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.
This is a pilot study evaluating the toxicity and early efficacy of dabrafenib and/or trametinib combined with nivolumab for the treatment of BRAF-altered or NF altered gliomas. While dabrafenib, trametinib, and nivolumab have been used for pediatric gliomas in previous studies, this will be the first pediatric study evaluating the combination of these agents. This study will evaluate the use of dabrafenib, trametinib, and nivolumab in patients in recurrent, refractory, or progressive low grade gliomas harboring BRAFV600 mutations who have previously been treated with MAPK inhibition alone. The same combination will be explored in newly diagnosed or recurrent BRAFV600 mutant high grade glioma. This study will also evaluate the use of trametinib and nivolumab in patients with recurrent, refractory, or progressive low grade gliomas harboring a KIAA1549 BRAF fusion who have previously been treated with MAPK inhibition alone. The same combination will be explored in NF altered transforming or high grade glioma or high grade glioma harboring a KIAA1549 BRAF fusion. The objective of this study is to understand the safety and tolerability of the combination of dabrafenib, trametinib, and/or nivolumab in pediatrics. Secondarily, this study will evaluate for an early efficacy signal of the combination therapy and compare to historical treatment response to MAPK inhibition alone.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
27
Trametinib combined with nivolumab (Cohort A)
Dabrafenib + trametinib combined with nivolumab (Cohort B)
Children's National Hospital
Washington D.C., District of Columbia, United States
NOT_YET_RECRUITINGAnn & Robert H. Lurie Children's Hospital of Chicago
Chicago, Illinois, United States
RECRUITINGMemorial Sloan Kettering Cancer Center
New York, New York, United States
NOT_YET_RECRUITINGSafety 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.
Time frame: The dose limiting toxicity (DLT) period is 28 days.
Response assessment
Objective response rate will be utilized to assess response to combination therapy. Magnetic resonance imaging (MRI) will be evaluated for response utilizing RANO/iRANO criteria. Best response and duration of response be assessed. An objective response is a partial or complete response (PR or CR) sustained for at least 12 weeks.
Time frame: From enrollment through end of treatment at 1 year
Assessment of "Better Response"
At enrollment, information will be entered by the study team regarding prior treatment with MAPK inhibition alone. The best response and duration of this response will be recorded. This will be compared to response on study treatment. A "better response" would be considered an improvement of best response from stable disease to partial response, partial response to complete response, or progressive disease to stable disease OR a similar best response that is maintained for 12 weeks longer or more.
Time frame: From enrollment to the end of treatment at 1 year
Progression free survival
Progression will be determined by magnetic resonance imaging (MRI) assessment using RANO/iRANO criteria.
Time frame: From enrollment through long term follow up (5 years post treatment)
Overall Survival (OS)
Overall survival will be assessed by time to event (death).
Time frame: Time of enrollment through long term follow up (5 years post treatment)
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