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

NCT01700699 | Unknown

• 1 other identifier: BRAF-TKI-DTC1
• Study Type: observational
• Target: 50
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Differentiated Thyroid Cancer

Keywords

thyroid cancer; tyrosine kinase inhibitors; BRAF; Sorafenib; Pazopanib; Sunitinib; Cabozantinib

Outcome Measures

Primary Outcomes (1)

• Percentage of BRAFV600E alleles in tumor tissue before TKI treatment

  within 1 month after the patient has entered the study

Secondary Outcomes (1)

• Percentage of BRAFV600E alleles in tumor tissue post-TKI treatment

  within 30 days from the availability of the tissue sample

Study Arms (6)

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

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

primary care clinic

You may qualify if:

• 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

You may not qualify if:

• concurrent Hashimoto's thyroiditis

Sponsors & Collaborators

• University of Salerno: lead

Study Sites (1)

Department of Medicine and Surgery, Univeristy of Salerno

Baronissi, Salerno, 84081, Italy

RECRUITING

Related 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.

  PMID: 22508706 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Primary and metastatic tumor tissue, frozen or formaldehyde fixed-paraffin embedded from block, genomic DNA already extracted from tumor tissue

MeSH Terms

Conditions

Thyroid Neoplasms

Condition Hierarchy (Ancestors)

Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Head and Neck Neoplasms; Endocrine System Diseases; Thyroid Diseases

Study Officials

• Mario Vitale, MD

  Univeristy of Salerno, Italy

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Mario Vitale, MD

CONTACT

+39 089672539; mavitale@unisa.it

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Endocrinology at the School of Medicine, University of Salerno, Director of the Endocrinology Unit, University Hospital of Salerno, Italy

Study Record Dates

• First Submitted: September 22, 2012
• First Posted: October 4, 2012
• Study Start: October 1, 2012
• Primary Completion: October 1, 2013
• Study Completion: October 1, 2013
• Last Updated: October 23, 2012

Record last verified: 2012-10

Locations

IT (1)