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

Differentiated Thyroid Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01700699
• Other study ID #: BRAF-TKI-DTC1
• Status: Recruiting
• Phase: N/A
• First received: September 22, 2012
• Last updated: October 20, 2012
• Start date: October 2012
• Est. completion date: October 2013

Study information

• Verified date: October 2012
• Source: University of Salerno
• Contact: Mario Vitale, MD
• Phone: +39 089672539
• Email: mavitale[@]unisa.it
• Is FDA regulated: No
• Health authority: Italy: Ethics Committee
• Study type: Observational

Clinical Trial Summary

• 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: October 2013
• Est. primary completion date: October 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A and older

Eligibility

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 Design

Observational Model: Cohort, Time Perspective: Retrospective

Related Conditions & MeSH terms

• Differentiated Thyroid Cancer
• Thyroid Diseases
• Thyroid Neoplasms

Locations

Country	Name	City	State
Italy	Department of Medicine and Surgery, Univeristy of Salerno	Baronissi	Salerno

Sponsors (1)

Lead Sponsor	Collaborator
University of Salerno

Country where clinical trial is conducted

Italy, 

References & Publications (4)

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. — View 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of BRAFV600E alleles in tumor tissue before TKI treatment		within 1 month after the patient has entered the study	No
Secondary	Percentage of BRAFV600E alleles in tumor tissue post-TKI treatment		within 30 days from the availability of the tissue sample	No