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Trial Title: A Study to Assess the Efficacy and Safety of FORE8394 in Participants with Cancer Harboring BRAF Alterations

NCT ID: NCT05503797

Condition: Cancer Harboring BRAF Alterations

Conditions: Official terms:
Cobicistat

Conditions: Keywords:
BRAF alterations
BRAF Fusions
BRAF V600E
BRAF Class 1
BRAF Class 2

Study type: Interventional

Study phase: Phase 2

Overall status: Recruiting

Study design:

Allocation: Randomized

Intervention model: Parallel Assignment

Intervention model description: All four open-label subprotocols will enroll patients independently of one another, in parallel. Subprotocol D is a 2-arm, randomized study. The other subprotocols are single-arm.

Primary purpose: Treatment

Masking: None (Open Label)

Intervention:

Intervention type: Drug
Intervention name: Plixorafenib
Description: Oral tablets
Arm group label: Subprotocol A
Arm group label: Subprotocol B
Arm group label: Subprotocol C
Arm group label: Subprotocol D

Other name: FORE8394

Other name: PLX8394

Intervention type: Drug
Intervention name: Cobicistat
Description: Oral tablets
Arm group label: Subprotocol B
Arm group label: Subprotocol C
Arm group label: Subprotocol D

Other name: TYBOST(R)

Summary: The objective of this study is to evaluate the efficacy 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 solid tumors, melanoma, thyroid, or recurrent primary CNS tumors harboring BRAF V600E mutation. This will be conducted as four open-label subprotocols (F8394-201A; F8394-201B; F8394-201C; F8394-201D) under one master protocol.

Criteria for 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 at CLIA or CLIA-equivalent laboratory or sponsor-designated central laboratory. 4. Have an archival tissue sample available meeting protocol requirements. If an archival tissue sample is not available, a newly obtained (before treatment) tumor biopsy may be submitted instead. 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 except for 1. Alopecia (Grade ≤2) 2. Sensory neuropathy (Grade ≤2) 3. 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. 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. Consult the Medical Lead to discuss and determine if participant is eligible for enrollment. 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 blood 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. Tissue obtained most proximal to initiating this subprotocol is preferred. 5. Measurable disease based upon specified response criteria, as determined by the radiographic BICR. 6. All adverse events related to prior therapies (eg, chemotherapy, radiotherapy, surgery) must have resolved to Grade 1 or baseline except for: 1. Alopecia (Grade ≤2) 2. Sensory neuropathy (Grade ≤2) 3. 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 7. 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. Documented BRAF V600E mutation in tumor and/or blood detected by an analytically validated test at CLIA or CLIA-equivalent laboratory approved by sponsor or sponsor-designated central test. 4. Have an archival tissue sample available meeting protocol requirements. If an archival tissue sample is not available, a newly obtained (before treatment) tumor biopsy may be submitted instead. 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 except for 1. Alopecia (Grade ≤2) 2. Sensory neuropathy (Grade ≤2) 3. 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. 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. Consent to provide a tumor biopsy. 4. All adverse events related to prior therapies (chemotherapy; radiotherapy; surgery) must have resolved to Grade 1 or baseline except for 1. Alopecia (Grade ≤2) 2. Sensory neuropathy (Grade ≤2) 3. 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. 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 MAPK inhibitors active for Class 2 BRAF alterations for advanced unresectable or metastatic disease (including but not limited to tovorafenib [formerly known as DAY 101, TAK 580, and MLN 2480], KIN-2787, BGB-3245, and CFT1946). - Note: Participants with pediatric-type LGGs (molecular classification by WHO2021; diagnosed at ≤25 years of age) who had received prior treatment(s) with RAF/BRAF inhibitors are eligible for enrollment, provided there was no evidence of tumor progression on that therapy or within 4 weeks of discontinuation, based upon radiographic assessment. 4. 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. 5. Malignancy with co-occurring activating RAS mutation(s) at any time. 6. Uncontrolled intercurrent illness that would limit compliance with study requirements. 7. Current or planned participation in a study of an investigational agent or device. 8. 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). 9. Are currently receiving (within 7 days of Cycle 1 Day 1) or are planning to receive during participation: 1. Agents that are known strong inducers or inhibitors of CYP3A4 . Restrictions include foods or herbal medications, including grapefruit juice, grapefruit/grapefruit related citrus fruits (eg, Seville oranges, pomelos), and St. John's Wort. 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. Current or planned participation in a study of an investigational agent or device. 6. 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, 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. 8. Are currently receiving (within 7 days of Cycle 1 Day 1) or are planning to receive during participation: 1. 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. 2. 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. Subprotocol C: 1. Diagnosis of colorectal adenocarcinoma or pancreatic ductal adenocarcinoma (neuroendocrine or acinar tumors are eligible). 2. Participant has CNS metastases. If participants have symptoms that could be indicative of CNS metastases or tumors that are at high risk of CNS metastases, CNS imaging is required prior to the first dose of plixorafenib (MRI with contrast preferred). 3. Prior treatment with BRAF, ERK, and/or MEK inhibitor(s). 4. Known or suspected neurofibromatosis-1 (NF-1) and/or RAS related gene alterations. 5. Uncontrolled intercurrent illness that would limit compliance with study requirements. 6. Active infection requiring systemic therapy. 7. Current or planned participation in a study of an investigational agent or device. 8. 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, small bowel resection). 9. Grade ≥ 2 changes in AST, ALT, gamma-glutamyl transaminase (GGT), or bilirubin attributed to prior immune checkpoint inhibitor treatment are exclusionary, even if resolved. 10. Are currently receiving (within 7 days of Cycle 1 Day 1) or are planning to receive during participation: 1. 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. 2. 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. Subprotocol D: 1. Known or suspected neurofibromatosis-1 (NF-1) and/or RAS related gene alterations. 2. Participant has CNS metastases. 3. Uncontrolled intercurrent illness that would limit compliance with study requirements. 4. Active infection requiring systemic therapy. 5. Current or planned participation in a study of an investigational agent or device. 6. 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, 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. 8. Are currently receiving (within 7 days of Cycle 1 Day 1) or are planning to receive during participation: 1. 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. 2. 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.

Gender: All

Minimum age: 10 Years

Maximum age: N/A

Healthy volunteers: No

Locations:

Facility:
Name: UCSF Helen Diller Family Comprehensive Cancer Center

Address:
City: San Francisco
Zip: 94143
Country: United States

Status: Recruiting

Contact:
Last name: Nicholas Butowski

Facility:
Name: University of California Los Angeles Rheumatology

Address:
City: Westwood
Zip: 90095-6984
Country: United States

Status: Recruiting

Contact:
Last name: Noah Federman

Facility:
Name: University of Miami Hospital and Clinics

Address:
City: Miami
Zip: 33136
Country: United States

Status: Recruiting

Contact:
Last name: Macarena De la Fuente

Facility:
Name: The John Hopkins Hospital

Address:
City: Baltimore
Zip: 21287
Country: United States

Status: Recruiting

Contact:
Last name: Karisa Schreck

Facility:
Name: Tufts Medical Center

Address:
City: Boston
Zip: 02111
Country: United States

Status: Recruiting

Contact:
Last name: Jeyapalan Suriya

Facility:
Name: St. Luke's Hospital

Address:
City: Duluth
Zip: 55805
Country: United States

Status: Recruiting

Contact:
Last name: Homam Alkaied

Facility:
Name: Mosaic Life Care at Saint Joseph - Medical Center

Address:
City: St Joseph
Zip: 64506
Country: United States

Status: Recruiting

Contact:
Last name: Rony Abou-Jawde

Facility:
Name: Nebraska Cancer Specialists - Midwest Cancer Center - Legacy

Address:
City: Omaha
Zip: 68130
Country: United States

Status: Recruiting

Contact:
Last name: Joel Michalski

Facility:
Name: Overlook Medical Center

Address:
City: Summit
Zip: 07901
Country: United States

Status: Recruiting

Contact:
Last name: Robert Aiken

Facility:
Name: Columbia University Irving Medical Center

Address:
City: New York
Zip: 10032
Country: United States

Status: Recruiting

Contact:
Last name: Luca Szalontay

Facility:
Name: Memorial Sloan Kettering Cancer Center

Address:
City: New York
Zip: 10065
Country: United States

Status: Recruiting

Contact:
Last name: Eric Sherman

Facility:
Name: Nationwide Children's Hospital

Address:
City: Colombus
Zip: 43205
Country: United States

Status: Recruiting

Contact:
Last name: Mark Ranalli

Facility:
Name: Toledo Clinic Cancer Center

Address:
City: Toledo
Zip: 43623
Country: United States

Status: Recruiting

Contact:
Last name: Rex Mowat

Facility:
Name: Lifespan Cancer Institute - Rhode Island Hospital

Address:
City: Providence
Zip: 02903
Country: United States

Status: Recruiting

Contact:
Last name: Samit Sarangi

Facility:
Name: Baylor Scott & White Research Institute

Address:
City: Dallas
Zip: 75246
Country: United States

Status: Recruiting

Contact:
Last name: Karen Fink

Facility:
Name: Baylor Scott & White Medical Center

Address:
City: Temple
Zip: 43205
Country: United States

Status: Recruiting

Contact:
Last name: Jennifer Murillo

Facility:
Name: University of Washington School of Medicine

Address:
City: Seattle
Zip: 98109
Country: United States

Status: Recruiting

Contact:
Last name: Vyshak Venur

Facility:
Name: West Virginia University Health Sciences Campus

Address:
City: Morgantown
Zip: 26506
Country: United States

Status: Recruiting

Contact:
Last name: Sonikpreet Aulakh

Facility:
Name: Sunny brook Health Sciences Centre- Bayview Campus

Address:
City: Toronto
Zip: M4N 3M5
Country: Canada

Status: Recruiting

Contact:
Last name: Mary Jane Lim-Fay

Facility:
Name: Centre Hospitalier Universitaire Sainte-Justine

Address:
City: Montréal
Zip: H3T 1C5
Country: Canada

Status: Recruiting

Contact:
Last name: Sebastien Perreault

Facility:
Name: Institut Bergonie

Address:
City: Bordeaux Cedex
Zip: 33000
Country: France

Status: Recruiting

Contact:
Last name: Antoine Italiano

Facility:
Name: Hôpital Nord de Marseille

Address:
City: Marseille
Zip: 13005
Country: France

Status: Recruiting

Contact:
Last name: Pascale Tomasini

Facility:
Name: Hôpital Morvan

Address:
City: Brest
Zip: 29200
Country: France

Status: Recruiting

Contact:
Last name: Jean-Philippe Metges

Facility:
Name: Hôpital Universitaire Pitié Salpêtrière

Address:
City: Paris
Zip: 75013
Country: France

Status: Recruiting

Contact:
Last name: Mehdi Touat

Facility:
Name: Institut de Cancerologie de l'Ouest- Angers

Address:
City: Angers
Zip: 49055
Country: France

Status: Recruiting

Contact:
Last name: Lila Autier

Facility:
Name: Gustave Roussy

Address:
City: Villejuif
Zip: 94805
Country: France

Status: Recruiting

Contact:
Last name: Mihaela Diana Aldea

Facility:
Name: Universitätsklinikum Heidelberg

Address:
City: Heidelberg
Zip: 69120
Country: Germany

Status: Recruiting

Contact:
Last name: Antje Wick

Facility:
Name: Krankenhaus Nordwest

Address:
City: Frankfurt
Zip: 60488
Country: Germany

Status: Recruiting

Contact:
Last name: Thorsten Oliver Götze

Facility:
Name: Charité - Universitätsmedizin Berlin

Address:
City: Berlin
Zip: 13353
Country: Germany

Status: Recruiting

Contact:
Last name: Dominik Modest

Facility:
Name: Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" - IRST

Address:
City: Meldola
Zip: 47014
Country: Italy

Status: Recruiting

Contact:
Last name: Alberto Farolfi

Facility:
Name: Istituto Nazionale Tumori IRCCS Fondazione G. Pascale

Address:
City: Napoli
Zip: 80131
Country: Italy

Status: Recruiting

Contact:
Last name: Paolo Ascierto

Facility:
Name: Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) - Ospedale San Raffaele

Address:
City: Milan
Zip: 20132
Country: Italy

Status: Recruiting

Contact:
Last name: Andrea Necchi

Facility:
Name: Catholic University of Korea Saint Vincent's Hospital

Address:
City: Suwon-si
Zip: 16247
Country: Korea, Republic of

Status: Recruiting

Contact:
Last name: Byoung Yong Shim

Facility:
Name: Seoul National University Hospital

Address:
City: Suwon
Zip: 443-721
Country: Korea, Republic of

Status: Recruiting

Contact:
Last name: Hyun Woo Lee

Facility:
Name: Dong-A University Hospital

Address:
City: Busan
Zip: 602-812
Country: Korea, Republic of

Status: Recruiting

Contact:
Last name: Sung Yong Oh

Facility:
Name: Chonnam National University Hwasun Hospital

Address:
City: Hwasun
Zip: 58128
Country: Korea, Republic of

Status: Recruiting

Contact:
Last name: In-Jae Oh

Facility:
Name: Seoul National University Hospital

Address:
City: Seoul
Zip: 03080
Country: Korea, Republic of

Status: Recruiting

Contact:
Last name: Tae Min Kim

Facility:
Name: Severance Hospital

Address:
City: Seoul
Zip: 03722
Country: Korea, Republic of

Status: Recruiting

Contact:
Last name: Sang Joon Shin

Facility:
Name: Hospital Clinico Universitarlo de Santiago

Address:
City: Santiago De Compostela
Zip: 15706
Country: Spain

Status: Recruiting

Contact:
Last name: Alexandra Cortegoso

Facility:
Name: Hospital Clinico Universitarlo de Valencia

Address:
City: València
Zip: 46010
Country: Spain

Status: Recruiting

Contact:
Last name: Valentina Gambardella

Facility:
Name: Hospital Universitari Vall d'Hebron

Address:
City: Barcelona
Zip: 08035
Country: Spain

Status: Recruiting

Contact:
Last name: Maria Vieito Villar

Facility:
Name: Hospital Infantil Universitario Niño Jesús

Address:
City: Madrid
Zip: 28009
Country: Spain

Status: Recruiting

Contact:
Last name: Atienza Alvaor Lassaletta

Facility:
Name: Hospital Universitario 12 de Octubre

Address:
City: Madrid
Zip: 28041
Country: Spain

Status: Recruiting

Contact:
Last name: Guillermo De Velasco Oria de Rueda

Facility:
Name: Hospital Universitario Virgen del Rocío

Address:
City: Sevilla
Zip: 41013
Country: Spain

Status: Recruiting

Contact:
Last name: Alejandro Falcon Gonzalez

Facility:
Name: Skånes Universitetssjukhus

Address:
City: Lund
Zip: 221 85
Country: Sweden

Status: Recruiting

Contact:
Last name: Ana Carneiro

Facility:
Name: Karolinska Universitetssjukhuset

Address:
City: Solna
Zip: 171 64
Country: Sweden

Status: Recruiting

Contact:
Last name: Jeffrey Yachnin

Facility:
Name: The Christie NHS Foundation Trust

Address:
City: Manchester
Zip: M20 4BX
Country: United Kingdom

Status: Recruiting

Contact:
Last name: Colin Lindsay

Facility:
Name: Sarah Cannon Research Institute

Address:
City: London
Zip: W1G 6AD
Country: United Kingdom

Status: Recruiting

Contact:
Last name: Elisa Fontana

Start date: February 21, 2023

Completion date: August 28, 2026

Lead sponsor:
Agency: Fore Biotherapeutics
Agency class: Industry

Source: Fore Biotherapeutics

Record processing date: ClinicalTrials.gov processed this data on November 12, 2024

Source: ClinicalTrials.gov page: https://clinicaltrials.gov/ct2/show/NCT05503797

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