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

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

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.

Study Overview

• Status: Unknown
• Conditions: Non-small Cell Lung Cancer Metastatic

Detailed Description

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.

• Study Type: Observational
• Enrollment (Actual): 29

Contacts and Locations

Study Locations

• Canada
  • Quebec, Canada, G1V 4G5
    • Institut Universitaire de cardiologie et de pneumonologie
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • Ottawa Hospital
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Hospital
  • Quebec
    • Montreal, Quebec, Canada
      • Centre Hospitalier de l'Universite de Montreal
    • Montreal, Quebec, Canada, H3T 1E2
      • McGill University Health Center (JGH, St-Mary's, MGH, RVH)
    • Montréal, Quebec, Canada, H4J 1C5
      • Hôpital du Sacré-Coeur de Montréal
    • Rimouski, Quebec, Canada, G5L 5T1
      • CSSS Rimouski
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Centre Hospitalier Universitaire de Sherbrooke

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) found positive for ALK mutation from participating hospitals in Quebec.

Description

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.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Pharmacoeconomic main study; Patients from Quebec and Ontario (first or second line treatment)
Biomarker sub-study; Patients from Quebec only (first or second line treatment)

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Jewish General Hospital
• Collaborators: Pfizer; PeriPharm; Quebec Clinical Research Organization in Cancer; Personalized Medicine Partnership for Cancer
• Investigators: Principal Investigator: Jason Agulnik, MD, Jewish General Hospital; Principal Investigator: Victor Cohen, MD, Jewish General Hospital

Publications and helpful links

General Publications

• Doebele RC, Pilling AB, Aisner DL, Kutateladze TG, Le AT, Weickhardt AJ, Kondo KL, Linderman DJ, Heasley LE, Franklin WA, Varella-Garcia M, Camidge DR. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res. 2012 Mar 1;18(5):1472-82. doi: 10.1158/1078-0432.CCR-11-2906. Epub 2012 Jan 10.
• Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, Ou SH, Dezube BJ, Janne PA, Costa DB, Varella-Garcia M, Kim WH, Lynch TJ, Fidias P, Stubbs H, Engelman JA, Sequist LV, Tan W, Gandhi L, Mino-Kenudson M, Wei GC, Shreeve SM, Ratain MJ, Settleman J, Christensen JG, Haber DA, Wilner K, Salgia R, Shapiro GI, Clark JW, Iafrate AJ. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010 Oct 28;363(18):1693-703. doi: 10.1056/NEJMoa1006448. Erratum In: N Engl J Med. 2011 Feb 10;364(6):588.
• Katayama R, Shaw AT, Khan TM, Mino-Kenudson M, Solomon BJ, Halmos B, Jessop NA, Wain JC, Yeo AT, Benes C, Drew L, Saeh JC, Crosby K, Sequist LV, Iafrate AJ, Engelman JA. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med. 2012 Feb 8;4(120):120ra17. doi: 10.1126/scitranslmed.3003316. Epub 2012 Jan 25.
• Camidge DR, Doebele RC. Treating ALK-positive lung cancer--early successes and future challenges. Nat Rev Clin Oncol. 2012 Apr 3;9(5):268-77. doi: 10.1038/nrclinonc.2012.43.
• Couetoux du Tertre M, Marques M, McNamara S, Gambaro K, Hoffert C, Tremblay L, Bouchard N, Diaconescu R, Blais N, Couture C, Pelsser V, Wang H, McIntosh L, Hindie V, Parent S, Cortes L, Breton YA, Pottiez G, Croteau P, Higenell V, Izzi L, Spatz A, Cohen V, Batist G, Agulnik J. Discovery of a putative blood-based protein signature associated with response to ALK tyrosine kinase inhibition. Clin Proteomics. 2020 Feb 7;17:5. doi: 10.1186/s12014-020-9269-6. eCollection 2020.

Study record dates

Study Major Dates

• Study Start: January 1, 2014
• Primary Completion (Anticipated): March 1, 2018
• Study Completion (Anticipated): June 1, 2018

Study Registration Dates

• First Submitted: December 20, 2013
• First Submitted That Met QC Criteria: January 17, 2014
• First Posted (Estimate): January 22, 2014

Study Record Updates

• Last Update Posted (Actual): August 30, 2017
• Last Update Submitted That Met QC Criteria: August 29, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: ALK-positive
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
• Other Study ID Numbers: Q-CROC-05

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED