/province [30] 0 0
Milano
Country [31] 0 0
Italy
State/province [31] 0 0
Milan
Country [32] 0 0
Korea, Republic of
State/province [32] 0 0
Gyeonggi-do
Country [33] 0 0
Korea, Republic of
State/province [33] 0 0
Gyeonggido
Country [34] 0 0
Korea, Republic of
State/province [34] 0 0
Gyeongsangnam-do
Country [35] 0 0
Korea, Republic of
State/province [35] 0 0
Jeollanam-do
Country [36] 0 0
Korea, Republic of
State/province [36] 0 0
Seoul Teugbyeoisi
Country [37] 0 0
Korea, Republic of
State/province [37] 0 0
Seoul Teugbyeolsi
Country [38] 0 0
Spain
State/province [38] 0 0
A Coruña
Country [39] 0 0
Spain
State/province [39] 0 0
Valencia
Country [40] 0 0
Spain
State/province [40] 0 0
Barcelona
Country [41] 0 0
Spain
State/province [41] 0 0
Madrid
Country [42] 0 0
Spain
State/province [42] 0 0
Sevilla
Country [43] 0 0
Sweden
State/province [43] 0 0
Skåne Län
Country [44] 0 0
Sweden
State/province [44] 0 0
Stockholms Län
Country [45] 0 0
United Kingdom
State/province [45] 0 0
England
Country [46] 0 0
United Kingdom
State/province [46] 0 0
London

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Fore Biotherapeutics
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Jessica Rine
Address 0 0
Country 0 0
Phone 0 0
610-442-4517
Fax 0 0
Email 0 0
[email protected]
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
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 document/s available: Study protocol
When will data be available (start and end dates)?
Starting 6 months after publication of summary data and ending 36 months following article publication.
Available to whom?
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.
Available for what types of analyses?
How or where can data be obtained?


What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

No documents have been uploaded by study researchers.

Results not provided in https://clinicaltrials.gov/study/NCT05503797