Impact of BRAFV600E Intratumor Heterogeneity in Thyroid Cancer Treated With Tyrosine Kinase Inhibitors - Full Text View

Purpose

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.

Condition
Differentiated Thyroid Cancer

Study Type:	Observational
Study Design:	Observational Model: Cohort Time Perspective: Retrospective
Official Title:	Impact of BRAFV600E Intratumor Heterogeneity on the Efficacy of Tyrosine Kinase Inhibitors in the Treatment of Radioiodine-resistant Thyroid Cancer

Resource links provided by NLM:

MedlinePlus related topics: Cancer Thyroid Cancer Thyroid Diseases

Drug Information available for: Tyrosine Thyroid Sorafenib Sunitinib malate Pazopanib Sorafenib tosylate Sunitinib

U.S. FDA Resources

Further study details as provided by University of Salerno:

Primary Outcome Measures:

Percentage of BRAFV600E alleles in tumor tissue before TKI treatment [ Time Frame: within 1 month after the patient has entered the study ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Percentage of BRAFV600E alleles in tumor tissue post-TKI treatment [ Time Frame: within 30 days from the availability of the tissue sample ] [ Designated as safety issue: No ]

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

Estimated Enrollment:	50
Study Start Date:	October 2012
Estimated Study Completion Date:	October 2013
Estimated Primary Completion Date:	October 2013 (Final data collection date for primary outcome measure)

Groups/Cohorts
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

Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No
Sampling Method:	Non-Probability Sample

Study Population

primary care clinic

Criteria

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01700699

Contacts

Contact: Mario Vitale, MD

+39 089672539

mavitale@unisa.it

Locations

Italy
Department of Medicine and Surgery, Univeristy of Salerno	Recruiting
Baronissi, Salerno, Italy, 84081
Contact: Mario Vitale, MD +39 089672539 mavitale@unisa.it
Principal Investigator: Mario Vitale, MD

Sponsors and Collaborators

University of Salerno

Investigators

Principal Investigator:

Mario Vitale, MD

Univeristy of Salerno, Italy

More Information

Publications:

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. Epub 2012 Apr 16.

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. Epub 2011 Dec 14.

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. Epub 2008 Jun 9.

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. Epub 2009 Mar 2.

Responsible Party:	Mario Vitale, Professor of Endocrinology at the School of Medicine, University of Salerno, Director of the Endocrinology Unit, University Hospital of Salerno, Italy, University of Salerno
ClinicalTrials.gov Identifier:	NCT01700699 History of Changes
Other Study ID Numbers:	BRAF-TKI-DTC1
Study First Received:	September 22, 2012
Last Updated:	October 20, 2012
Health Authority:	Italy: Ethics Committee

Keywords provided by University of Salerno:

thyroid cancer
tyrosine kinase inhibitors
BRAF
Sorafenib

Pazopanib
Sunitinib
Cabozantinib

Additional relevant MeSH terms:

Thyroid Neoplasms
Thyroid Diseases
Endocrine Gland Neoplasms
Neoplasms by Site
Neoplasms
Head and Neck Neoplasms
Endocrine System Diseases
Sorafenib
Sunitinib
Antineoplastic Agents

Therapeutic Uses
Pharmacologic Actions
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors

ClinicalTrials.gov processed this record on May 21, 2013