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Recurrent MelanomaPhase 2NCT01701037

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

A Phase 2 study testing dabrafenib, trametinib and laboratory biomarker analysis in people with Recurrent Melanoma and Stage IIB Melanoma (Locally Advanced), run by Vanderbilt-Ingram Cancer Center at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 18 to 90 years
What is being tested?
dabrafenib, trametinib and laboratory biomarker analysis
Could I receive a placebo?
No, everyone receives an active treatment
How many people
13 participants
Where
1 siteUnited States
Study dates
Jan 2013to Apr 2015
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 90 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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

Who cannot join

  • 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
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  • 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.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Vanderbilt-Ingram Cancer Center

    Nashville, Tennessee, 37232-6838

Other trials in United States

About this study

Official title: 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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. 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:

  1. 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:

  1. 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.

Being tested
dabrafenib, trametinib, laboratory biomarker analysis
Keywords
Melanoma, B-RAF, biomarkers, targeted therapy, resistance
Medical subject headings
Melanoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • dabrafenibDrug

    Also called BRAF inhibitor GSK2118436, GSK2118436

    150 mg given PO

  • trametinibDrug

    Also called GSK1120212

    2 mg given PO

  • laboratory biomarker analysisOther

    Correlative studies

Study groups in NCT01701037
Study groupRoleWhat they receive
Dabrafenib and TrametinibExperimentalPatients 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.
Receives: Drug: dabrafenib; Drug: trametinib; Other: laboratory biomarker analysis

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Clinical Tumor Response Rate (Response is Based on Greater Than 30% Reduction From Baseline in Tumor Volume by RECIST Criteria) at 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.

    Measured: day 14

Secondary outcomes (5)

  1. Change in Tumor Volume Reduction in Participants With Intrinsic Resistance to B-RAF Targeted Therapy From Day 14 to 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.

    Measured: Day 14 and day 28

  2. Number of Patients With Worst Grade Toxicities by Grade According to National Cancer Institute (NCI) CTCAE Version 4.0

    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

    Measured: Up to 3 months

  3. Investigational Agent Taken

    Median number of pills taken

    Measured: Up to 3 months

  4. Percent of Patients Completing Second and Third (Surgical) Biopsies

    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.

    Measured: Up to 3 months

  5. Percentage of Biopsies With Adequate Tissue for Biomarker Analysis

    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.

    Measured: Up to 3 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted4 Oct 2012 (estimated)
  2. Study startJan 2013
  3. Primary completionFeb 2015
  4. Study completionApr 2015

Why it stopped: PI leaving VICC, low future accrual predicted, continued funding improbable,

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Other
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
13 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01701037
Sponsor's protocol ID
VICC MEL 1263
Other IDs
NCI-2012-01699
Status last verified
Jun 2017
First submitted
21 Sep 2012
Last updated
23 Jun 2017
Data monitoring committee
Yes

Publications

  • Johnson AS, Crandall H, Dahlman K, Kelley MC. Preliminary results from a prospective trial of preoperative combined BRAF and MEK-targeted therapy in advanced BRAF mutation-positive melanoma. J Am Coll Surg. 2015 Apr;220(4):581-93.e1. doi: 10.1016/j.jamcollsurg.2014.12.057. Epub 2015 Jan 30.

    PubMed 25797743

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing dabrafenib, trametinib and laboratory biomarker analysis in people with Recurrent Melanoma and Stage IIB Melanoma (Locally Advanced), run by Vanderbilt-Ingram Cancer Center at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 19 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 23 Jun 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 23 Jun 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome 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). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01701037, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Jun 2017.

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