Histological Characterization and Differentiation of Rash From Other Epidermal Growth Factor Receptor (EGFR) Inhibitors

Study Description

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Brief Summary:

The purpose of this study is to characterize the microscopic findings of skin rash associated with the use of chemotherapeutic anticancer agents known as epidermal growth factor inhibitors (EGFRIs).

Condition or disease	Intervention/treatment
Skin Rash	Procedure: Skin Biopsy of Skin Rash Secondary to EGFRI Use

Detailed Description:

Epidermal growth factor (EGF) and its receptor, the EGFR, are known to be key drivers in cellular proliferation and survival. Malignant tumors result from uncontrolled cell proliferation. The use of drugs which target the EGF receptor has offered patients with non-small cell lung cancer, pancreatic cancer, head and neck cancer, and colorectal cancer additional targeted anti-cancer therapy in addition to their chemotherapeutic regimens. As a result of increased use of these EGFR inhibitors, adverse events have emerged involving the skin, hair, nails and eyes. While the EGFR inhibitors block the signal transduction that interfere with cellular proliferation and survival of cancerous cells, they also affect the normal EGF function in the skin (papulopustular rash), hair, and nails. In this study, we seek to histologically characterize the papulopustular rash in patients who have been treated with lapatinib and compare our findings with those associated with three other EGFRIs, cetuximab, erlotinib and panitumumab.

Study Design

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Study Type :	Observational
Actual Enrollment :	32 participants
Observational Model:	Cohort
Time Perspective:	Retrospective
Official Title:	Histological Characterization and Differentiation of Rash From Other EGFR Inhibitors
Study Start Date :	April 2008
Actual Primary Completion Date :	August 2010
Actual Study Completion Date :	August 2010

Groups and Cohorts

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Group/Cohort	Intervention/treatment
L; Patients treated with lapatinib who developed skin toxicities and have been biopsied for skin rash.	Procedure: Skin Biopsy of Skin Rash Secondary to EGFRI Use; Patients who were treated with lapatinib, cetuximab, panitumumab or erlotinib who subsequently developed a skin rash have been biopsied as standard of care. The biopsies will be used for this study.
C; Patients treated with cetuximab who developed skin toxicities and have been biopsied for skin rash.	Procedure: Skin Biopsy of Skin Rash Secondary to EGFRI Use; Patients who were treated with lapatinib, cetuximab, panitumumab or erlotinib who subsequently developed a skin rash have been biopsied as standard of care. The biopsies will be used for this study.
P; Patients treated with panitumumab who developed skin toxicities and have been biopsied for skin rash.	Procedure: Skin Biopsy of Skin Rash Secondary to EGFRI Use; Patients who were treated with lapatinib, cetuximab, panitumumab or erlotinib who subsequently developed a skin rash have been biopsied as standard of care. The biopsies will be used for this study.
E; Patients treated with erlotinib who developed skin toxicities and have been biopsied for a skin rash.	Procedure: Skin Biopsy of Skin Rash Secondary to EGFRI Use; Patients who were treated with lapatinib, cetuximab, panitumumab or erlotinib who subsequently developed a skin rash have been biopsied as standard of care. The biopsies will be used for this study.

Outcome Measures

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Primary Outcome Measures :

1. Differences in Histologic Alterations in Rash Caused by Lapatinib, a Dual HER1/2 Inhibitor (HER1/2i), and the Single HER1 Inhibitors (HER1i) Cetuximab, Erlotinib,and Panitumumab. [ Time Frame: 6 months ]

Biospecimen Retention:   Samples With DNA

Skin tissue biopsies.

Eligibility Criteria

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Ages Eligible for Study:	Child, Adult, Senior
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No
Sampling Method:	Non-Probability Sample

Study Population

Patients selected for this study were treated with lapatinib, erlotinib, panitumumab or cetuximab, developed skin toxicities and were biopsied as standard of care for skin rash at the Department of Dermatology, Northwestern University.

Criteria

Inclusion Criteria:

• Patients treated with lapatinib who developed skin toxicities and were biopsied.
• Patients treated with erlotinib, cetuximab, or panitumumab who have been biopsied for skin rash.

Exclusion Criteria:

• Patients who do not fit above criteria.

Contacts and Locations

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611

Sponsors and Collaborators

Northwestern University

GlaxoSmithKline

Investigators

Principal Investigator:	Mario Lacouture, MD	Northwestern University, Department of Dermatology

More Information

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications of Results:

Nardone B, Nicholson K, Newman M, Guitart J, Gerami P, Talarico N, Yang XJ, Rademaker A, West DP, Lacouture ME. Histopathologic and immunohistochemical characterization of rash to human epidermal growth factor receptor 1 (HER1) and HER1/2 inhibitors in cancer patients. Clin Cancer Res. 2010 Sep 1;16(17):4452-60. doi: 10.1158/1078-0432.CCR-10-0421. Epub 2010 Aug 23.

Other Publications:

Gullick WJ. The Type 1 growth factor receptors and their ligands considered as a complex system. Endocr Relat Cancer. 2001 Jun;8(2):75-82. Review.

Marmor MD, Skaria KB, Yarden Y. Signal transduction and oncogenesis by ErbB/HER receptors. Int J Radiat Oncol Biol Phys. 2004 Mar 1;58(3):903-13. Review.

Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2000 Oct 13;103(2):211-25. Review.

Robert C, Soria JC, Spatz A, Le Cesne A, Malka D, Pautier P, Wechsler J, Lhomme C, Escudier B, Boige V, Armand JP, Le Chevalier T. Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet Oncol. 2005 Jul;6(7):491-500. Review.

Fuchs E, Raghavan S. Getting under the skin of epidermal morphogenesis. Nat Rev Genet. 2002 Mar;3(3):199-209. Review.

Lacouture ME. Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer. 2006 Oct;6(10):803-12. Review.

Jost M, Kari C, Rodeck U. The EGF receptor - an essential regulator of multiple epidermal functions. Eur J Dermatol. 2000 Oct-Nov;10(7):505-10. Review.

Rodeck U, Jost M, Kari C, Shih DT, Lavker RM, Ewert DL, Jensen PJ. EGF-R dependent regulation of keratinocyte survival. J Cell Sci. 1997 Jan;110 ( Pt 2):113-21.

Peus D, Hamacher L, Pittelkow MR. EGF-receptor tyrosine kinase inhibition induces keratinocyte growth arrest and terminal differentiation. J Invest Dermatol. 1997 Dec;109(6):751-6.

Hauser PJ, Agrawal D, Hackney J, Pledger WJ. STAT3 activation accompanies keratinocyte differentiation. Cell Growth Differ. 1998 Oct;9(10):847-55.

Mimeault M, Bonenfant D, Batra SK. New advances on the functions of epidermal growth factor receptor and ceramides in skin cell differentiation, disorders and cancers. Skin Pharmacol Physiol. 2004 Jul-Aug;17(4):153-66. Review.

Woodworth CD, Michael E, Marker D, Allen S, Smith L, Nees M. Inhibition of the epidermal growth factor receptor increases expression of genes that stimulate inflammation, apoptosis, and cell attachment. Mol Cancer Ther. 2005 Apr;4(4):650-8.

Lorch JH, Klessner J, Park JK, Getsios S, Wu YL, Stack MS, Green KJ. Epidermal growth factor receptor inhibition promotes desmosome assembly and strengthens intercellular adhesion in squamous cell carcinoma cells. J Biol Chem. 2004 Aug 27;279(35):37191-200. Epub 2004 Jun 16.

Pastore S, Mascia F, Mariotti F, Dattilo C, Mariani V, Girolomoni G. ERK1/2 regulates epidermal chemokine expression and skin inflammation. J Immunol. 2005 Apr 15;174(8):5047-56.

Fisher GJ, Datta SC, Talwar HS, Wang ZQ, Varani J, Kang S, Voorhees JJ. Molecular basis of sun-induced premature skin ageing and retinoid antagonism. Nature. 1996 Jan 25;379(6563):335-9.

El-Abaseri TB, Putta S, Hansen LA. Ultraviolet irradiation induces keratinocyte proliferation and epidermal hyperplasia through the activation of the epidermal growth factor receptor. Carcinogenesis. 2006 Feb;27(2):225-31. Epub 2005 Aug 25.

Moy B, Goss PE. Lapatinib: current status and future directions in breast cancer. Oncologist. 2006 Nov-Dec;11(10):1047-57. Review.

Albanell J, Rojo F, Averbuch S, Feyereislova A, Mascaro JM, Herbst R, LoRusso P, Rischin D, Sauleda S, Gee J, Nicholson RI, Baselga J. Pharmacodynamic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: histopathologic and molecular consequences of receptor inhibition. J Clin Oncol. 2002 Jan 1;20(1):110-24.

Busse D, Doughty RS, Ramsey TT, Russell WE, Price JO, Flanagan WM, Shawver LK, Arteaga CL. Reversible G(1) arrest induced by inhibition of the epidermal growth factor receptor tyrosine kinase requires up-regulation of p27(KIP1) independent of MAPK activity. J Biol Chem. 2000 Mar 10;275(10):6987-95.

Pérez-Soler R, Delord JP, Halpern A, Kelly K, Krueger J, Sureda BM, von Pawel J, Temel J, Siena S, Soulières D, Saltz L, Leyden J. HER1/EGFR inhibitor-associated rash: future directions for management and investigation outcomes from the HER1/EGFR inhibitor rash management forum. Oncologist. 2005 May;10(5):345-56. Review.

Molinari E, De Quatrebarbes J, André T, Aractingi S. Cetuximab-induced acne. Dermatology. 2005;211(4):330-3.

Nelson MH, Dolder CR. Lapatinib: a novel dual tyrosine kinase inhibitor with activity in solid tumors. Ann Pharmacother. 2006 Feb;40(2):261-9. Epub 2006 Jan 17. Review.

Cameron D. Lapatinib plus capecitabine in patients with HER2-positive advanced breast cancer. Clin Adv Hematol Oncol. 2007 Jun;5(6):456-8.

Responsible Party:	Mario Lacouture, MD, Northwestern University, Department of Dermatology
ClinicalTrials.gov Identifier:	NCT00709878 History of Changes
Other Study ID Numbers:	GSK-Lapatinib
First Posted:	July 3, 2008
Results First Posted:	September 23, 2010
Last Update Posted:	March 17, 2015
Last Verified:	February 2015

Keywords provided by Northwestern University:

skin rash, lapatinib, cetuximab, erlotinib, panitumumab

Additional relevant MeSH terms:

Exanthema; Skin Diseases; Lapatinib; Cetuximab; Erlotinib Hydrochloride	Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action