Study to Evaluate Resistance Mechanisms and Real-world Pharmacoeconomics of Crizotinib in NSCLC Patients

Study Overview
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Brief Summary
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This is a phase IV multicenter trial to evaluate the mechanisms of resistance and pharmacoeconomic (PE) impact of crizotinib and its companion diagnostic test used in a real-life setting in advanced ALK-positive non-small cell lung cancer (NSCLC) patients. The study will address two anticipated issues surrounding personalized medicine and treatment with crizotinib: it will enable real-life Heath Economics and Outcome Research (HEOR) it will validate and/or identify new blood-based or tissue-based biomarkers of resistance to crizotinib. At least 30 patients will be recruited in Quebec and Ontario for the PE study. Patients will be asked to complete quality-of-life questionnaires at regular intervals in a real-life setting of treatment with crizotinib. Approximately 25 patients will be recruited to the biomarker sub-study in Quebec to understand resistance mechanisms of crizotinib. In these patients, a biopsy from any accessible metastatic lesion will be obtained when the patient is no longer responding to treatment, as well as blood sampling during regular treatment visits.

Detailed Description
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This is a phase IV multicenter trial to evaluate the mechanisms of resistance and pharmacoeconomic (PE) impact of crizotinib and its companion diagnostic test used in a real-life setting in advanced ALK-positive non-small cell lung cancer (NSCLC) patients. NSCLC represent 80% of all new cases of lung cancer. One molecular subtype of NSCLC is the ALK-positive subtype. The anaplastic lymphoma kinase (ALK) is a transmembrane receptor tyrosine kinase. Activation of ALK occurs through the formation of gene fusions and in NSCLC, the gene fusion partner for ALK is primarily EML4. The resulting fusion protein is capable of activating the ALK kinase domain, leading to cell growth. The estimated prevalence for ALK rearrangements in NSCLC is 3-5%, and is more commonly found amongst patients with adenocarcinoma histology, in never smokers and in those who are known to be wild type for EGFR and KRAS. Crizotinib is a potent inhibitor of ALK and is approved for the treatment of advanced ALK+ NSCLC patients. This is an example of personalized medicine, where patients are selected for treatment based upon a molecular assay, and are provided a specific therapy (crizotinib) for their disease. The pharmacoeconomic impact of using genetic information in early treatment decisions in NSCLC has not been determined. Despite the benefits of crizotinib, some patients do not respond to treatment and most patients will eventually develop resistance. To date, it is unclear why some rare patients do not respond to treatment and the resistance mechanisms of crizotinib have not been fully elucidated. The study will address two anticipated issues surrounding personalized medicine and treatment with crizotinib: it will enable real-life Heath Economics and Outcome Research (HEOR) it will validate and/or identify new blood-based or tissue-based biomarkers of resistance to crizotinib. At least 30 patients will be recruited in Quebec and Ontario for the PE study. Patients will be asked to complete quality-of-life questionnaires at regular intervals in a real-life setting of treatment with crizotinib. Approximately 25 patients will be recruited to the biomarker sub-study in Quebec to understand resistance mechanisms of crizotinib. In these patients, a biopsy from any accessible metastatic lesion will be obtained when the patient is no longer responding to treatment, as well as blood sampling during regular treatment visits.

Official Title
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A Phase IV Multicenter Trial to Evaluate the Resistance Mechanisms and Real-world Pharmacoeconomics of Crizotinib and Its Companion Diagnostic Test in Advanced ALK-positive Non-small Cell Lung Cancer (NSCLC) Patients

Conditions
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Non-small Cell Lung Cancer Metastatic

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with histologically confirmed locally advanced or metastatic NSCLC Presence of the ALK-fusion oncogene (ALK+) as determined using a validated testing platform Measurable disease according to RECIST v. 1.1 Planned or ongoing treatment with crizotinib Signed and dated IRB-approved informed consent document Ability to read and understand English or French 18 years of age or older Exclusion Criteria: Acquired immunodeficiency syndrome (AIDS-related illnesses) or known HIV disease. Unwilling to provide consent for genetic studies of the tumor, whole blood, or plasma specimens.

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 |
| --- | --- |
| Pharmacoeconomic main study<br>Patients from Quebec and Ontario (first or second line treatment) | |
| Biomarker sub-study<br>Patients from Quebec only (first or second line treatment) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The pharmacoeconomic impact of using personalized medicine for the treatment of ALK+ lung cancer. | Pharmacoeconomic impact (cost-effectiveness and cost utility) will be evaluated by questionnaires completed by the patient and caregiver. These include quality of life, health resource utilization, work productivity and activity impairment, and health questionnaires | From the date of registration until date of death from any cause, assessed up to 60 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Type of resistance mechanisms identified in crizotinib-resistant tumors | A biopsy will be taken from a metastatic lesion that has progressed despite treatment with crizotinib. Genomic material will be isolated and sequenced to identify causes of acquired resistance to crizotinib. | At progression of disease, an expected average of 24 months. | 
| Change in blood-based biomarkers of response to crizotinib. | Plasma will be isolated from patients pre-treatment, at every disease assessment, at progression of disease, and at treatment discontinuation. This will be used to identify changes in blood-based biomarkers using proteomics analysis by mass spectrometry. | From the date of registration until the date of treatment discontinuation, an expected average of 24 months. | 
| Number of participants with adverse events related to the biopsy procedure. | Adverse events possibly, probably or definitely related to the biopsy procedure will be reported according to the The NCI's Common Toxicity Criteria version 4.0 | Up to 4 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ALK-positive