Informations générales (source: ClinicalTrials.gov)
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
Interventional
Phase 2
Fore Biotherapeutics (Voir sur ClinicalTrials)
février 2023
décembre 2026
25 juillet 2025
The objective of this Master Protocol is to evaluate the efficacy and safety 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 rare BRAF V600-mutated solid tumors, melanoma, thyroid,
or recurrent primary CNS tumors.
Etablissements
| Les établissements d'Île-de-France ayant mis à jour leurs données Origine et niveau de fiabilité des données | |||||
|---|---|---|---|---|---|
| CLCC INSTITUT GUSTAVE ROUSSY | Claudia PARISI | 14/06/2024 08:13:38 | Contacter | ||
| Les établissements sans correspondance certaine dans le répertoire FINESS dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| Hôpital Morvan - 29200 - Brest - Finistère - France | Contact (sur clinicalTrials) | ||||
| Hôpital Nord de Marseille - 13005 - Marseille - Bouches-du-Rhône - France | Contact (sur clinicalTrials) | ||||
| Hôpital Universitaire Pitié Salpêtrière - 75013 - Paris - Ile-de-France - France | Contact (sur clinicalTrials) | ||||
| Institut Bergonie - 33000 - Bordeaux Cedex - Aquitaine - France | Contact (sur clinicalTrials) | ||||
| Institut de Cancerologie de l'Ouest- Angers - 49055 - Angers - Pays De La Loire - France | Contact (sur clinicalTrials) | ||||
| Institut Universitaire du Cancer de Toulouse Oncopole - 31059 - Toulouse - France | Contact (sur clinicalTrials) | ||||
Critères
Tous
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.
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.
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.
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.