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Biomarkers of Response and Resistance to Sequential B-RAF and MEK Targeted Therapy in a Pre-Surgical Model of Advanced, Operable Melanoma

Phase 2
18 Years
90 Years
Open (Enrolling)
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)

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Trial Information

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.

Inclusion Criteria:

- Signed written informed consent

- Patients with locally-or regionally advanced melanoma being considered for resection
of the lesion(s) for local-regional control and potential cure

- Patients with limited, resectable metastatic disease (three or fewer lesions)
are eligible if surgical resection is considered to be the best therapeutic

- Patients with AJCC clinical stage IIb-IV disease at initial diagnosis, or
patients with melanoma of any stage with advanced local or regional recurrence,
with or without limited resectable metastatic disease, would be eligible

- B-RAF V-600 mutation positive by snapshot molecular analysis

- Individuals with B-RAF V-600 mutations other than V600E are eligible

- Measurable disease, i.e. presenting with at least one measurable lesion per Response
Evaluation Criteria in Solid tumors (RECIST) 1.1

- All prior treatment related toxicities must be Common Terminology Criteria for
Adverse Events (CTCAE) (Version 4.0) =< Grade 1 at the time of enrollment

- Adequate baseline organ function defined by the criteria below:

- Absolute Neutrophil Count (ANC) >= 1.5 X 10^9/L

- Platelet Count >= 60 X 10^9/L

- Hemoglobin >= 9 g/dl

- Creatinine =< 2 mg/dl

- Aspartate aminotransferase (AST) =< 100 U/L

- Alanine aminotransferase (ALT) =< 100 U/L

- Alkaline Phosphatase =< 380 U/L

- Total Bilirubin =< 2.0 mg/dl

- Women of childbearing potential must have a negative serum pregnancy test within 14
days of first dose of study treatment and agree to use effective contraception during
the study and for 7 days following the last dose of study treatment

- Men with a female partner of childbearing potential must have either had a prior
vasectomy or agree to use effective contraception from 1 day prior to administration
of the first dose of study treatment until 7 days after the last dose of study

Exclusion Criteria:

- ECOG Performance Status > 2

- Lactating female

- Any serious and/or unstable pre-existing medical, psychiatric disorder, or other
conditions that could interfere with subject's safety, obtaining informed consent or
compliance to the study procedures

- Any serious medical condition that would render the patient unable to undergo
surgical resection or would limit life expectancy to less than 1 year

- Any prohibited medication

- Administration of an investigational drug within 30 days or 5 half-lives, whichever
is longer, preceding the first dose of study treatment

- A known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to GSK-2118436 (dabrafenib) or GSK-1120212 (trametinib) or
excipient that contraindicates their participation

- Patients with a history of severe cardiovascular disease as defined:

- Symptomatic or uncontrolled cardiac arrhythmias

- Treatment refractory hypertension, defined as a systolic blood pressure > 160mm
Hg and/or diastolic > 100 mmHg which cannot be controlled by antihypertensive

- Current ≥ NYHA Class II congestive heart failure

- History of myocardial infarction or unstable angina within 6 months prior to
study entry.

- History of stroke or TIA within 6 months prior to study entry

- QTc ≥ 480 msec

- Cardiac valvular disease ≥ grade 2

- Patients with a known history of glucose-6-phosphate dehydrogenase (G6PD) deficiency.

- Patients with a history of interstitial lung disease or interstitial pneumonitis

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label

Outcome Measure:

Clinical tumor response, in terms of change (greater than 30% reduction in tumor volume by RECIST criteria) and association with biomarker expression

Outcome Description:

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.

Outcome Time Frame:

Baseline and day 14

Safety Issue:


Principal Investigator

Mark Kelley

Investigator Role:

Principal Investigator

Investigator Affiliation:

Vanderbilt-Ingram Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

January 2013

Completion Date:

December 2014

Related Keywords:

  • 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)
  • Melanoma, B-RAF, biomarkers, targeted therapy, resistance
  • Melanoma



Vanderbilt-Ingram Cancer Center Nashville, Tennessee  37232-6838