Dabrafenib and Trametinib in Treating Patients With BRAF Mutated Ameloblastoma

Phase 2

Completed

Conditions: BRAF Gene Mutation
Ameloblastoma

Interventions: Drug: Dabrafenib
Drug: Trametinib

Registration Number: NCT02367859

Lead Sponsor: Stanford University

Brief Summary: This pilot clinical trial studies dabrafenib and trametinib in treating patients with ameloblastoma and a specific mutation (change) in the BRAF gene. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 1

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (dabrafenib)	Dabrafenib	Patients receive dabrafenib PO BID every 12 hours plus trametinib 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.
Treatment (dabrafenib)	Trametinib	Patients receive dabrafenib PO BID every 12 hours plus trametinib 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.

Primary Outcome Measures

Name	Time	Method
Tumor Response	6 weeks	Tumor response was assessed per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Overall tumor response was assessed as the number of participants achieving either a complete response (CR) or a partial response (PR). The criteria are: * CR = Disappearance of all target lesions * PR = ≥ 30% decrease in the sum of the longest diameter of target lesions * Overall Response (OR) = CR + PR * Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions, and/or the appearance of one or more new lesion(s) * Stable disease (SD) = Small changes that do not meet any of the above criteria The outcome is reported as the number of participants achieving the different levels of tumor response per RECIST, a number without dispersion.

Secondary Outcome Measures

Name	Time	Method
Percent Tumor Necrosis	6 weeks	Percent of tumor necrosis at the time of endpoint biopsy or surgical resection will be assessed. The tumor specimen from resection will be examined and the volume of the necrosis compared to the volume of the total tumor determined by central pathology. Percent tumor necrosis, in increments of 10%, will be determined. The outcome will be reported as the mean percent tumor necrosis, with standard deviation.
Change in Proliferation	6 weeks	An immunohistochemical laboratory analysis to assess proliferation will be performed on the initial pre-treatment biopsy (baseline) vs either the endpoint tumor biopsy or the tumor specimen from the resection. Ki-67 immunohistochemistry will be scored by at least 2 pathologists using percentage positive cells as the primary metric. Proliferation will be assessed as the difference from baseline in Ki-67 labeling to the end of treatment (tumor biopsy or the tumor specimen). The outcome will be expressed as the mean, with standard deviation.
Phosphorylation of Tumor Markers MEK and ERK	6 weeks	An immunohistochemical laboratory analysis to assess phosphorylation of the tumor markers MEK and ERK on the initial pre-treatment biopsy (baseline) vs either the endpoint tumor biopsy or the tumor specimen from the resection. Immunohistochemistry will be scored by at least 2 pathologists using percentage positive cells and intensity of staining as the primary metrics. Phosphorylation of MEK and ERK will be assessed as the observed difference in phosphorylated MEK and ERK labeling from baseline to the end of treatment (tumor biopsy or the tumor specimen). The outcome will be expressed as the mean, with standard deviation.