Dabrafenib and Trametinib in Treating Patients With BRAF Mutated Ameloblastoma

• ClinicalTrials.gov Identifier: NCT02367859
• Recruitment Status: Completed
• First Posted: February 20, 2015
• Results First Posted: January 21, 2020
• Last Update Posted: January 21, 2020
• Sponsor: Stanford University
• Collaborator: Novartis Pharmaceuticals
• Information provided by (Responsible Party): A. Dimitrios Colevas, 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; 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

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 1 participants
• Allocation: N/A
• 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
• Actual Primary Completion Date: November 5, 2018
• Actual Study Completion Date: June 26, 2019

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; Drug: Trametinib; Given PO; Other Name: Mekinist

Outcome Measures

Primary Outcome Measures :

1. Tumor Response [ Time Frame: 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 :

1. Percent Tumor Necrosis [ Time Frame: 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.
2. Change in Proliferation [ Time Frame: 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.
3. Phosphorylation of Tumor Markers MEK and ERK [ Time Frame: 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.

Eligibility Criteria

• 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

Locations

United States, California

Stanford University, School of Medicine

Stanford, California, United States, 94305

Sponsors and Collaborators

Stanford University

Novartis Pharmaceuticals

Investigators

• Principal Investigator: Alexander Colevas; Stanford University

  Study Documents (Full-Text)

Documents provided by A. Dimitrios Colevas, Stanford University:

Informed Consent Form  [PDF] December 18, 2018

Study Protocol and Statistical Analysis Plan  [PDF] August 21, 2018

More Information

Additional Information:

Stanford Cancer Institute Trials 

• Responsible Party: A. Dimitrios Colevas, Professor of Medicine (Oncology) and Otolaryngology, Stanford University
• ClinicalTrials.gov Identifier: NCT02367859
• Other Study ID Numbers: IRB-32275; NCI-2015-00169 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); ENT0043 ( Other Identifier: OnCore )
• First Posted: February 20, 2015
• Results First Posted: January 21, 2020
• Last Update Posted: January 21, 2020
• Last Verified: January 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Keywords provided by A. Dimitrios Colevas, Stanford University:

ameloblastoma; BRAF; odontogenic cancer; adamantinoma

Additional relevant MeSH terms:

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