Who can participate?

Key Inclusion Criteria:

• Patients must have one of the following histologies with molecularly-confirmed diagnosis that is recurrent or progressive. 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. 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. A target lesion should be chosen
    • Patients are required to have weight >= 9 kg to enroll on any stratum in the Phase I or Phase II
  • Phase I only
    
    • Patients enrolled on the 8 mg/kg/day (dose level 1) must have a weight < 90 kg
    • Patients enrolled on the 15 mg/kg/day (dose level 2) must have a weight < 80 kg
    • Patients enrolled on the 20 mg/kg/day (dose level 3) must have a weight < 68 kg
      
      • Patients must have received prior therapy other than surgery and must have fully recovered from the acute treatment related toxicities (defined as =< grade 1) of all prior chemotherapy, immunotherapy, radiotherapy or any other treatment modality prior to entering this study
      • Only applicable to LGG patients on Phase I and all patients on Phase II
  • Patients must have received prior RAF and/or MEK inhibitor therapy and meet one of the following criteria:
    
    • Did not experience an objective response (defined as < PR) OR
    • Achieved an objective response (CR or PR) but progressed while on active therapy
  • HGG patients on Phase I: may be enrolled regardless of prior MEK /RAF treatment
• Imaging must be available for central review to confirm eligibility for LGG patients on the Phase I study and all patients on the Phase II study
  
  • Patients with HGG on the phase I study do not require central imaging review for eligibility
  • Patients with LGG on the Phase I study will not require real-time central imaging review, but imaging must be available for retrospective review in case the subject was enrolled at the RP2D and may be counted as part of the phase II study
• Patients must have received their last dose of known myelosuppressive anticancer therapy at least 21 days prior to enrollment or at least 42 days if nitrosourea
• Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the investigational or biologic agent >= 7 days prior to study enrollment. For biologic agents or monoclonal antibodies with a prolonged half-life, at least three half-lives must have elapsed prior to enrollment
• Patients must have had their last fraction of:
  
  • Craniospinal irradiation, whole brain radiation, total body irradiation or radiation to >= 50% of pelvis or spine >= 6 weeks (42 days) prior to enrollment
• ** Focal irradiation >= 14 days prior to enrollment
• Patients with neurological deficits should have deficits that are stable for a minimum of 7 days prior to enrollment.
• Patients with seizure disorders may be enrolled if seizures are controlled. Patients may take non-enzyme inducing anti-epileptic medications
• Patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to enrollment
• Karnofsky performance scale (KPS for > 16 years of age) or Lansky performance score (LPS for =< 16 years of age) assessed within 7 days of enrollment must be >= 50
  
  • Patients who are unable to walk because of neurologic deficits, but who are up in a wheelchair, will be considered ambulatory for assessing the performance score
• Absolute neutrophil count >= 1.0 x 10^9 cells/ L
• Platelets >= 100 x 10^9 cells/ L (unsupported, defined as no platelet transfusion within 7 days)
• Hemoglobin >= 8 g/dl (may receive transfusions)
• Total bilirubin =< 1.5 times institutional upper limit of normal (ULN)
• Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 3 x institutional upper limit of normal (ULN)
• Albumin >= 3 g/dl
• Serum creatinine based on age/gender. Patients that do not meet these criteria but have a 24-hour creatinine clearance or glomerular filtration rate (GFR) (radioisotope or iothalamate) >= 70 mL/min/1.73 m^2 are eligible
  
  • Age: 1 to < 2 years; maximum serum creatinine (mg/dL): 0.6 (male); 0.6 (female)
  • Age: 2 to < 6 years; maximum serum creatinine (mg/dL): 0.8 (male); 0.8 (female)
  • Age: 6 to < 10 years; maximum serum creatinine (mg/dL): 1 (male); 1 (female)
  • Age: 10 to < 13 years; maximum serum creatinine (mg/dL): 1.2 (male); 1.2 (female)
  • Age: 13 to < 16 years; maximum serum creatinine (mg/dL): 1.5 (male); 1.4 (female)
  • Age: >= 16 years; maximum serum creatinine (mg/dL): 1.7 (male); 1.4 (female)
• Left ventricular ejection fraction greater than the institutional lower limit of normal by echo (while not receiving medications for cardiac function)
• Corrected QT (QTc) =< 480 msec
• Female patients of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• Females of child-bearing potential must use a highly effective method of contraception during dosing of study treatment and for 16 weeks after stopping study medication.
• Sexually active males must use a condom during intercourse while on study and for 16 weeks after stopping study treatment and agree not to father a child during this period
• The patient or parent/guardian is able to understand the consent and is willing to sign a written informed consent document according to institutional guidelines

Key Exclusion Criteria:

• Breast-feeding women 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 does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Patients with NF1 and history of plexiform neurofibroma will be permitted to enroll
  • Patients with a previously documented retinal vein occlusion or severe retinopathy
  • Presence of active gastrointestinal (GI) disease or other condition (e.g., small bowel or large bowel resection) that will interfere significantly with the absorption of drugs
• Patients who are unable to discontinue prohibited medications or herbal preparations within 7 days of enrollment and 14 days of starting study therapy
• Patients who are receiving any other anti-cancer or investigational drug therapy are ineligible
• Patients with a history of a known hypersensitivity to dabrafenib, trametinib, HCQ, or any of their excipients or compounds of similar chemical or biologic composition
• Prisoners will be excluded from this study.
• Patients who in the opinion of the investigator are unwilling or unable to return for required follow-up visits or obtain follow-up studies required to assess toxicity to therapy or to adhere to drug administration plan, other study procedures, and study restrictions