Dabrafenib Alone and in Combination With Trametinib Before Surgery in Treating Patients With Locally or Regionally Advanced Melanoma That Can Be Removed By Surgery
|Recurrent Melanoma Stage IIB Melanoma (Locally Advanced) Stage IIC Melanoma (Locally Advanced) Stage IIIA Melanoma Stage IIIB Melanoma Stage IIIC Melanoma Stage IV Melanoma (Limited, Resectable)||Drug: dabrafenib Drug: trametinib Other: laboratory biomarker analysis||Phase 2|
|Study Design:||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
|Official Title:||Biomarkers of Response and Resistance to Sequential B-RAF and MEK Targeted Therapy in a Pre-Surgical Model of Advanced, Operable Melanoma|
- Clinical Tumor Response Rate (Response is Based on Greater Than 30% Reduction From Baseline in Tumor Volume by RECIST Criteria) at Day 14. [ Time Frame: day 14 ]Tumor response is defined as greater than 30% reduction from baseline in tumor volume by RECIST criteria. To determine whether a patient is responded at day 14, the patient must have the tumor volume evaluated at both baseline and day 14. The tumor response rate is calculated as the proportion of patients responded among all evaluated patients.
- Change in Tumor Volume Reduction in Participants With Intrinsic Resistance to B-RAF Targeted Therapy From Day 14 to Day 28. [ Time Frame: Day 14 and day 28 ]Tumor volume reduction is calculated as the tumor volume change relative to the baseline measurement (percent). Change in tumor volume reduction from day 14 to day 28 is calculated as the difference of tumor volume reduction at day 28 and day 14. The median and Inter-Quartile Range are reported.
- Number of Patients With Worst Grade Toxicities by Grade According to National Cancer Institute (NCI) CTCAE Version 4.0 [ Time Frame: Up to 3 months ]
The intensity of the adverse event will be graded according to Version 4.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events (June 14, 2010):
Grade 1 - Mild Grade 2 - Moderate Grade 3 - Severe or medically significant Grade 4 - Life-threatening Grade 5 - Death related to adverse event
- Investigational Agent Taken [ Time Frame: Up to 3 months ]Median number of pills taken
- Percent of Patients Completing Second and Third (Surgical) Biopsies [ Time Frame: Up to 3 months ]Biopsies will be assessed whether or not tissue is acquired at specified time points. Tissue is obtained through core, punch, incisional or excisional biopsy or surgical resection, based upon the clinical situation. Standard operating procedures for biopsies, sample preparation and analysis have been defined.
- Percentage of Biopsies With Adequate Tissue for Biomarker Analysis [ Time Frame: Up to 3 months ]Measured by the percent of tumor necrosis on hematoxylin and eosin stains; RNA gel electrophoresis, percent of adequate tissue for immunohistochemical stains in tissue microarray and cyTOF analysis.
|Study Start Date:||January 2013|
|Study Completion Date:||April 2015|
|Primary Completion Date:||February 2015 (Final data collection date for primary outcome measure)|
Experimental: Dabrafenib and Trametinib
Patients receive dabrafenib PO BID on days 1-28 adding trametinib on days 15-28 followed by surgery on days 28-30. Treatment continues in the absence of unacceptable toxicity.
150 mg given PO
Other Names:Drug: trametinib
2 mg given PO
Other Name: GSK1120212Other: laboratory biomarker analysis
I. To identify markers of intrinsic resistance to v-Raf murine sarcoma viral oncogene homolog B1 (B-RAF) targeted therapy in B-RAF mutation-positive melanoma.
I. To determine if intrinsic resistance can be reversed by mitogen activated protein kinase (MEK) targeted therapy and to identify biomarkers that correlate with this response.
II. To evaluate the feasibility of pre-surgical targeted therapy and serial tumor biopsies in patients with advanced, operable melanoma to determine if this model can be used to evaluate novel combinations of molecular targeted therapy in the future.
I. To determine if pre-surgical B-RAF and MEK targeted therapy is active and well tolerated in patients with advanced, operable melanoma. These findings may be used to support clinical trials in un-resectable, B-RAF mutation-positive melanoma.
Patients receive dabrafenib orally (PO) twice daily (BID) on days 1-28 adding trametinib on days 15-28 followed by surgery on days 28-30. Treatment continues until the day prior to surgery in the absence of unacceptable toxicity.
After completion of study treatment, patients are followed up for 3 months.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01701037
|United States, Tennessee|
|Vanderbilt-Ingram Cancer Center|
|Nashville, Tennessee, United States, 37232-6838|
|Principal Investigator:||Mark Kelley||Vanderbilt-Ingram Cancer Center|