Biomarkers of Response and Resistance to Sequential B-RAF and MEK Targeted Therapy in a Pre-Surgical Model of Advanced, Operable Melanoma
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.
Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label
Clinical tumor response, in terms of change (greater than 30% reduction in tumor volume by RECIST criteria) and association with biomarker expression
Tumor response summarized in frequency tables and incidence compared using the chi-square or Fisher's exact test. Biomarker expression summarized using minimum, 25th, 50th (median), 75th, and maximum values. Spearman (nonparametric) correlation statistic used to assess strength of association between biomarker expression and tumor volume between any two time points. Logistic regression used to assess the association between biomarker expression and patient response by RECIST criteria. 95% confidence intervals will be calculated for all point estimates.
Baseline and day 14
Vanderbilt-Ingram Cancer Center
United States: Food and Drug Administration
VICC MEL 1263
|Vanderbilt-Ingram Cancer Center||Nashville, Tennessee 37232-6838|