MAPK Inhibition Combined With Anti-PD1 Therapy for BRAF-altered Pediatric Gliomas

NCT06712875 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: LCH24C02
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 3

Brief Summary

Pediatric gliomas harboring BRAF-alterations, commonly BRAFV600 mutation or KIAA1549-BRAF fusion, are currently treated with either chemotherapy or mitogen activated protein kinase (MAPK) inhibitors, such as, dabrafenib and/or trametinib. Unfortunately, some BRAF-altered gliomas can progress or have rebound growth after discontinuation of therapy. Data from BRAFV600E-mutant melanoma has shown potential synergy between MAPK inhibition and anti-programmed cell death 1 (anti-PD1) checkpoint blockade. Anti-PD1 therapy, such as, nivolumab can block the PD1 receptor on T cells, a marker of T cell exhaustion, allowing a continued or more robust anti-tumor immune response. Here, investigators will combine MAPK inhibition with anti-PD1 therapy in recurrent, refractory low grade BRAF-altered glioma and newly diagnosed or recurrent BRAF-altered or NF-altered high grade glioma.

Conditions

Low Grade Glioma; High Grade Glioma

Keywords

BRAF; BRAFV600; KIAA1549 BRAF fusion; nivolumab; dabrafenib; trametinib; MAPK inhibition combined with anti-PD1 immunotherapy; recurrent low grade glioma; high grade glioma

Outcome Measures

Primary Outcomes (1)

• Safety based on number of participants with treatment-related adverse events based on scoring from CTCAE v4.0

  This study will utilize a rolling 6 design and enroll 12 evaluable patients in each cohort (Cohort A and B). Two dose levels will be utilized to assess safety and tolerability. Dose level 1 includes 100% dosing of dabrafenib and/or trametinib and nivolumab. A dose level -1 will be utilized if dose level 1 is not tolerable and will include 100% dosing of nivolumab with 70% dosing of dabrafenib and/or trametinib.

  The dose limiting toxicity (DLT) period is 28 days.

Secondary Outcomes (4)

• Response assessment

  From enrollment through end of treatment at 1 year

• Assessment of "Better Response"

  From enrollment to the end of treatment at 1 year

• Progression free survival

  From enrollment through long term follow up (5 years post treatment)

• Overall Survival (OS)

  Time of enrollment through long term follow up (5 years post treatment)

Study Arms (2)

Trametinib combined with nivolumab (Cohort A)

EXPERIMENTAL

Patients with histologically confirmed diagnosis of pediatric high- or low-grade glioma harboring a KIAA1549-BRAF fusion. Patients with NF1-associated gliomas or NF1-altered glioma. Patients in Cohort A will receive trametinib and nivolumab combination therapy. Trametinib will be administered at 0.025 mg/kg/dose orally once daily. Nivolumab will be administered at 6 mg/kg/dose intravenously every 4 weeks. Cycle length will be every 28 days. Treatment will include 1 year or 13 cycles of combination therapy, whichever comes first. For patients with high grade glioma, therapy can be continued beyond the 13 cycles if they are deemed to have clinical benefit from the therapy. Patients will be followed for up to 5 years to evaluate clinical endpoints.

Drug: Trametinib and Nivolumab

Dabrafenib + trametinib combined with nivolumab (Cohort B)

EXPERIMENTAL

Patients with histologically confirmed diagnosis of pediatric low-grade glioma harboring a BRAFV600 mutation that is recurrent or progressive or non-brainstem pediatric high-grade glioma harbor ng BRAFV600 mutation that is newly diagnosed, recurrent, or progressive. Cohort B will receive trametinib, nivolumab dabrafenib combination therapy. Trametinib will be administered at 0.025 mg/kg/dose orally once daily. Nivolumab will be administered at 6 mg/kg/dose intravenously every 4 weeks. Dabrafenib will be administered at a dose of 5.25 mg/kg/day orally divided into two doses, which shall be taken 12 hours apart. Cycle length will be every 28 days. Treatment will include 1 year or 13 cycles of combination therapy, whichever comes first. For patients with high grade glioma, therapy can be continued beyond the 13 cycles if they are deemed to have clinical benefit from the therapy. Patients will be followed for up to 5 years to evaluate clinical endpoints.

Drug: Dabrafenib, trametinib, nivolumab

Interventions

Trametinib and Nivolumab DRUG

Trametinib combined with nivolumab (Cohort A)

Trametinib combined with nivolumab (Cohort A)

Dabrafenib, trametinib, nivolumab DRUG

Dabrafenib + trametinib combined with nivolumab (Cohort B)

Dabrafenib + trametinib combined with nivolumab (Cohort B)

Eligibility Criteria

• Age: 1 Year - 26 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Cohort A Only:
• Patients with histologically confirmed diagnosis of pediatric high- or low-grade glioma harboring a KIAA1549-BRAF fusion: Low-grade glioma that is recurrent or progressive OR High-grade glioma that is newly diagnosed or recurrent OR
• Patients with NF1-associated gliomas or NF1-altered glioma: Low-grade glioma that is recurrent or progressive OR High-grade glioma that is newly diagnosed or recurrent OR Transforming glioma that is newly diagnosed or recurrent
• Cohort B Only:
• Patients with histologically confirmed diagnosis of pediatric low-grade glioma harboring a BRAFV600 mutation that is recurrent or progressive OR
• Patients with histologically confirmed diagnosis of non-brainstem pediatric high-grade glioma harboring BRAFV600 mutation that is newly diagnosed, recurrent, or progressive
• All Cohorts:
• Patients must be ≥1 and ≤26 years of age at the time of enrollment.
• Patients must have a performance status of Karnofsky \>50% for patients \>16 years old and Lansky \>50% for patients \<16 years old.
• Patients must have adequate organ and bone marrow function
• The effects of dabrafenib, trametinib, and nivolumab on the developing human fetus are unknown. For this reason, patients of childbearing potential (POCBP) and patients with sperm-producing reproductive capacity (PWSPRC) must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) from time of informed consent for the duration of study participation and for 30 days following completion of therapy. POCBP must have a negative pregnancy test.
• Patients with neurological deficits that are stable for a minimum of 1 week prior to enrollment are eligible.
• Note: A baseline detailed neurological exam should clearly document the neurological status of the patient at the time of enrollment on the study.
• \- Patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to enrollment. Total dexamethasone dose at time of enrollment must be less than or equal to 2 mg/day total or 0.5 mg/kg/day, whichever is smaller.
• LGG Only

You may not qualify if:

• Patients with disseminated disease.
• Patients who have had prior radiation therapy \<12 weeks prior to registration.
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> Grade 1) (with the exception of alopecia).
• Patients who receiving any other investigational agents. Note: There will be a 21-day washout period for all chemotherapeutic agents, a washout period of two half-lives for any targeted agents (e.g., MAPK inhibitors), and/or a washout period of 4 weeks for any antibody therapies (e.g., bevacizumab).
• Patients who have a history of allergic reactions attributed to compounds of similar chemical or biological composition to dabrafenib, trametinib, or nivolumab.
• Patients who have received MAPK inhibitor and checkpoint blockade combination therapy.
• Note: Patients may have received MAPK inhibitor monotherapy or checkpoint blockade monotherapy.
• Patients who previously discontinued BRAF inhibitor (type 1 inhibitor or dimer inhibitor, such as, DAY101), MEK inhibitor, or the combination because of grade 3 or higher toxicity or clinically significant grade 2 toxicity requiring discontinuation of therapy are not eligible.
• Patients with the following:
• Known autoimmune disorders
• Immune disorders
• Immunodeficiencies
• Patients with Crohn's disease, ulcerative colitis, or other inflammatory bowel disease.
• Patients with active pancreatitis or history of pancreatitis within the last 3 months.
• Patients with active interstitial lung disease (ILD)/pneumonitis or a history of ILD/pneumonitis requiring treatment with systemic steroids.

Sponsors & Collaborators

• Ann & Robert H Lurie Children's Hospital of Chicago: lead

Study Sites (3)

Children's National Hospital

Washington D.C., District of Columbia, 20010, United States

NOT YET RECRUITING

Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, 60611, United States

RECRUITING

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

NOT YET RECRUITING

MeSH Terms

Conditions

Glioma

Interventions

trametinib; Nivolumab; dabrafenib

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Ashley Plant-Fox, MD

  Ann & Robert H Lurie Children's Hospital of Chicago

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Monica Newmark

CONTACT

312-227-4847; mnewmark@luriechildrens.org

Ashley Plant-Fox, MD

CONTACT

312-227-4874; aplant@luriechildrens.org

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Pilot study evaluating toxicity and early efficacy

Study Record Dates

• First Submitted: November 26, 2024
• First Posted: December 2, 2024
• Study Start: April 1, 2025
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): June 1, 2029
• Last Updated: May 29, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)