Dabrafenib and Trametinib in Treating Patients With BRAF Mutated Ameloblastoma

• Sponsor: Stanford University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02367859
• Collaborator: Novartis Pharmaceuticals (Industry)
• Enrollment: 1
• Location: 1
• Arm: 1
• Actual Duration (Months): 23.3
• Patients Per Site Per Month: 0

Study Details

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:

1. To observe the response rate of ameloblastoma to dabrafenib and trametinib at 6 weeks.

SECONDARY OBJECTIVES:

1. 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
• 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: Jul 17, 2017
• Actual Primary Completion Date: Nov 5, 2018
• Actual Study Completion Date: Jun 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 Names: Mekinist

Outcome Measures

Primary Outcome Measures

1. 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

1. 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.

2. 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.

3. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

	Site	City	State	Country	Postal Code
1	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)

• Informed Consent Form - Dec 18, 2018
• Study Protocol and Statistical Analysis Plan - Aug 21, 2018

More Information

Additional Information:

• Stanford Cancer Institute Trials

Publications

None provided.

• 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; ENT0043
• First Posted: Feb 20, 2015
• Last Update Posted: Jan 21, 2020
• Last Verified: Jan 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• 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, Professor of Medicine (Oncology) and Otolaryngology, Stanford University: ameloblastoma; BRAF; odontogenic cancer; adamantinoma
• Additional relevant MeSH terms: Ameloblastoma; Adamantinoma; Trametinib; Dabrafenib

Study Results

Participant Flow

Arm/Group Title	Treatment (Dabrafenib)
Arm/Group Description	Patients receive dabrafenib orally twice daily every 12 hours plus trametinib daily orally 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.
Period Title: Overall Study
STARTED	1
COMPLETED	1
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment (Dabrafenib)
Arm/Group Description	Patients receive dabrafenib orally twice daily every 12 hours plus trametinib daily orally 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.
Overall Participants	1
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	1 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	1 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	1 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 100%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	0 0%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	1 100%

Outcome Measures

1. Primary Outcome

Title	Tumor Response
Description	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.
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Dabrafenib)
Arm/Group Description	Patients receive dabrafenib orally twice daily every 12 hours plus trametinib daily orally 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.
Measure Participants	1
Complete Response (CR)	0 0%
Partial Response (PR)	0 0%
Overall Response (OR)	0 0%
Progressive disease (PD)	0 0%
Stable disease (SD)	1 100%

2. Secondary Outcome

Title	Percent Tumor Necrosis
Description	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.
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

On the basis of futility due to study closure with inadequate accrual, post-surgical research specimens were not analyzed.

Arm/Group Title	Treatment (Dabrafenib)
Arm/Group Description	Patients receive dabrafenib orally twice daily every 12 hours plus trametinib daily orally 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.
Measure Participants	0

3. Secondary Outcome

Title	Change in Proliferation
Description	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.
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

On the basis of futility due to study closure with inadequate accrual, post-surgical research specimens were not analyzed.

Arm/Group Title	Treatment (Dabrafenib)
Arm/Group Description	Patients receive dabrafenib orally twice daily every 12 hours plus trametinib daily orally 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.
Measure Participants	0

4. Secondary Outcome

Title	Phosphorylation of Tumor Markers MEK and ERK
Description	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.
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

On the basis of futility due to study closure with inadequate accrual, post-surgical research specimens were not analyzed.

Arm/Group Title	Treatment (Dabrafenib)
Arm/Group Description	Patients receive dabrafenib orally twice daily every 12 hours plus trametinib daily orally 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.
Measure Participants	0

Adverse Events

Time Frame	6 weeks
Arm/Group Title	Treatment (Dabrafenib)
Arm/Group Description	Patients receive dabrafenib orally twice daily every 12 hours plus trametinib daily orally 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.
All Cause Mortality
	Treatment (Dabrafenib)
	Affected / at Risk (%)	# Events
Total	0/1 (0%)
Serious Adverse Events
	Treatment (Dabrafenib)
	Affected / at Risk (%)	# Events
Total	0/1 (0%)
Other (Not Including Serious) Adverse Events
	Treatment (Dabrafenib)
	Affected / at Risk (%)	# Events
Total	1/1 (100%)
General disorders
Flu like symptoms	1/1 (100%)	1
Fatigue	1/1 (100%)	1
Investigations
Weight loss	1/1 (100%)	1
Metabolism and nutrition disorders
Anorexia	1/1 (100%)	1
Musculoskeletal and connective tissue disorders
Myalgia	1/1 (100%)	1
Nervous system disorders
Headache	1/1 (100%)	1
Skin and subcutaneous tissue disorders
Rash acneform	1/1 (100%)	1
Dermatologic syndrome	1/1 (100%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.