Molecular Determinants of Acquired Clinical Resistance to Crizotinib in Non-small Cell Lung Cancer Harboring a Translocation or Inversion Event Involving the ALK Gene Locus

Study Overview
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Brief Summary
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The purpose of this study is to try to learn more about how small molecule kinase inhibitor medications work in treating lung cancer. Crizotinib (PF-02341066) is a drug that has been shown to shrink tumors in some patients with lung cancer. While the investigators know how this drug works to stop the growth of tumors that depend on change in the gene named ALK (also called EML4-ALK), the investigators do not know why the drug stops working. The investigators would like to examine the tumor to help us better understand why crizotinib has stopped working as well as it once did. The tumor will be examined with multiple tests to look for the reason that crizotinib stopped working.

Official Title
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Molecular Determinants of Acquired Clinical Resistance to Crizotinib in Non-small Cell Lung Cancer Harboring a Translocation or Inversion Event Involving the ALK Gene Locus

Conditions
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Lung Cancer

Intervention / Treatment
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* Genetic: obtain tissue specimens


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥18 years of age Histologically proven diagnosis of NSCLC at MSKCC Tumor positive for a translocation or inversion event involving the ALK gene locus Clinical response to treatment with crizotinib as defined by either: Radiographic partial or complete response defined by RECIST or WHO OR: Radiographic stable disease for at least 8 weeks Radiographic progression of disease amenable to biopsy while on treatment with crizotinib as defined by RECIST or WHO Signed informed consent Exclusion Criteria: Deemed by their treating physician to be medically unfit for biopsy Women who are pregnant or breast-feeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| patients with Non Small Cell Lung cancer<br>This is a protocol to obtain and/or analyze tissue specimens of patients with NSCLC harboring an activating ALK inversion or translocation that have had a previous clinical response to tyrosine kinase inhibitor therapy and subsequently experience progressive disease. The tissue will be used to identify changes in the ALK gene that are acquired during treatment with an ALK TKI and may account for acquired resistance. | Genetic: obtain tissue specimens<br>* One core biopsy specimen will be placed in formalin and processed for cytogenetic and FISH analyses as well as DNA for ALK sequencing. The second core biopsy specimen will be immediately frozen in liquid nitrogen and stored in a -80 degree freezer for research specimen. Collection will be performed on-site at the time of the procedure.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the frequency of acquired mutations | ALK sequence from tumor tissue pre-treatment in patients that respond to crizotinib will be compared to ALK sequence in tumor tissue after the development of resistance when there is persistence of the original ALK inversion or translocation event. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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core biopsy, Resistance to Crizotinib, Non-small Cell Lung Cancer, 11-014