Description:
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.
Title
- Brief Title: Dabrafenib Alone and in Combination With Trametinib Before Surgery in Treating Patients With Locally or Regionally Advanced Melanoma That Can Be Removed By Surgery
- 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 Trial IDs
- ORG STUDY ID:
VICC MEL 1263
- SECONDARY ID:
NCI-2012-01699
- NCT ID:
NCT01701037
Conditions
- 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)
Interventions
Drug | Synonyms | Arms |
---|
dabrafenib | BRAF inhibitor GSK2118436, GSK2118436 | Dabrafenib and Trametinib |
trametinib | GSK1120212 | Dabrafenib and Trametinib |
Purpose
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.
Detailed Description
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.
Trial Arms
Name | Type | Description | Interventions |
---|
Dabrafenib and Trametinib | Experimental | 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. | |
Eligibility Criteria
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 history of interstitial lung disease or interstitial pneumonitis
- A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or
Hepatitis C Virus (HCV) infection.
- History of another active malignancy within the past 5 years, or any malignancy with a
confirmed activating RAS mutation. Please note that prospective RAS mutation testing
is not required, however, if results of previous RAS testing are known, they must be
used in assessing eligibility. Subjects with a history of completely resected
non-melanoma skin cancer are eligible.
- A history or current evidence/risk of retinal vein occlusion (RVO) or CSR including:
- a. Presence of predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or
ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a
history of hyperviscosity or hypercoagulability syndromes); or
- b. Visible retinal pathology as assessed by ophthalmic examination that is considered
a risk factor for RVO or CSR such as:
- i. Evidence of new optic disc cupping;
- ii. Evidence of new visual field defects on automated perimetry;
- iii. Intraocular pressure >21 mmHg as measured by tonography.
Maximum Eligible Age: | 90 Years |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | 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 |
Safety Issue: | |
Description: | 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. |
Secondary Outcome Measures
Measure: | 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 |
Safety Issue: | |
Description: | 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. |
Measure: | 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 |
Safety Issue: | |
Description: | 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 |
Measure: | Investigational Agent Taken |
Time Frame: | Up to 3 months |
Safety Issue: | |
Description: | Median number of pills taken |
Measure: | Percent of Patients Completing Second and Third (Surgical) Biopsies |
Time Frame: | Up to 3 months |
Safety Issue: | |
Description: | 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. |
Measure: | Percentage of Biopsies With Adequate Tissue for Biomarker Analysis |
Time Frame: | Up to 3 months |
Safety Issue: | |
Description: | 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. |
Details
Phase: | Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Terminated |
Lead Sponsor: | Vanderbilt-Ingram Cancer Center |
Trial Keywords
- Melanoma, B-RAF, biomarkers, targeted therapy, resistance
Last Updated
June 23, 2017