Dabrafenib and Trametinib in Treating Patients With Erdheim Chester Disease and BRAF Mutation

Inclusion Criteria:

• All patients will be previously or simultaneously enrolled in the natural history ECDprotocol #11-HG-0207, "Clinical and Basic Investigations into Erdheim Chesterdisease"; eligible patients must have been diagnosed with Erdheim Chester disease,confirmed by pathological evaluation of the affected tissue with adequate staining;affected tissue must harbor the BRAF V600E or V600K mutation

• Patients must have measurable disease, defined as at least one lesion that can beaccurately measured in at least one dimension (longest diameter to be recorded fornon-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventionaltechniques or as >= 10 mm with spiral CT scan, MRI, or calipers by clinical exam

• Prior treatment, involving interferon, anakinra, imatinib, steroids, chemotherapywith, but not limited to cladribine, vinblastine, 6-mercaptopurine and etoposide, orother medications used empirically for the treatment of ECD, will be acceptable;these therapies should have been completed and discontinued 4 weeks or more prior toenrollment in this study

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

• Life expectancy of greater than 3 months

• Able to swallow and retain oral medication and must not have any clinicallysignificant gastrointestinal abnormalities that may alter absorption such asmalabsorption syndrome or major resection of the stomach or bowels

• Patients must have BRAFV600E or BRAFV600K mutations, identified by a Food and DrugAdministration (FDA)-approved test at a Clinical Laboratory Improvement Amendments (CLIA)-certified lab; if test at CLIA-certified lab used a non-FDA approved method,information about the assay must be provided; (FDA approved tests for BRAF V600mutations in melanoma include: THxID BRAF Detection Kit and Cobas 4800 BRAF V600Mutation Test)

• Absolute neutrophil count (ANC) >= 1.2 x 10^9/L

• Hemoglobin >= 9 g/dL

• Platelets >= 100 x 10^9/L

• Albumin >= 2.5 g/dL

• Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN) except subjectswith known Gilbert's syndrome

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 xinstitutional ULN

• Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gaultformula) >= 50 mL/min

• Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastintime (PTT) =< 1.3 x institutional ULN; subjects receiving anticoagulation treatmentmay be allowed to participate with INR established within the therapeutic range priorto randomization

• Left ventricular ejection fraction >= institutional lower limit of normal (LLN) byechocardiogram (ECHO)

• Women of childbearing potential must have a negative serum pregnancy test within 14days prior to registration or randomization

• Women of child-bearing potential must agree to use adequate contraception (barriermethod of birth control, or abstinence; hormonal contraception is not allowed) forthe duration of study participation, and for at least 2 weeks after treatment withdabrafenib or for 4 months after dabrafenib in combination with trametinib; should awoman become pregnant or suspect she is pregnant while she is participating in thisstudy, she should inform her treating physician immediately

• Therapeutic level dosing of warfarin can be used with close monitoring of PT/INR bythe site; exposure may be decreased due to enzyme induction when on treatment, thuswarfarin dosing may need to be adjusted based upon PT/INR; consequently, whendiscontinuing dabrafenib, warfarin exposure may be increased and thus closemonitoring via PT/INR and warfarin dose adjustments must be made as clinicallyappropriate; prophylactic low dose warfarin may be given to maintain central catheterpatency

• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Inability to provide informed consent

• Prior systemic anti-cancer therapy (chemotherapy with delayed toxicity, extensiveradiation therapy, immunotherapy, biologic therapy, or vaccine therapy) within thelast 3 weeks; chemotherapy regimens without delayed toxicity within the last 2 weekspreceding the first dose of study treatment

• Use of other investigational drugs within 28 days (or five half-lives, whichever isshorter; with a minimum of 14 days from the last dose) preceding the first dose ofstudy treatment and during the study; patients that have used other BRAF ormitogen-activated protein kinase kinase (MEK) inhibitor are excluded

• Current use of a prohibited medication; patients receiving any medications orsubstances that are strong inhibitors or inducers of cytochrome P450, family 3,subfamily A (CYP3A) or cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8)are ineligible; current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) orbreast cancer resistance protein 1 (Bcrp1) should also be excluded

• Unresolved toxicity of National Cancer Institute Common Terminology Criteria forAdverse Events, version 4.0 (NCI CTCAE v4.0) grade 2 or higher from previousanti-cancer therapy, except alopecia, at the time of randomization

• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviraltherapy are ineligible

• A history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (with theexception of cleared HBV and HCV infection, which will be allowed)

• Presence of malignancy other than the study indication under this trial within 5years of study enrollment

• Patients with history of rat sarcoma (RAS) mutation-positive tumors are not eligibleregardless of interval from the current study; note: prospective RAS testing is notrequired; however, if the results of previous RAS testing are known, they must beused in assessing eligibility

• Leptomeningeal or brain metastases or metastases causing spinal cord compression thatare symptomatic or untreated or not stable for >= 3 months (must be documented byimaging) or requiring corticosteroids; subjects on a stable dose of corticosteroids > 1 month or who have been off of corticosteroids for at least 2 weeks can be enrolledwith approval of the Cancer Therapy Evaluation Program (CTEP) medical monitor;subjects must also be off of enzyme-inducing anticonvulsants for > 4 weeks

• History or evidence of cardiovascular risks, except stable ECD cardiac lesion,including any of the following:

• QT interval corrected for heart rate using the Bazett's formula (QTcB) >= 480msec

• History of acute coronary syndromes (including myocardial infarction or unstableangina), coronary angioplasty, or stenting within the past 24 weeks prior torandomization

• History or evidence of current class II, III, or IV heart failure as defined bythe New York Heart Association (NYHA) functional classification system

• Intra-cardiac defibrillators

• Abnormal cardiac valve morphology (>= grade 2) documented by ECHO; (subjectswith grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered onstudy); subjects with moderate valvular thickening should not be entered onstudy

• History or evidence of current clinically significant uncontrolled cardiacarrhythmias; clarification; subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible

• Treatment refractory hypertension defined as a blood pressure of systolic > 140mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensivetherapy

• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugschemically related to the study treatments, their excipients, and/or dimethylsulfoxide (DMSO)

• Any serious or unstable pre-existing medical conditions (aside from malignancyexceptions specified above), psychiatric disorders, or other conditions that couldinterfere with the subject's safety, obtaining informed consent, or compliance withstudy procedures

• Pregnant women are excluded from this study; breastfeeding should be discontinuedprior to treatment with dabrafenib/trametinib

• History of retinal vein occlusion (RVO)

• Interstitial lung disease or pneumonitis not secondary to ECD

• Central serous retinopathy (CSR) including presence of predisposing factors to RVO orCSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled diabetesmellitus, or a history of hyperviscosity or hypercoagulability syndromes); or visiblepathology (e.g., evidence of optic disc cupping, evidence of new visual field defectson automated perimetry, or intraocular pressure > 21 mmHg as measured by tonography)as assessed by ophthalmic examination

• Inability to travel to the National Institutes of Health (NIH) Clinical Center

• Patients with wild type BRAF gene molecular results on ECD affected tissue

• Patients with confirmed diagnosis of ECD that are asymptomatic and with no visceralinvolvement are not eligible for this trial (patients with no target lesions as perResponse Evaluation Criteria in Solid Tumors [RECIST] 1.1 criteria