RECRUITING

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

Conditions

Low Grade Glioma High Grade Glioma BRAF BRAFV600 KIAA1549 BRAF fusion nivolumab dabrafenib trametinib MAPK inhibition combined with anti-PD1 immunotherapy recurrent low grade glioma

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

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.

Official Title

A Pilot Study Evaluating the Toxicity and Clinical Benefit of Mitogen-activated Protein Kinase (MAPK) Pathway Inhibition Combined with Programmed Cell Death-1 Checkpoint Blockade (anti-PD1) for the Treatment of BRAF-altered Pediatric Gliomas

Quick Facts

Study Start:2025-03

Study Completion:2029-06

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:RECRUITING

Study ID

NCT06712875

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Ages Eligible for Study:1 Year to 26 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:No

Standard Ages:CHILD, ADULT

Inclusion Criteria	Exclusion Criteria
* 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 * 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 * 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. * Patients must have received a prior BRAF inhibitor (first or second generation), MEK inhibitor, or a combination. The response to this therapy must be known and information provided at study enrollment. * Patients must have recovered from acute treatment-related toxicities (defined as \<Grade 1, excludes alopecia) prior to entering this study. * Patients must have received prior radiotherapy \>12 weeks prior to enrollment. * Patients must have recovered from acute treatment-related toxicities (defined as \<Grade 1, excludes alopecia) prior to entering this study. * NF1 patients with transforming gliomas and high-grade gliomas are eligible regardless of prior systemic therapy. * Patients who have received prior radiation therapy must have experienced progression post-radiation OR have measurable disease defined as residual tumor \>1cm in at least one dimension	* 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. * 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. * Patients who have a known active Human Immunodeficiency Virus (HIV), Hepatitis B, or Hepatitis C infection are ineligible. Patient must have documented evidence of negative tests for the presence of HIV, Hepatitis B surface antigen, and Hepatitis C (anti-HCV antibody OR Hep C RNA-qualitative). * Patients who have received a major surgical procedure ≤ 28 days of beginning study treatment, or minor surgical procedures (including VP shunt placement or stereotactic biopsy of the tumor) ≤ 7 days are not eligible. * Patients who are taking herbal preparations. These medications include but are not limited to St. John's wort, kava, ephedra (ma hung), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. Cannabis products of any type are not allowed throughout the study. Patients should stop using these herbal medications or cannabis products 7 days prior to enrollment. * Patients who are pregnant. Patients of childbearing potential must have a negative serum or urine pregnancy test. (If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.) * Patients who are lactating (unless they have agreed to not breastfeed). Breastfeeding patients are excluded from this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies. * Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic, or other organ dysfunction), that in the opinion of the investigator would compromise the patient's ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results. * Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen for this trial. * Patients with bulky tumor on imaging are ineligible. Bulky tumor is defined as: * Tumor with any evidence of clinically significant uncal herniation or midline shift * Tumor with diameter of \>5cm in one dimension on T2/FLAIR except for those patients with newly diagnosed HGG treated following irradiation without signs of tumor progression. For the latter group, a maximum diameter of contrast enhancing solid or necrotic tumor and of T2/FLAIR abnormality will be 5 cm and 8 cm, respectively. * Tumor that in the opinion of the site investigator, shows significant mass effect * Metastatic disease: Patients with ≤ 5 separate foci of metastatic disease not causing mass effect on adjacent parenchyma and each measuring less than 0.5 cm in maximum diameter will be eligible for this arm of the study. Patients with leptomeningeal disease are eligible. * Multi-focal disease (patients with multi-focal parenchymal disease will be eligible if the sum of the product of the maximum perpendicular diameters of all measurable non-contiguous lesions is less than 16 cm2 based on the T2/FLAIR abnormality).

Inclusion Criteria

Exclusion Criteria

* 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
* 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
* 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.
* Patients must have received a prior BRAF inhibitor (first or second generation), MEK inhibitor, or a combination. The response to this therapy must be known and information provided at study enrollment.
* Patients must have recovered from acute treatment-related toxicities (defined as \<Grade 1, excludes alopecia) prior to entering this study.
* Patients must have received prior radiotherapy \>12 weeks prior to enrollment.
* Patients must have recovered from acute treatment-related toxicities (defined as \<Grade 1, excludes alopecia) prior to entering this study.
* NF1 patients with transforming gliomas and high-grade gliomas are eligible regardless of prior systemic therapy.
* Patients who have received prior radiation therapy must have experienced progression post-radiation OR have measurable disease defined as residual tumor \>1cm in at least one dimension

* 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.
* 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.
* Patients who have a known active Human Immunodeficiency Virus (HIV), Hepatitis B, or Hepatitis C infection are ineligible. Patient must have documented evidence of negative tests for the presence of HIV, Hepatitis B surface antigen, and Hepatitis C (anti-HCV antibody OR Hep C RNA-qualitative).
* Patients who have received a major surgical procedure ≤ 28 days of beginning study treatment, or minor surgical procedures (including VP shunt placement or stereotactic biopsy of the tumor) ≤ 7 days are not eligible.
* Patients who are taking herbal preparations. These medications include but are not limited to St. John's wort, kava, ephedra (ma hung), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. Cannabis products of any type are not allowed throughout the study. Patients should stop using these herbal medications or cannabis products 7 days prior to enrollment.
* Patients who are pregnant. Patients of childbearing potential must have a negative serum or urine pregnancy test. (If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.)
* Patients who are lactating (unless they have agreed to not breastfeed). Breastfeeding patients are excluded from this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies.
* Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic, or other organ dysfunction), that in the opinion of the investigator would compromise the patient's ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results.
* Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen for this trial.
* Patients with bulky tumor on imaging are ineligible. Bulky tumor is defined as:
* Tumor with any evidence of clinically significant uncal herniation or midline shift
* Tumor with diameter of \>5cm in one dimension on T2/FLAIR except for those patients with newly diagnosed HGG treated following irradiation without signs of tumor progression. For the latter group, a maximum diameter of contrast enhancing solid or necrotic tumor and of T2/FLAIR abnormality will be 5 cm and 8 cm, respectively.
* Tumor that in the opinion of the site investigator, shows significant mass effect
* Metastatic disease: Patients with ≤ 5 separate foci of metastatic disease not causing mass effect on adjacent parenchyma and each measuring less than 0.5 cm in maximum diameter will be eligible for this arm of the study. Patients with leptomeningeal disease are eligible.
* Multi-focal disease (patients with multi-focal parenchymal disease will be eligible if the sum of the product of the maximum perpendicular diameters of all measurable non-contiguous lesions is less than 16 cm2 based on the T2/FLAIR abnormality).

Contacts and Locations

Study Contact

Monica Newmark

CONTACT

312-227-4847

mnewmark@luriechildrens.org

Ashley Plant-Fox, MD

CONTACT

312-227-4874

aplant@luriechildrens.org

Principal Investigator

Ashley Plant-Fox, MD

PRINCIPAL_INVESTIGATOR

Ann & Robert H Lurie Children's Hospital of Chicago

Study Locations (Sites)

Children's National Hospital

Washington DC, District of Columbia, 20010

United States

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

Chicago, Illinois, 60611

United States

Memorial Sloan Kettering Cancer Center

New York, New York, 10065

United States

Collaborators and Investigators

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

Ashley Plant-Fox, MD, PRINCIPAL_INVESTIGATOR, Ann & Robert H Lurie Children's Hospital of Chicago

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

Study Start Date2025-03

Study Completion Date2029-06

Study Record Updates

Study Start Date2025-03

Study Completion Date2029-06

Terms related to this study

Keywords Provided by Researchers

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

Additional Relevant MeSH Terms

Low Grade Glioma
High Grade Glioma