Dabrafenib and Trametinib in Treating Patients With BRAF Mutated Ameloblastoma

• Sponsor: Stanford University
• Information provided by (Responsible Party): Stanford University

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Ameloblastoma; BRAF Gene Mutation	Drug: Dabrafenib; Other: Laboratory Biomarker Analysis; Drug: Trametinib	Phase 2

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	17 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Pilot Study of Dabrafenib and Trametinib for Patients With BRAF Mutated Ameloblastoma
Actual Study Start Date :	July 17, 2017
Estimated Primary Completion Date :	October 2019
Estimated Study Completion Date :	August 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment (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.	Drug: Dabrafenib; Given PO; Other Names: BRAF Inhibitor GSK2118436; GSK-2118436A; GSK2118436; Tafinlar; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Trametinib; Given PO; Other Name: Mekinist

Outcome Measures

Primary Outcome Measures :

1. Response rate according to RECIST version (v)1.1 [ Time Frame: 6 weeks ]
   RECIST v1.1 response rate

Secondary Outcome Measures :

1. Percent tumor necrosis [ Time Frame: At the time of endpoint biopsy or surgical resection ]
   Routine Hematoxylin and Eosin slide review will measure extent of tumor necrosis. Percentage of tumor necrosis by volume assessed. The biopsy slide of the resection specimen examined and the volume of the necrosis compared to the volume of the total tumor determined by the centrally reviewing pathologists and percentage readouts of tumor necrosis, in increments of 10%, will be determined. In addition to measuring tumor necrosis the slide review will estimate therapy effect on intact cells by estimating the percent cells with therapy-associated nuclear atypia.
2. Change in percent proliferation index by Ki67 immunohistochemistry [ Time Frame: Baseline to time of endpoint biopsy or surgical resection ]
   Proliferation index evaluation will be performed in the laboratory on the initial pre-treatment biopsy and either the endpoint biopsy or the resection specimen. Ki-67 immunohistochemistry will be scored by at least two pathologists using percentage positive cells as the primary metric. The results of the immunohistochemical analysis will be expressed as both raw data in addition to a ratio between pre- and post- treatment.
3. Change in expression of phosphorylation of MEK and ERK by immunohistochemistry [ Time Frame: Baseline to time of endpoint biopsy or surgical resection ]
   Immunohistochemistry evaluation for MEK/ERK will be performed on the initial pre-treatment biopsy and either the endpoint biopsy or the resection specimen. Immunohistochemistry will be scored by at least two pathologists using percentage positive cells and intensity of staining as the primary metrics. The results of the immunohistochemical analysis will be expressed as both raw data in addition to a ratio between pre- and post- treatment.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Contacts

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Contact: Elizabeth Winters	650-721-6509	ewinters@stanford.edu

Locations

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United States, California
Stanford University, School of Medicine	Recruiting
Stanford, California, United States, 94305
Contact: Elizabeth Winters 650-721-6509 ewinters@stanford.edu
Principal Investigator: Alexander D. Colevas
Sub-Investigator: Jonathan Pollack
Sub-Investigator: Davud Sirjani
Sub-Investigator: Robert West

Sponsors and Collaborators

Stanford University

Investigators

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Principal Investigator:	Alexander Colevas	Stanford University

More Information

Additional Information:

Stanford Cancer Institute Trials 

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Responsible Party:	Stanford University
ClinicalTrials.gov Identifier:	NCT02367859 History of Changes
Other Study ID Numbers:	ENT0043; NCI-2015-00169 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); ENT0043 ( Other Identifier: Stanford University Hospitals and Clinics )
First Posted:	February 20, 2015
Last Update Posted:	July 12, 2018
Last Verified:	July 2018

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Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Stanford University:

ameloblastoma; BRAF; odontogenic cancer; adamantinoma

Additional relevant MeSH terms:

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Ameloblastoma; Adamantinoma; Odontogenic Tumors; Neoplasms by Histologic Type; Neoplasms; Bone Neoplasms; Neoplasms by Site; Bone Diseases	Musculoskeletal Diseases; Trametinib; Dabrafenib; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action