Cancer Harboring BRAF Alterations, HGG, LGG, Solid Tumors
Conditions
Keywords
BRAF alterations, BRAF Fusions, BRAF V600E, BRAF Class 1, BRAF Class 2, High grade glioma, low grade glioma, HGG, LGG, Solid tumors, Biliary tract cancer, Ovarian cancer, Fallopian tube cancer, Primary peritoneal cancer, Anaplastic thyroid cancer, Cholangiocarcinoma, Bladder cancer, Uterine cancer, Hepatocellular carcinoma, Gastrointestinal stromal tumor (GIST), Breast cancer, Children, Pediatric, Adolescent, Young adult
Brief summary
The objective of this Master Protocol is to evaluate the efficacy and safety of plixorafenib in participants with BRAF altered (BRAF V600E or BRAF fusions) locally advanced or metastatic solid tumors, or recurrent or progressive primary central nervous system (CNS) tumors, including rare BRAF V600E-mutated solid tumors, including anaplastic thyroid, ovarian, cholangiocarcinoma or other rare cancers.
Interventions
DRUGPlixorafenib
Oral tablets
Sponsors
Fore Biotherapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
All four open-label single-arm subprotocols will enroll patients independently of one another, in parallel.
Eligibility
Sex/Gender
ALL
Age
8 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Subprotocol A: 1. Male and female, ≥8 years of age, and weighing ≥25 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, ≥8 years of age, and weighing ≥25 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 (8-17 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, ≥8 years of age, and weighing ≥25 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. Subprotocol D: 1. Male and female, ≥8 years of age, and weighing ≥25 kg. 2. Histologic diagnosis of a solid tumor harboring a BRAF V600E mutation and not eligible for other subprotocols. 3. Measurable disease on CT, MRI, or physical exam. 4. Evidence of BRAF V600E mutation in tumor and/or blood detected by genomic tests. 5. Consent to provide a tumor biopsy. 6. Willingness to comply with the ECG substudy procedures. 7. All adverse events related to prior therapies (chemotherapy; radiotherapy; surgery) must have resolved to Grade 1 or baseline.
Exclusion criteria
Subprotocol A: 1. Prior treatment with RAF/BRAF inhibitors active for Class 2 BRAF alterations for advanced unresectable or metastatic disease. 2. Prior treatment with a MEK inhibitor. 3. Tyrosine kinase inhibitor(s) and/or targeted therapies are allowed (other than BRAF/MAPK pathway inhibitors per
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) (Subprotocols A, B and C) | Up to approximately 4 years | ORR will be determined by standard tumor response criteria by blinded independent central review (BICR). |
| Pharmacokinetics (Subprotocol D) | Up to approximately 4 years | Systemic exposure of plixorafenib measured by Cmax and AUC |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) by BICR (Subprotocols A, B and C) | Up to approximately 4 years | DOR will be determined by standard tumor response criteria per BICR (subprotocols A-C) |
| ORR per Investigator Assessment | Up to approximately 4 years | ORR will be determined by standard tumor response criteria by Investigator Assessment. |
| DOR per Investigator Assessment | Up to approximately 4 years | DOR will be determined by standard tumor response criteria. |
| 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 (Subprotocols A, B and C) | Up to approximately 4 years | — |
| Progression Free Survival (PFS) by BICR (Subprotocols A, B and C) | Up to approximately 4 years | — |
| PFS per Investigator's Assessment | Up to approximately 4 years | — |
| Overall Survival | Up to approximately 4 years | — |
| Percentage of Participants with PFS at 6 months, 12 months and 24 months | 6 months, 12 months and 24 months | BICR (Subprotocols A, B and C) and by Investigator Assessment (Subprotocols A, B, C and D) |
| Disease Control Rate (DCR) | Up to approximately 4 years | — |
| Number of Participants who Experience Treatment-emergent Adverse Events (TEAEs) | Up to approximately 4 years | — |
| Plasma Concentrations of Plixorafenib | Up to approximately 4 years | — |
| Plasma Concentrations of Plixorafenib Metabolites | Up to approximately 4 years | — |
Countries
Australia, Canada, France, Germany, Italy, Netherlands, Norway, South Korea, Spain, Sweden, United Kingdom, United States
Contacts
CONTACTJessica Rine
CONTACTGeri Bardelli
Outcome results
None listed