Impact of BRAFV600E Intratumor Heterogeneity in Thyroid Cancer Treated With Tyrosine Kinase Inhibitors

October 20, 2012 updated by: Mario Vitale, University of Salerno

Impact of BRAFV600E Intratumor Heterogeneity on the Efficacy of Tyrosine Kinase Inhibitors in the Treatment of Radioiodine-resistant Thyroid Cancer

  • Background: BRAFV600E is the most frequent oncogene in differentiated thyroid cancer (DTC) occurring in about 50% of cases. Clinical trials with tyrosine kinase inhibitors (TKI) with specific activity against BRAF in metastatic radioiodine-resistant DTC (MRR-DTC) are ongoing. Very recently it has been demonstrated that DTC often consists of a mixture of tumor cells with wild-type and mutant BRAF. The subclonal occurrence of BRAFV600E in MRR-DTC could disable the therapy with BRAF targeted TKI and be responsible of the frequent defeats of this treatment. A therapeutic strategy based upon BRAF inhibitors in tumors bearing subclonal BRAFV600E could be initially successful hitting the tumor cells expressing the oncogene, and after the initial tumor growth arrest and/or shrinkage, the oncogene negative cells insensitive or less sensitive to the treatment, could restart the growth of the tumor causing the progression of the disease and the escape from the clinical response.
  • Aims: To determine the impact of subclonal BRAFV600E on the efficacy of BRAF inhibitors in the treatment of MRR-DTC.
  • Study design: Primary tumor tissues will be analyzed for the presence of BRAFV600E by pyrosequencing or other quantitative assay. If available, synchronous metastases and post-therapy metachronous metastases will be analyzed as well. The clinical response will be determined according to RECIST, and the association with the percentage of BRAFV600E alleles will be evaluated. Attention will be paid to the possible difference of BRAFwild-type/BRAFV600E ratio between primary tumors and synchronous metastases, primary tumors and post-therapy metachronous metastases, and between responsive and resistant synchronous tumor lesions.

Study Overview

Status

Unknown

Conditions

Study Type

Observational

Enrollment (Anticipated)

50

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
    • Salerno
      • Baronissi, Salerno, Italy, 84081
        • Recruiting
        • Department of Medicine and Surgery, Univeristy of Salerno

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

primary care clinic

Description

Inclusion Criteria:

  • subjects any sex any age with metastatic or unresectable thyroid carcinoma treated with tyrosine kinase inhibitors
  • evidence of measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST)
  • availability of study end points including best response, duration of response, and time to disease progression (based on RECIST), clinical progression, or death
  • availability of tumor tissue samples, frozen or formaldehyde fixed-paraffin embedded from block, genomic DNA already extracted from tumor tissue

Exclusion Criteria:

  • concurrent Hashimoto's thyroiditis

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Retrospective

Cohorts and Interventions

Group / Cohort
Sorafenib
Assessment of percentage of BRAFV600E in tissue specimens of MRR-DTC patients treated with Sorafenib
Axitinib
Assessment of percentage of BRAFV600E in tissue specimens of MRR-DTC patients treated with Axitinib
Pazopanib
Assessment of percentage of BRAFV600E in tissue specimens of MRR-DTC patients treated with Pazopanib
TKI
Assessment of percentage of BRAFV600E in tissue specimens of MRR-DTC patients treated with different type of tyrosine kinase inhibitor
Motesanib
Assessment of percentage of BRAFV600E in tissue specimens of MRR-DTC patients treated with Motesanib
Sunitinib
Assessment of percentage of BRAFV600E in tissue specimens of MRR-DTC patients treated with Sunitinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Percentage of BRAFV600E alleles in tumor tissue before TKI treatment
Time Frame: within 1 month after the patient has entered the study
within 1 month after the patient has entered the study

Secondary Outcome Measures

Outcome Measure
Time Frame
Percentage of BRAFV600E alleles in tumor tissue post-TKI treatment
Time Frame: within 30 days from the availability of the tissue sample
within 30 days from the availability of the tissue sample

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Salerno

Investigators

  • Principal Investigator: Mario Vitale, MD, Univeristy of Salerno, Italy

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2012

Primary Completion (Anticipated)

October 1, 2013

Study Completion (Anticipated)

October 1, 2013

Study Registration Dates

First Submitted

September 22, 2012

First Submitted That Met QC Criteria

October 1, 2012

First Posted (Estimate)

October 4, 2012

Study Record Updates

Last Update Posted (Estimate)

October 23, 2012

Last Update Submitted That Met QC Criteria

October 20, 2012

Last Verified

October 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • BRAF-TKI-DTC1

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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