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Dabrafenib Alone and in Combination With Trametinib Before Surgery in Treating Patients With Locally or Regionally Advanced Melanoma That Can Be Removed By Surgery

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2013 by Vanderbilt-Ingram Cancer Center
Sponsor:
Collaborators:
National Comprehensive Cancer Network
Information provided by (Responsible Party):
Mark Kelley, MD, Vanderbilt-Ingram Cancer Center
ClinicalTrials.gov Identifier:
NCT01701037
First received: September 21, 2012
Last updated: March 29, 2013
Last verified: March 2013

September 21, 2012
March 29, 2013
January 2013
October 2014   (final data collection date for primary outcome measure)
Clinical tumor response, in terms of change (greater than 30% reduction in tumor volume by RECIST criteria) and association with biomarker expression [ Time Frame: Baseline and day 14 ] [ Designated as safety issue: No ]
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.
Same as current
Complete list of historical versions of study NCT01701037 on ClinicalTrials.gov Archive Site
  • Change in incremental clinical tumor response (greater than 30% tumor volume reduction by RECIST criteria) in participants with intrinsic resistance to B-RAF targeted therapy [ Time Frame: Day 14 and day 28 ] [ Designated as safety issue: No ]
    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.
  • 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 ] [ Designated as safety issue: Yes ]
    Events will be summarized by frequency and proportion of total subjects, by system organ class and preferred term.
  • Median number of the investigational agent taken per patient [ Time Frame: Up to 3 months ] [ Designated as safety issue: No ]
    Participants that receive all planned doses of the investigational agent. this outcome measure is captured by completion of a pill diary used by the patient to record pills taken.
  • Percent of patients completing second and third (surgical) biopsies [ Time Frame: Up to 3 months ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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.
Same as current
Not Provided
Not Provided
 
Dabrafenib Alone and in Combination With Trametinib Before Surgery in Treating Patients With Locally or Regionally Advanced Melanoma That Can Be Removed By Surgery
Biomarkers of Response and Resistance to Sequential B-RAF and MEK Targeted Therapy in a Pre-Surgical Model of Advanced, Operable Melanoma

This phase II trial studies how well giving dabrafenib alone and in combination with trametinib before surgery works in treating patients with advanced melanoma that can be removed by surgery. Studying samples of tumor tissue in the laboratory from patients receiving dabrafenib and trametinib may help doctors learn more about the effects of these drugs on cells and help identify biomarkers that determine which patients will respond to these drugs best.

PRIMARY OBJECTIVES:

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.

SECONDARY OBJECTIVES:

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.

TERTIARY OBJECTIVES:

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.

OUTLINE:

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.

Interventional
Phase 2
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
  • 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
    150 mg given PO
    Other Names:
    • BRAF inhibitor GSK2118436
    • GSK2118436
  • Drug: trametinib
    2 mg given PO
    Other Name: GSK1120212
  • Other: laboratory biomarker analysis
    Correlative studies
Experimental: Basic science (dabrafenib, 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.
Interventions:
  • Drug: dabrafenib
  • Drug: trametinib
  • Other: laboratory biomarker analysis
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
20
December 2014
October 2014   (final data collection date for primary outcome measure)

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 option
    • 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 treatment

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 therapy.
    • 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
Both
18 Years to 90 Years
No
Contact: VICC Clinical Trials Information Program 800-811-8480
United States
 
NCT01701037
VICC MEL 1263, NCI-2012-01699
Yes
Mark Kelley, MD, Vanderbilt-Ingram Cancer Center
Vanderbilt-Ingram Cancer Center
  • National Cancer Institute (NCI)
  • National Comprehensive Cancer Network
Principal Investigator: Mark Kelley Vanderbilt-Ingram Cancer Center
Vanderbilt-Ingram Cancer Center
March 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP