Dabrafenib and Trametinib in Treating Patients With BRAF Mutated Ameloblastoma

A Pilot Study of Dabrafenib and Trametinib for Patients With BRAF Mutated Ameloblastoma

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.

Study Overview

• Status: Completed
• Conditions: Ameloblastoma; BRAF Gene Mutation
• Intervention / Treatment: Drug: Trametinib; Drug: Dabrafenib

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 Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University, School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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: Trametinib; Given PO; Other Names: Mekinist; Drug: Dabrafenib; Given PO; Other Names: Tafinlar; GSK2118436; BRAF Inhibitor GSK2118436; GSK-2118436A

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor Response	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.	6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Tumor Necrosis	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.	6 weeks
Change in Proliferation	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.	6 weeks
Phosphorylation of Tumor Markers MEK and ERK	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.	6 weeks

Collaborators and Investigators

• Sponsor: Stanford University
• Collaborators: Novartis Pharmaceuticals
• Investigators: Principal Investigator: Alexander Colevas, Stanford University

Publications and helpful links

Helpful Links

• Stanford Cancer Institute Trials

Study record dates

Study Major Dates

• Study Start (Actual): July 17, 2017
• Primary Completion (Actual): November 5, 2018
• Study Completion (Actual): June 26, 2019

Study Registration Dates

• First Submitted: February 13, 2015
• First Submitted That Met QC Criteria: February 13, 2015
• First Posted (Estimated): February 20, 2015

Study Record Updates

• Last Update Posted (Actual): January 30, 2024
• Last Update Submitted That Met QC Criteria: January 7, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: BRAF; ameloblastoma; odontogenic cancer; adamantinoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Musculoskeletal Diseases; Bone Diseases; Bone Neoplasms; Odontogenic Tumors; Adamantinoma; Ameloblastoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Trametinib; Dabrafenib
• Other Study ID Numbers: IRB-32275; NCI-2015-00169 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); ENT0043 (Other Identifier: OnCore)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No