Dabrafenib and Trametinib for BRAF V600 Mutant Low-Grade Gliomas
PNOC037
A Phase 2 De-escalation Study of Dabrafenib and Trametinib for Patients With BRAF V600 Mutant Low-Grade Gliomas
2 other identifiers
interventional
96
1 country
4
Brief Summary
This phase II trial studies how well de-escalating the drugs dabrafenib and trametinib works in treating patients with low-grade gliomas that have a BRAF V600 gene mutation. Dabrafenib and trametinib are in a class of medications called kinase inhibitors. They work by blocking the action of abnormal proteins that signals tumor cells to multiply. This helps stop the spread of tumor cells. This trial may help doctors determine the best dosing strategy for patients who have received dabrafenib and trametinib for 12-24 months: Either stopping dabrafenib and trametinib completely or slowly reducing the dose for an additional 6 months.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for phase_2
Started Nov 2025
Longer than P75 for phase_2
4 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
July 31, 2025
CompletedFirst Posted
Study publicly available on registry
August 7, 2025
CompletedStudy Start
First participant enrolled
November 7, 2025
CompletedPrimary Completion
Last participant's last visit for primary outcome
March 31, 2032
ExpectedStudy Completion
Last participant's last visit for all outcomes
March 31, 2032
March 12, 2026
January 1, 2026
6.4 years
July 31, 2025
March 10, 2026
Conditions
Outcome Measures
Primary Outcomes (1)
Rebound rate (RR)
The Rebound rate is defined as increase in tumor size by 25% or more by Response Assessment in Pediatric Neuro-Oncology-Low Grade Glioma (RAPNO-LGG) criteria and/or clinical progression necessitating the re-institution of therapy occurring within 4 months off therapy for participants with BRAF V600 mutant LGG after abruptly stopping or weaning off dabrafenib and trametinib. RR will be reported by cohort and arm.
Up to a maximum of 34 months
Study Arms (4)
Cohort 1: Arm A (Newly diagnosed, Dabrafenib, Trametinib followed by treatment stop)
EXPERIMENTALParticipants with newly diagnosed BRAF V600 mutant LGGs receive dabrafenib PO twice per day (BID) and trametinib PO once daily (QD) on days 1-28 of each cycle. Cycles repeat every 28 days for a minimum of 12 cycles and continues until confirmed best response or for up to a maximum of 24 cycles in the absence of disease progression or unacceptable toxicity. Participants then stop treatment with dabrafenib and trametinib. Participants also undergo ECHO, MRI, and blood sample collection throughout the study and may optionally undergo lumbar puncture for collection of CSF.
Cohort 1: Arm B (Newly diagnosed, Dabrafenib, Trametinib followed by weaning)
EXPERIMENTALParticipants with newly diagnosed BRAF V600 mutant LGGs receive dabrafenib PO twice per day (BID) and trametinib PO once daily (QD) on days 1-28 of each cycle. Cycles repeat every 28 days for a minimum of 12 cycles and continues until confirmed best response or for up to a maximum of 24 cycles in the absence of disease progression or unacceptable toxicity. Participants then receive dabrafenib PO BID and trametinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Participants also undergo ECHO, MRI, and blood sample collection throughout the study and may optionally undergo lumbar puncture for collection of CSF.
Cohort 2: Arm A (Recurrent LGG, Dabrafenib, Trametinib followed by treatment stop)
EXPERIMENTALParticipants with recurrent/progressive BRAF V600 mutant LGGs receive dabrafenib PO twice per day (BID) and trametinib PO once daily (QD) on days 1-28 of each cycle. Cycles repeat every 28 days for a minimum of 12 cycles and continues until confirmed best response or for up to a maximum of 24 cycles in the absence of disease progression or unacceptable toxicity. Participants then stop treatment with dabrafenib and trametinib. Participants also undergo ECHO, MRI, and blood sample collection throughout the study and may optionally undergo lumbar puncture for collection of CSF.
Cohort 2: Arm B (Recurrent LGG, Dabrafenib, Trametinib followed by weaning)
EXPERIMENTALParticipants with recurrent/progressive BRAF V600 mutant LGGs receive dabrafenib PO twice per day (BID) and trametinib PO once daily (QD) on days 1-28 of each cycle. Cycles repeat every 28 days for a minimum of 12 cycles and continues until confirmed best response or for up to a maximum of 24 cycles in the absence of disease progression or unacceptable toxicity. Participants then receive dabrafenib PO BID and trametinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Participants also undergo ECHO, MRI, and blood sample collection throughout the study and may optionally undergo lumbar puncture for collection of CSF.
Interventions
Undergo imaging by MRI
Under collection of blood and optional CSF samples
Undergo optional lumbar puncture
Given orally (PO)
Given PO
Eligibility Criteria
You may qualify if:
- Participants must have histologically confirmed LGG World Health Organization (WHO) Grade I or II with BRAF V600 mutation confirmed by immunohistochemistry or sequencing
- Participants must have measurable tumor.
- \* For participants with measurable disease, this will be defined as lesions that can be accurately measured in two dimensions (longest diameter to be recorded) with a minimum size of no less than double the slice thickness. Previously irradiated lesions are considered non-measurable except in cases of documented progression of the lesion since the completion of radiation therapy. Participants without measurable disease may be considered for enrollment and followed for survival and progression purposes but will not be included as part of a measurable disease cohort.
- Cohort 1:
- Participants must have no prior therapy, except for surgical intervention (i.e. biopsy or resection)
- Participants may currently be taking dabrafenib and trametinib as frontline therapy, with a maximum duration of 21 months and participants must not yet have met criteria for confirmed best response as defined in this protocol. For participants entering the trial currently taking dabrafenib and trametinib, they must be taking a dose that is within 20% of the standard dosing for both drugs based on age and weight. Participants who are already on dabrafenib and trametinib when enrolling on trial and whose dosing deviates more than 20% from the protocol nomogram need to be discussed with the study chairs. Eligibility for these participants will be based on ability to wean within the parameters of the protocol
- Cohort 2:
- \* Participants must have a history of recurrent or progressive disease following prior therapy (e.g., carboplatin and vincristine, vinblastine, bevacizumab, mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor, radiation therapy etc). Participants who previously completed a course of therapy with dabrafenib and trametinib, who did not progress on this therapy, and who are beyond 6 months from completion of therapy are eligible for retreatment.
- \*\* Participants may currently be taking dabrafenib and trametinib as therapy for disease recurrence, for a maximum duration of 21 months and participants must not yet have met criteria for confirmed best response as defined in this protocol. For participants entering the trial currently taking dabrafenib and trametinib, they must be taking dose that is within 20% of the standard dosing for both drugs based on age and weight. Participants who are already on dabrafenib and trametinib when enrolling on trial and whose dosing deviates more than 20% from the protocol nomogram need to be discussed with the study chairs. Eligibility for these participants will be based on ability to wean within the parameters of the protocol
- Participants must have received their last dose of chemotherapy 3 weeks prior to enrollment (6 weeks for nitrosoureas) and recovered from acute adverse events due to agents administered
- Participants must be at least 7 days since the completion of therapy with a biologic or small molecule agent except dabrafenib and trametinib. For any agent with known adverse events that can occur beyond 7 days after administration, the period prior to enrollment must be beyond the time during which adverse events are known to occur. Such participants must be discussed with study chairs
- Radiation:
- No prior radiation is allowed for participants in Cohort 1
- Participants in Cohort 2 must have:
- Had their last fraction of local irradiation to primary tumor ≥ 12 weeks prior to registration
- +17 more criteria
You may not qualify if:
- Participant's tumor has any of the following additional previously known or expected activating molecular alterations:
- Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) mutation
- Histone H3 mutation (p.K28M, p.G35R, p.G35V)
- Neurofibromatosis Type 1 (NF-1) loss of function alteration
- Participants who are receiving any other investigational agents
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to dabrafenib and trametinib
- Medications that are affected by the induction of CYP3A4 and CYP2C9 should be avoided or used cautiously. Dabrafenib has been shown to induce CYP3A4 and CYP2C9. In addition, dabrafenib is an in vitro inducer of CYP2B6, CYP2C8, CYP2C19, Uridine 5'-diphospho (UDP)-glucuronosyltransferase. Co-administration of dabrafenib and medications which are affected by the induction of these enzymes (including warfarin) and transporters may result in loss of efficacy. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the Physicians' Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the participant and/or legal parent or guardian will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection
- Women of childbearing potential must not be pregnant or breast-feeding
- Human immunodeficiency virus (HIV) positive participants will be ineligible if HIV therapy regimen has not been stable for at least 4 weeks or there is intent to change the regimen within 8 weeks following enrollment, or if they are severely immunocompromised
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Rising Tide Foundationcollaborator
- University of California, San Franciscolead
Study Sites (4)
University of Alabama at Birmingham
Birmingham, Alabama, 35233, United States
University of California, San Francisco
San Francisco, California, 94143, United States
John Hopkins Medical Center
Baltimore, Maryland, 21287, United States
St. Louis Children's Hospital Washington University in St. Louis
St Louis, Missouri, 63110, United States
MeSH Terms
Interventions
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Sabine Mueller, MD, PHD
University of California, San Francisco
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
July 31, 2025
First Posted
August 7, 2025
Study Start
November 7, 2025
Primary Completion (Estimated)
March 31, 2032
Study Completion (Estimated)
March 31, 2032
Last Updated
March 12, 2026
Record last verified: 2026-01
Data Sharing
- IPD Sharing
- Will share
- Shared Documents
- STUDY PROTOCOL, SAP, ICF
De-identified data may be provided to study collaborators during the course of the study