Clinical trial NCT02367859: Dabrafenib and Trametinib in Treating Patients With BRAF Mutated Ameloblastoma
Official title: A Pilot Study of Dabrafenib and Trametinib for Patients With BRAF Mutated Ameloblastoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Ameloblastoma
BRAF Gene Mutation
Keywords: ameloblastoma
BRAF
odontogenic cancer
adamantinoma
Lead sponsor: Stanford University
Sponsor class: OTHER
Collaborators: name: Novartis Pharmaceuticals
First posted: 2015-02-20
Enrollment: 1
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Tumor Response
timeFrame: 6 weeks
Secondary outcomes:
measure: Percent Tumor Necrosis
timeFrame: 6 weeks
measure: Change in Proliferation
timeFrame: 6 weeks
measure: Phosphorylation of Tumor Markers MEK and ERK
timeFrame: 6 weeks
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford University, School of Medicine
state: California
Study officials:
affiliation: Stanford University
name: Alexander Colevas
role: PRINCIPAL_INVESTIGATOR
References: