A Trial of Dabrafenib, Trametinib and Hydroxychloroquine for Patients With Recurrent LGG or HGG With a BRAF Aberration

Inclusion Criteria:

• • Patients must have one of the following histologies with molecularly-confirmeddiagnosis that is recurrent or progressive. Patients enrolled will be stratified asfollows:

• 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 withneurofibromatosis 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 aClinical Laboratory Improvement Act (CLIA)-certified laboratory.Immunohistochemistry for BRAF V600E alone is not adequate and must be confirmedmolecularly

• Phase II patients must have bi-dimensionally measurable disease defined asat least one lesion that can be accurately measured in at least twoplanes. A target lesion should be chosen

• Patients are required to have weight >= 9 kg to enroll on any stratum inthe 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 musthave 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 thisstudy

• Only applicable to LGG patients on Phase I and all patients on PhaseII

• Patients must have received prior RAF and/or MEK inhibitor therapy and meet oneof the following criteria:

• Did not experience an objective response (defined as < PR) OR

• Achieved an objective response (CR or PR) but progressed while on activetherapy

• 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 LGGpatients 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 reviewfor eligibility

• Patients with LGG on the Phase I study will not require real-time centralimaging review, but imaging must be available for retrospective review in casethe subject was enrolled at the RP2D and may be counted as part of the phase IIstudy

• Patients must have received their last dose of known myelosuppressiveanticancer therapy at least 21 days prior to enrollment or at least 42days if nitrosourea

• Patient must have recovered from any acute toxicity potentially related tothe agent and received their last dose of the investigational or biologicagent >= 7 days prior to study enrollment. For biologic agents ormonoclonal antibodies with a prolonged half-life, at least threehalf-lives must have elapsed prior to enrollment

• Patients must have had their last fraction of:

• Craniospinal irradiation, whole brain radiation, total body irradiation orradiation 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 stablefor a minimum of 7 days prior to enrollment.

• Patients with seizure disorders may be enrolled if seizures arecontrolled. Patients may take non-enzyme inducing anti-epilepticmedications

• Patients who are receiving dexamethasone must be on a stable or decreasingdose for at least 1 week prior to enrollment

• Karnofsky performance scale (KPS for > 16 years of age) or Lanskyperformance score (LPS for =< 16 years of age) assessed within 7 days ofenrollment must be >= 50

• Patients who are unable to walk because of neurologic deficits, but who are upin a wheelchair, will be considered ambulatory for assessing the performancescore

• Absolute neutrophil count >= 1.0 x 10^9 cells/ L

• Platelets >= 100 x 10^9 cells/ L (unsupported, defined as no platelettransfusion 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 thesecriteria but have a 24-hour creatinine clearance or glomerular filtrationrate (GFR) (radioisotope or iothalamate) >= 70 mL/min/1.73 m^2 areeligible

• 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 lowerlimit of normal by echo (while not receiving medications for cardiacfunction)

• Corrected QT (QTc) =< 480 msec

• Female patients of childbearing potential must have a negative serum orurine pregnancy test within 72 hours prior to receiving the first dose ofstudy medication. If the urine test is positive or cannot be confirmed asnegative, a serum pregnancy test will be required

• Females of child-bearing potential must use a highly effective method ofcontraception during dosing of study treatment and for 16 weeks afterstopping study medication.

• Sexually active males must use a condom during intercourse while on studyand for 16 weeks after stopping study treatment and agree not to father achild during this period

• The patient or parent/guardian is able to understand the consent and iswilling to sign a written informed consent document according toinstitutional guidelines

Exclusion Criteria:

• • Breast-feeding women are excluded from this study due to risks of fetal andteratogenic adverse events as seen in animal/human studies

• Patients with any clinically significant unrelated systemic illness (seriousinfections or significant cardiac, pulmonary, hepatic or other organdysfunction), that in the opinion of the investigator would compromise thepatient's ability to tolerate protocol therapy, put them at additional risk fortoxicity or would interfere with the study procedures or results:

• Patients with a prior or concurrent malignancy whose natural history ortreatment does not have the potential to interfere with the safety orefficacy assessment of the investigational regimen are eligible for thistrial. Patients with NF1 and history of plexiform neurofibroma will bepermitted to enroll

• Patients with a previously documented retinal vein occlusion or severeretinopathy

• Presence of active gastrointestinal (GI) disease or other condition (e.g.,small bowel or large bowel resection) that will interfere significantlywith the absorption of drugs

• Patients who are unable to discontinue prohibited medications or herbalpreparations within 7 days of enrollment and 14 days of starting study therapy

• Patients who are receiving any other anti-cancer or investigational drugtherapy 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 biologiccomposition

• Prisoners will be excluded from this study.

• Patients who in the opinion of the investigator are unwilling or unable toreturn for required follow-up visits or obtain follow-up studies required toassess toxicity to therapy or to adhere to drug administration plan, otherstudy procedures, and study restrictions