Dabrafenib and Trametinib in Treating Patients with BRAF Mutated Ameloblastoma

Inclusion Criteria

• Histological diagnosis of ameloblastoma; all stages are eligible; patients must have evaluable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria
• B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E or other known dabrafenib sensitive BRAF mutation in tumor by any Clinical Laboratory Improvement Amendments (CLIA) certified lab; may include, for example, Sanger sequencing, SNaPshot platform, immunohistochemistry, Foundation One tests, etc.)
• Life expectancy > 3 months
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• Absolute neutrophil count (ANC) > 1.5 x10^9/L
• Platelet (PLT) > 99 x 10^9/L
• Hemoglobin > 8 g/dL
• Total bilirubin (Tbili) < 1.6 x upper limit of normal (ULN) * Except subjects with known Gilbert’s syndrome
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT) < 2.6 x upper limit of normal (ULN)
• Serum creatinine =< 1.5 mg/dL, or if serum creatinine is > 1.5 mg/dL, creatinine clearance must be >= 50 mL/min (calculate creatinine clearance using the Cockcroft-Gault formula
• Alkaline phosphatase (alk phos) < 2.6 x ULN
• Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.3 X ULN; subjects receiving anticoagulation treatment may be allowed to participate with INR established within the therapeutic range prior to randomization
• Ability to understand and the willingness to sign a written informed consent document
• Patients of childbearing potential must agree to use effective contraception until at least 6 months after treatment with dabrafenib and trametinib
• Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels
• Left ventricular ejection fraction equal to or greater than normal within 1 month of enrollment; echocardiography (ECHO) scans must be used throughout the study

Exclusion Criteria

• No prior treatment with agents targeting BRAF mutant tyrosine kinases or MEK inhibitors or radiation of target lesions
• Invasive malignancy other than ameloblastoma within 3 years, excluding curatively treated basal cell carcinoma, and other highly curable cancers such as early stage cutaneous squamous cell carcinoma (T1 NO) cervical carcinoma in situ (CIS), early stage prostate cancer, thyroid cancer, breast cancer, or history of malignancy with confirmed activating RAS mutation at any time
• Uncontrolled hypertension (systolic blood pressure > 140 mm Hg and diastolic blood pressure of > 90 mm Hg which cannot be controlled by anti-hypertensive therapy), congestive heart failure (CHF), or other major medical illness
• Prior allergic reactions attributed to compounds of similar chemical or biologic composition to dabrafenib or trametinib
• Concomitant use of strong inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) or cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8)
• Concomitant use of proton pump inhibitors, H2-receptor antagonists, antacids
• Known glucose-6-phosphate dehydrogenase (G6PD) deficiency
• Pregnant or nursing patients; women of childbearing potential must have a negative SERUM pregnancy test within 14 days of enrollment; women of child bearing potential must agree to use effective contraception for 14 days prior to enrollment, throughout the treatment period and for 4 to 6 months after the last dose of study treatment
• Electrocardiogram (EKG) with QTcB (Bazett’s formula) > 480 ms done within 14 days of enrollment
• Interstitial lung disease or pneumonitis
• A history of retinal vein occlusion (RVO)
• Congestive heart failure New York Heart Association (NYHA) class III or worse (marked limitation of physical activity; comfortable at rest; less than ordinary activity causes fatigue, palpitation, or dyspnea)
• A history of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within 6 months or a history or evidence of current clinically significant uncontrolled arrhythmias or intra-cardiac defibrillators or abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram; subjects with grade 1 abnormalities (i.e., mild regurgitations/stenosis) may be entered; subjects with moderate valvular thickening are not eligible; subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible
• Prior systemic anti-cancer treatment (chemotherapy, immunotherapy, biologic therapy, vaccine therapy or investigational treatment within 3 weeks preceding first dose of study treatment, or chemotherapy without delayed toxicity within 2 weeks preceding first dose of study treatment
• Any serious or unstable pre-existing medical conditions, psychiatric disorders or other conditions which could interfere with the subject’s safety, obtaining informed consent, or compliance with study procedures
• A history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection; subjects with laboratory evidence of cleared HBV and/or HCV will be allowed