Clinical trial NCT05503797: A Study to Assess the Efficacy and Safety of FORE8394 in Participants With Cancer Harboring BRAF Alterations
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Cancer Harboring BRAF Alterations
HGG
LGG
Solid Tumors
Melanoma BRAF V600E/K Mutated
Thyroid Cancer
Keywords: BRAF alterations
BRAF Fusions
BRAF V600E
BRAF Class 1
BRAF Class 2
High grade glioma
low grade glioma
HGG
LGG
Solid tumors
Lead sponsor: Fore Biotherapeutics
Sponsor class: INDUSTRY
First posted: 2022-08-17
Enrollment: 250
Sex: ALL
Minimum age (years): 10
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: All four open-label subprotocols will enroll patients independently of one another, in parallel. Subprotocols A-C are single-arm. Subprotocol D is a open-label cross over design.
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility 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.

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.

Primary outcomes:
measure: Objective Response Rate (ORR) (Subprotocols A, B and C)
timeFrame: Up to approximately 4 years
measure: Pharmacokinetics (Subprotocol D)
timeFrame: Up to approximately 4 years
Secondary outcomes:
measure: Duration of Response (DOR) by BICR (Subprotocols A, B and C)
timeFrame: Up to approximately 4 years
measure: ORR per Investigator Assessment
timeFrame: Up to approximately 4 years
measure: DOR per Investigator Assessment
timeFrame: Up to approximately 4 years
measure: Percentage of Participants with DOR at 6 months, 12 months, and 18 months
timeFrame: 6 months, 12 months and 18 months
measure: Time to Response by BICR (Subprotocols A, B and C)
timeFrame: Up to approximately 4 years
measure: Progression Free Survival (PFS) by BICR (Subprotocols A, B and C)
timeFrame: Up to approximately 4 years
measure: PFS per Investigator's Assessment
timeFrame: Up to approximately 4 years
measure: Overall Survival
timeFrame: Up to approximately 4 years
measure: Percentage of Participants with PFS at 6 months, 12 months and 24 months
timeFrame: 6 months, 12 months and 24 months
measure: Disease Control Rate (DCR)
timeFrame: Up to approximately 4 years
measure: Number of Participants who Experience Treatment-emergent Adverse Events (TEAEs)
timeFrame: Up to approximately 4 years
measure: Plasma Concentrations of Plixorafenib
timeFrame: Up to approximately 4 years
measure: Plasma Concentrations of Plixorafenib Metabolites
timeFrame: Up to approximately 4 years
measure: Subprotocol A: CNS-DOR by BICR
timeFrame: Up to approximately 4 years
measure: Subprotocol A: CNS-ORR by BICR
timeFrame: Up to approximately 4 years
measure: Subgroup analyses for efficacy endpoints in low-grade and high-grade primary CNS tumors will be reported.
timeFrame: Up to approximately 4 years
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: UCSF Helen Diller Family Comprehensive Cancer Center
state: California
city: Westwood
country: United States
facility: University of California Los Angeles Rheumatology
state: California
city: Miami
country: United States
facility: University of Miami Hospital and Clinics
state: Florida
city: Baltimore
country: United States
facility: The John Hopkins Hospital
state: Maryland
city: Rockville
country: United States
facility: Maryland Oncology Hematology- Columbia
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Duluth
country: United States
facility: St. Luke's Hospital
state: Minnesota
city: Saint Joseph
country: United States
facility: Mosaic Life Care at Saint Joseph - Medical Center
state: Missouri
city: Omaha
country: United States
facility: Nebraska Cancer Specialists - Midwest Cancer Center - Legacy
state: Nebraska
city: Summit
country: United States
facility: Overlook Medical Center
state: New Jersey
city: New York
country: United States
facility: Columbia University Irving Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Maumee
country: United States
facility: Taylor Cancer Research Center
state: Ohio
city: Toledo
country: United States
facility: Toledo Clinic Cancer Center
state: Ohio
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Providence
country: United States
facility: Lifespan Cancer Institute - Rhode Island Hospital
state: Rhode Island
city: Dallas
country: United States
facility: Baylor Scott & White Research Institute
state: Texas
city: Temple
country: United States
facility: Baylor Scott & White Medical Center
state: Texas
city: Seattle
country: United States
facility: University of Washington School of Medicine
state: Washington
city: Morgantown
country: United States
facility: West Virginia University Health Sciences Campus
state: West Virginia
city: New Lambton Heights
country: Australia
facility: Newcastle Private Hospital
state: New South Wales
city: Melbourne
country: Australia
facility: The Alfred
state: Victoria
city: Randwick
country: Australia
facility: Sydney Children's Hospital Network - Randwick
city: Toronto
country: Canada
facility: Sunny brook Health Sciences Centre- Bayview Campus
state: Ontario
city: Montréal
country: Canada
facility: Centre Hospitalier Universitaire Sainte-Justine
state: Quebec
city: Bordeaux Cedex
country: France
facility: Institut Bergonie
state: Aquitaine
city: Marseille
country: France
facility: Hôpital Nord de Marseille
state: Bouches-du-Rhône
city: Brest
country: France
facility: Hôpital Morvan
state: Finistère
city: Paris
country: France
facility: Hôpital Universitaire Pitié Salpêtrière
state: Ile-de-France
city: Angers
country: France
facility: Institut de Cancerologie de l'Ouest- Angers
state: Pays De La Loire
city: Villejuif
country: France
facility: Gustave Roussy
state: Val-de-Marne
city: Toulouse
country: France
facility: Institut Universitaire du Cancer de Toulouse Oncopole
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
state: Baden-Württemberg
city: Frankfurt
country: Germany
facility: Krankenhaus Nordwest
state: Hessen
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin
city: Meldola
country: Italy
facility: Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" - IRST
state: Forli-Cesena
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori IRCCS Fondazione G. Pascale
state: Naples
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia
city: Milan
country: Italy
facility: Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) - Ospedale San Raffaele
city: Suwon-si
country: Korea, Republic of
facility: Catholic University of Korea Saint Vincent's Hospital
state: Gyeonggi-do
city: Suwon
country: Korea, Republic of
facility: Seoul National University Hospital
state: Gyeonggido
city: Busan
country: Korea, Republic of
facility: Dong-A University Hospital
state: Gyeongsangnam-do
city: Hwasun
country: Korea, Republic of
facility: Chonnam National University Hwasun Hospital
state: Jeollanam-do
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
state: Seoul Teugbyeoisi
city: Seoul
country: Korea, Republic of
facility: Severance Hospital
state: Seoul Teugbyeolsi
city: Santiago De Compostela
country: Spain
facility: Hospital Clinico Universitarlo de Santiago
state: A Coruña
city: València
country: Spain
facility: Hospital Clinico Universitarlo de Valencia
state: Valencia
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Infantil Universitario Niño Jesús
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocío
city: Lund
country: Sweden
facility: Skånes Universitetssjukhus
state: Skåne Län
city: Solna
country: Sweden
facility: Karolinska Universitetssjukhuset
state: Stockholms Län
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
state: England
city: London
country: United Kingdom
facility: Sarah Cannon Research Institute
Study officials:
References: