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.
In this phase I/II study, the investigators will investigate the safety and efficacy of dabrafenib + trametinib + HCQ (D+T+HCQ) and trametinib + HCQ (T+HCQ) in pediatric and young adult patients with BRAF-altered or NF1-associated gliomas who have previously received a RAF and/or MEK inhibitor. 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. Aside from overlapping skin toxicity of dabrafenib and trametinib, which preliminarily does not appear worse in the D+T combination in adults and children, potential for ocular toxicity, which has been observed with each agent as monotherapy, will require close monitoring. An important outcome of this study will be improved understanding of resistance mechanisms and the role of autophagy in BRAF-altered or NF1-associated gliomas through sequencing of pre- and post-RAFi or MEKi tumor (when available) and measurement of autophagy inhibition in throughout protocol therapy. Phase I: The primary objective of the Phase I component is to estimate the maximum tolerated doses (MTD) and recommended Phase II doses (RP2D) of D+T+HCQ and T+HCQ in children and young adults with recurrent or progressive glioma treated with prior RAF and/or MEK inhibitor therapy. 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. Hydroxychloroquine will only be administered by oral suspension. Within each combination, Dabrafenib and Hydroxychloroquine will be administered twice a day in a 28-day course. Trametinib will be administered once a day for 28 days during each course. One course is equivalent to 28 days. Therapy with either combination may continue for up to 2 years (26 courses) in the absence of disease progression or unacceptable toxicity. Phase II Potential patients for the Phase II portion of the trial must provide magnetic resonance imaging studies for central review for screening prior to enrollment: (1) prior targeted MEK/RAF therapy baseline, (2) prior MEK/RAF therapy best response, (3) scan at off treatment, and if different from off treatment (4) scan documenting PD associated with prior MEK/RAF targeted therapy. Additional scans may be requested from the site if the required eligibility assessments cannot be completed based on these minimal imaging requirements. In the Phase II portion of the trial, patients will continue to receive either the D +T+HCQ or T+HCQ combination at the RP2D defined in the Phase I portion. All drugs will be given continuously without a break unless required for excess toxicity. For Phase I subjects who are treated at the MTD a similar review will take place retrospectively to determine whether the patients meet the criteria to be included in the Phase II cohort.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
57
Dabrafenib capsule; Dabrafenib Dispersible Tablet
Tablet; Powder for Oral Solution
Tablet
Phoenix Children's Hospital
Phoenix, Arizona, United States
Children's Hospital Los Angeles
Los Angeles, California, United States
Lucile Packard Children's Hospital at Stanford University Medical Center
Palo Alto, California, United States
Children's Hospital Colorado
Aurora, Colorado, United States
Children's National Medical Center
Washington D.C., District of Columbia, United States
University of Florida
Gainesville, Florida, United States
Children's Healthcare of Atlanta
Atlanta, Georgia, United States
Lurie Children's Hospital-Chicago
Chicago, Illinois, United States
National Cancer Institute Pediatric Oncology Branch
Bethesda, Maryland, United States
Memorial Sloan Kettering Cancer Center
New York, New York, United States
...and 5 more locations
Maximum Tolerated Dose (MTD)/ Recommended Phase 2 Dose (RP2D)
Testing the safety/tolerability of adding HCQ to Dabrafenib + Trametinib or to Trametinib
Time frame: Approximately 28 days from start of therapy
Maximum Plasma Concentration
Maximum plasma concentration Dabrafenib+Trametinib+Hydroxychloroquine or Trametinib +Hydroxychloroquine
Time frame: 1-4 days
Area under the curve (AUC)
AUC for Dabrafenib+Trametinib+Hydroxychloroquine or Trametinib +Hydroxychloroquine
Time frame: 1-4 days
Phase II: Sustained objective response rate.
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
Time frame: Up to approximately 2 years from the start of therapy
Phase I: Dose limiting toxicities of D + T HCQ or T + HCQ
Describe the dose limiting toxicities separately for each stratum
Time frame: course 1 of therapy, approximately 28 days from start of therapy
Phase I: Response Rate
Proportion of patients who achieve either a partial or a complete response among those with measureable disease at enrollment.
Time frame: Up to approximately 2 years from start of therapy
Phase II: Progression-free survival
Time from enrollment up to disease progression or death or loss to follow-up, whichever is first
Time frame: Start of protocol therapy until progression or last follow-up, up to approximately 2 years from start of treatment
Phase II: Visual outcome based on Teller Grating Acuity at 55 cm in the left eye in children with tumor involving the visual pathway
Teller Grating Acuity at 55 cm in the left eye in children with tumor involving the visual pathway
Time frame: Throughout study therapy, up to approximately 2 years from start of therapy
Phase I and II: Autophagy inhibition as assessed by the accumulation of LC3II in peripheral blood mononuclear cells
Accumulation of LC3II in peripheral blood mononuclear cells
Time frame: Approximately 2 years from start of therapy]
Phase I and II: Autophagy inhibition as assessed by the accumulation of p62 in peripheral blood mononuclear cells
Accumulation of p62 in peripheral blood mononuclear cells
Time frame: Approximately 2 years from start of therapy
Phase I and II: Presence of MAPK pathway aberrations (other than BRAF) as assessed by whole exome sequencing
MAPK pathway aberrations (other than BRAF) assessed by whole exome sequencing
Time frame: At time of study enrollment
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)
Evaluating matched primary and recurrent/progressive in tumor in plasma (and CSF if clinically indicated)
Time frame: At enrollment and at the time of every MRI study up to approximately 2 years from the start of therapy
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.