<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01700699</url>
  </required_header>
  <id_info>
    <org_study_id>BRAF-TKI-DTC1</org_study_id>
    <nct_id>NCT01700699</nct_id>
  </id_info>
  <brief_title>Impact of BRAFV600E Intratumor Heterogeneity in Thyroid Cancer Treated With Tyrosine Kinase Inhibitors</brief_title>
  <official_title>Impact of BRAFV600E Intratumor Heterogeneity on the Efficacy of Tyrosine Kinase Inhibitors in the Treatment of Radioiodine-resistant Thyroid Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Salerno</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Salerno</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      -  Background: BRAFV600E is the most frequent oncogene in differentiated thyroid cancer&#xD;
           (DTC) occurring in about 50% of cases. Clinical trials with tyrosine kinase inhibitors&#xD;
           (TKI) with specific activity against BRAF in metastatic radioiodine-resistant DTC&#xD;
           (MRR-DTC) are ongoing. Very recently it has been demonstrated that DTC often consists of&#xD;
           a mixture of tumor cells with wild-type and mutant BRAF. The subclonal occurrence of&#xD;
           BRAFV600E in MRR-DTC could disable the therapy with BRAF targeted TKI and be responsible&#xD;
           of the frequent defeats of this treatment. A therapeutic strategy based upon BRAF&#xD;
           inhibitors in tumors bearing subclonal BRAFV600E could be initially successful hitting&#xD;
           the tumor cells expressing the oncogene, and after the initial tumor growth arrest&#xD;
           and/or shrinkage, the oncogene negative cells insensitive or less sensitive to the&#xD;
           treatment, could restart the growth of the tumor causing the progression of the disease&#xD;
           and the escape from the clinical response.&#xD;
&#xD;
        -  Aims: To determine the impact of subclonal BRAFV600E on the efficacy of BRAF inhibitors&#xD;
           in the treatment of MRR-DTC.&#xD;
&#xD;
        -  Study design: Primary tumor tissues will be analyzed for the presence of BRAFV600E by&#xD;
           pyrosequencing or other quantitative assay. If available, synchronous metastases and&#xD;
           post-therapy metachronous metastases will be analyzed as well. The clinical response&#xD;
           will be determined according to RECIST, and the association with the percentage of&#xD;
           BRAFV600E alleles will be evaluated. Attention will be paid to the possible difference&#xD;
           of BRAFwild-type/BRAFV600E ratio between primary tumors and synchronous metastases,&#xD;
           primary tumors and post-therapy metachronous metastases, and between responsive and&#xD;
           resistant synchronous tumor lesions.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>October 2012</start_date>
  <completion_date type="Anticipated">October 2013</completion_date>
  <primary_completion_date type="Anticipated">October 2013</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Retrospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Percentage of BRAFV600E alleles in tumor tissue before TKI treatment</measure>
    <time_frame>within 1 month after the patient has entered the study</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Percentage of BRAFV600E alleles in tumor tissue post-TKI treatment</measure>
    <time_frame>within 30 days from the availability of the tissue sample</time_frame>
  </secondary_outcome>
  <number_of_groups>6</number_of_groups>
  <enrollment type="Anticipated">50</enrollment>
  <condition>Differentiated Thyroid Cancer</condition>
  <arm_group>
    <arm_group_label>Sorafenib</arm_group_label>
    <description>Assessment of percentage of BRAFV600E in tissue specimens of MRR-DTC patients treated with Sorafenib</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Axitinib</arm_group_label>
    <description>Assessment of percentage of BRAFV600E in tissue specimens of MRR-DTC patients treated with Axitinib</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Pazopanib</arm_group_label>
    <description>Assessment of percentage of BRAFV600E in tissue specimens of MRR-DTC patients treated with Pazopanib</description>
  </arm_group>
  <arm_group>
    <arm_group_label>TKI</arm_group_label>
    <description>Assessment of percentage of BRAFV600E in tissue specimens of MRR-DTC patients treated with different type of tyrosine kinase inhibitor</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Motesanib</arm_group_label>
    <description>Assessment of percentage of BRAFV600E in tissue specimens of MRR-DTC patients treated with Motesanib</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sunitinib</arm_group_label>
    <description>Assessment of percentage of BRAFV600E in tissue specimens of MRR-DTC patients treated with Sunitinib</description>
  </arm_group>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Primary and metastatic tumor tissue, frozen or formaldehyde fixed-paraffin embedded from&#xD;
      block, genomic DNA already extracted from tumor tissue&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        primary care clinic&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  subjects any sex any age with metastatic or unresectable thyroid carcinoma treated&#xD;
             with tyrosine kinase inhibitors&#xD;
&#xD;
          -  evidence of measurable disease by Response Evaluation Criteria in Solid Tumors&#xD;
             (RECIST)&#xD;
&#xD;
          -  availability of study end points including best response, duration of response, and&#xD;
             time to disease progression (based on RECIST), clinical progression, or death&#xD;
&#xD;
          -  availability of tumor tissue samples, frozen or formaldehyde fixed-paraffin embedded&#xD;
             from block, genomic DNA already extracted from tumor tissue&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  concurrent Hashimoto's thyroiditis&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mario Vitale, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Univeristy of Salerno, Italy</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Mario Vitale, MD</last_name>
    <phone>+39 089672539</phone>
    <email>mavitale@unisa.it</email>
  </overall_contact>
  <location>
    <facility>
      <name>Department of Medicine and Surgery, Univeristy of Salerno</name>
      <address>
        <city>Baronissi</city>
        <state>Salerno</state>
        <zip>84081</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Mario Vitale, MD</last_name>
      <phone>+39 089672539</phone>
      <email>mavitale@unisa.it</email>
    </contact>
    <investigator>
      <last_name>Mario Vitale, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <reference>
    <citation>Guerra A, Fugazzola L, Marotta V, Cirillo M, Rossi S, Cirello V, Forno I, Moccia T, Budillon A, Vitale M. A high percentage of BRAFV600E alleles in papillary thyroid carcinoma predicts a poorer outcome. J Clin Endocrinol Metab. 2012 Jul;97(7):2333-40. doi: 10.1210/jc.2011-3106. Epub 2012 Apr 16.</citation>
    <PMID>22508706</PMID>
  </reference>
  <reference>
    <citation>Guerra A, Sapio MR, Marotta V, Campanile E, Rossi S, Forno I, Fugazzola L, Budillon A, Moccia T, Fenzi G, Vitale M. The primary occurrence of BRAF(V600E) is a rare clonal event in papillary thyroid carcinoma. J Clin Endocrinol Metab. 2012 Feb;97(2):517-24. doi: 10.1210/jc.2011-0618. Epub 2011 Dec 14.</citation>
    <PMID>22170714</PMID>
  </reference>
  <reference>
    <citation>Gupta-Abramson V, Troxel AB, Nellore A, Puttaswamy K, Redlinger M, Ransone K, Mandel SJ, Flaherty KT, Loevner LA, O'Dwyer PJ, Brose MS. Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol. 2008 Oct 10;26(29):4714-9. doi: 10.1200/JCO.2008.16.3279. Epub 2008 Jun 9.</citation>
    <PMID>18541894</PMID>
  </reference>
  <reference>
    <citation>Kloos RT, Ringel MD, Knopp MV, Hall NC, King M, Stevens R, Liang J, Wakely PE Jr, Vasko VV, Saji M, Rittenberry J, Wei L, Arbogast D, Collamore M, Wright JJ, Grever M, Shah MH. Phase II trial of sorafenib in metastatic thyroid cancer. J Clin Oncol. 2009 Apr 1;27(10):1675-84. doi: 10.1200/JCO.2008.18.2717. Epub 2009 Mar 2.</citation>
    <PMID>19255327</PMID>
  </reference>
  <verification_date>October 2012</verification_date>
  <study_first_submitted>September 22, 2012</study_first_submitted>
  <study_first_submitted_qc>October 1, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 4, 2012</study_first_posted>
  <last_update_submitted>October 20, 2012</last_update_submitted>
  <last_update_submitted_qc>October 20, 2012</last_update_submitted_qc>
  <last_update_posted type="Estimate">October 23, 2012</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Salerno</investigator_affiliation>
    <investigator_full_name>Mario Vitale</investigator_full_name>
    <investigator_title>Professor of Endocrinology at the School of Medicine, University of Salerno, Director of the Endocrinology Unit, University Hospital of Salerno, Italy</investigator_title>
  </responsible_party>
  <keyword>thyroid cancer</keyword>
  <keyword>tyrosine kinase inhibitors</keyword>
  <keyword>BRAF</keyword>
  <keyword>Sorafenib</keyword>
  <keyword>Pazopanib</keyword>
  <keyword>Sunitinib</keyword>
  <keyword>Cabozantinib</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Thyroid Neoplasms</mesh_term>
    <mesh_term>Thyroid Diseases</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01700699
org study id: BRAF-TKI-DTC1
nct id: NCT01700699
lead sponsor: 
has dmc: No
-  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.
observational model: Cohort
time perspective: Retrospective
measure: Percentage of BRAFV600E alleles in tumor tissue before TKI treatment
time frame: within 1 month after the patient has entered the study
measure: Percentage of BRAFV600E alleles in tumor tissue post-TKI treatment
time frame: within 30 days from the availability of the tissue sample
arm group label: Sorafenib
description: Assessment of percentage of BRAFV600E in tissue specimens of MRR-DTC patients treated with Sorafenib
arm group label: Axitinib
description: Assessment of percentage of BRAFV600E in tissue specimens of MRR-DTC patients treated with Axitinib
arm group label: Pazopanib
description: Assessment of percentage of BRAFV600E in tissue specimens of MRR-DTC patients treated with Pazopanib
arm group label: TKI
description: Assessment of percentage of BRAFV600E in tissue specimens of MRR-DTC patients treated with different type of tyrosine kinase inhibitor
arm group label: Motesanib
description: Assessment of percentage of BRAFV600E in tissue specimens of MRR-DTC patients treated with Motesanib
arm group label: Sunitinib
description: Assessment of percentage of BRAFV600E in tissue specimens of MRR-DTC patients treated with Sunitinib
Primary and metastatic tumor tissue, frozen or formaldehyde fixed-paraffin embedded from
      block, genomic DNA already extracted from tumor tissue
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: N/A
maximum age: N/A
healthy volunteers: No
last name: Mario Vitale, MD
role: Principal Investigator
affiliation: Univeristy of Salerno, Italy
last name: Mario Vitale, MD
phone: +39 089672539
email: mavitale@unisa.it
facility: 
status: Recruiting
contact: 
investigator: 
country: Italy
citation: Guerra A, Fugazzola L, Marotta V, Cirillo M, Rossi S, Cirello V, Forno I, Moccia T, Budillon A, Vitale M. A high percentage of BRAFV600E alleles in papillary thyroid carcinoma predicts a poorer outcome. J Clin Endocrinol Metab. 2012 Jul;97(7):2333-40. doi: 10.1210/jc.2011-3106. Epub 2012 Apr 16.
PMID: 22508706
citation: Guerra A, Sapio MR, Marotta V, Campanile E, Rossi S, Forno I, Fugazzola L, Budillon A, Moccia T, Fenzi G, Vitale M. The primary occurrence of BRAF(V600E) is a rare clonal event in papillary thyroid carcinoma. J Clin Endocrinol Metab. 2012 Feb;97(2):517-24. doi: 10.1210/jc.2011-0618. Epub 2011 Dec 14.
PMID: 22170714
citation: Gupta-Abramson V, Troxel AB, Nellore A, Puttaswamy K, Redlinger M, Ransone K, Mandel SJ, Flaherty KT, Loevner LA, O'Dwyer PJ, Brose MS. Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol. 2008 Oct 10;26(29):4714-9. doi: 10.1200/JCO.2008.16.3279. Epub 2008 Jun 9.
PMID: 18541894
citation: Kloos RT, Ringel MD, Knopp MV, Hall NC, King M, Stevens R, Liang J, Wakely PE Jr, Vasko VV, Saji M, Rittenberry J, Wei L, Arbogast D, Collamore M, Wright JJ, Grever M, Shah MH. Phase II trial of sorafenib in metastatic thyroid cancer. J Clin Oncol. 2009 Apr 1;27(10):1675-84. doi: 10.1200/JCO.2008.18.2717. Epub 2009 Mar 2.
PMID: 19255327
responsible party type: Principal Investigator
investigator affiliation: University of Salerno
investigator full name: Mario Vitale
investigator title: Professor of Endocrinology at the School of Medicine, University of Salerno, Director of the Endocrinology Unit, University Hospital of Salerno, Italy
mesh term: Thyroid Neoplasms
mesh term: Thyroid Diseases