Dabrafenib and Trametinib in Treating Patients With BRAF Mutated Ameloblastoma

PRIMARY OBJECTIVES:

I. To observe the response rate of ameloblastoma to dabrafenib and trametinib at 6 weeks.

SECONDARY OBJECTIVES:

I. Feasibility and safety in this patient population. II. Response will be assessed
pathologically. III. Two main histologic assays for treatment response will be used: tumor
necrosis and phosphorylated-mitogen-activated protein kinase kinase 1 (MEK),
phosphorylated-extracellular signal-regulated kinase (ERK), and Ki-67 levels as measured by
immunohistochemistry.

OUTLINE:

Patients receive dabrafenib orally (PO) twice daily (BID) every 12 hours and trametinib 2 mg
daily PO for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients
whose disease is judged to be not amenable to resection will continue dabrafenib and
trametinib indefinitely as long as there has not been tumor progression.

After completion of study treatment, patients are followed up for at least 4 weeks.

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)

- Aspartate aminotransferase (AST), alanine aminotransferase (ALT) < 2.6 x ULN

- Alkaline phosphatase (alk phos) < 2.6 x ULN

- Serum creatinine < 1.6 x ULN or creatinine clearance > 50 ml/min

- 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

- 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

Exclusion Criteria:

- No prior treatment with agents targeting BRAF mutant tyrosine kinases 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 or breast cancer

- Uncontrolled hypertension, chronic heart failure (CHF), or other major medical illness

- Prior allergic reactions attributed to compounds of similar chemical or biologic
composition to dabrafenib

- 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
pregnancy test within 14 days of enrollment

- 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 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