This phase I/II trial is designed to study the side effects, best dose and efficacy of adding hydroxychloroquine to dabrafenib and/or trametinib in children with low grade or high grade brain tumors previously treated with similar drugs that did not respond completely (progressive) or tumors that came back while receiving a similar agent (recurrent). Patients must also have specific genetic mutations including BRAF V600 mutations or BRAF fusion/duplication, with or without neurofibromatosis type 1. Neurofibromatosis type 1 is an inherited genetic condition that causes tumors to grow on nerve tissue. Hydroxychloroquine, works in different ways to stop the growth of tumor cells by killing the cells or stopping them from dividing. Trametinib and dabrafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving hydroxychloroquine with trametinib and/or dabrafenib may lower the chance of brain tumors growing or spreading compared to usual treatments.
Name: Dabrafenib
Name: Trametinib
Name: Hydroxychloroquine
Description: Testing the safety/tolerability of adding HCQ to Dabrafenib + Trametinib or to Trametinib
Measure: Maximum Tolerated Dose (MTD)/ Recommended Phase 2 Dose (RP2D) Time: Approximately 28 days from start of therapyDescription: Maximum plasma concentration Dabrafenib+Trametinib+Hydroxychloroquine or Trametinib +Hydroxychloroquine
Measure: Maximum Plasma Concentration Time: 1-4 daysDescription: AUC for Dabrafenib+Trametinib+Hydroxychloroquine or Trametinib +Hydroxychloroquine
Measure: Area under the curve (AUC) Time: 1-4 daysDescription: Number of patients who meet the "better response" criteria, which is a comparison of response on this current protocol therapy versus their best response to previous RAF and/or MEK inhibitor therapy
Measure: Phase II: Sustained objective response rate. Time: Up to approximately 2 years from the start of therapyDescription: Teller Grating Acuity at 55 cm in the left eye in children with tumor involving the visual pathway
Measure: Phase II: Visual outcome based on Teller Grating Acuity at 55 cm in the left eye in children with tumor involving the visual pathway Time: Throughout study therapy, up to approximately 2 years from start of therapyDescription: Accumulation of LC3II in peripheral blood mononuclear cells
Measure: Phase I and II: Autophagy inhibition as assessed by the accumulation of LC3II in peripheral blood mononuclear cells Time: Approximately 2 years from start of therapy]Description: Accumulation of p62 in peripheral blood mononuclear cells
Measure: Phase I and II: Autophagy inhibition as assessed by the accumulation of p62 in peripheral blood mononuclear cells Time: Approximately 2 years from start of therapyDescription: MAPK pathway aberrations (other than BRAF) assessed by whole exome sequencing
Measure: Phase I and II: Presence of MAPK pathway aberrations (other than BRAF) as assessed by whole exome sequencing Time: At time of study enrollmentDescription: Evaluating matched primary and recurrent/progressive in tumor in plasma (and CSF if clinically indicated)
Measure: Phase I and II: biomarker of resistance to RAF or MEK inhibitor therapy by evaluating matched primary and recurrent/progressive in tumor in plasma (and CSF if clinically indicated) Time: At enrollment and at the time of every MRI study up to approximately 2 years from the start of therapyAllocation: Non-Randomized
Parallel Assignment
There is one SNP
Phase I/II Trial of Dabrafenib, Trametinib, and Hydroxychloroquine (HCQ) for BRAF V600E-mutant or Trametinib and HCQ for BRAF Fusion/Duplication Positive or NF1-associated Recurrent or Progressive Gliomas in Children and Young Adults. --- V600E ---
Patients enrolled will be stratified as follows: - Phase I: - Stratum 1 LGG or HGG with BRAF V600E/D/K mutation - Stratum 2 LGG with BRAF duplication or fusion with any partner or LGG with neurofibromatosis type 1 - Phase II: - Stratum 3 LGG with BRAF V600E/D/K mutation - Stratum 4 HGG with BRAF V600E/D/K mutation - Stratum 5 LGG with BRAF duplication or fusion with any partner - Stratum 6 LGG with neurofibromatosis type 1 - BRAF alterations will be locally determined using molecular methods in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory. --- V600E ---
Patients enrolled will be stratified as follows: - Phase I: - Stratum 1 LGG or HGG with BRAF V600E/D/K mutation - Stratum 2 LGG with BRAF duplication or fusion with any partner or LGG with neurofibromatosis type 1 - Phase II: - Stratum 3 LGG with BRAF V600E/D/K mutation - Stratum 4 HGG with BRAF V600E/D/K mutation - Stratum 5 LGG with BRAF duplication or fusion with any partner - Stratum 6 LGG with neurofibromatosis type 1 - BRAF alterations will be locally determined using molecular methods in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory. --- V600E --- --- V600E ---
Patients enrolled will be stratified as follows: - Phase I: - Stratum 1 LGG or HGG with BRAF V600E/D/K mutation - Stratum 2 LGG with BRAF duplication or fusion with any partner or LGG with neurofibromatosis type 1 - Phase II: - Stratum 3 LGG with BRAF V600E/D/K mutation - Stratum 4 HGG with BRAF V600E/D/K mutation - Stratum 5 LGG with BRAF duplication or fusion with any partner - Stratum 6 LGG with neurofibromatosis type 1 - BRAF alterations will be locally determined using molecular methods in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory. --- V600E --- --- V600E --- --- V600E ---
Immunohistochemistry for BRAF V600E alone is not adequate and must be confirmed molecularly - Phase II patients must have bi-dimensionally measurable disease defined as at least one lesion that can be accurately measured in at least two planes. --- V600E ---
The goal of this study is to optimize the clinical effect of dabrafenib and trametinib by addressing intrinsic and acquired resistance that is well-described in V600E-mutant melanoma and for which there is preclinical and clinical evidence in pediatric gliomas. --- V600E ---
Patients with BRAF V600E LGG or HGG will receive the combination of D+T+HCQ given orally in the form of capsules which must be taken whole, or an oral solution made from tablets. --- V600E ---