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

• ClinicalTrials.gov Identifier: NCT02041468
• Recruitment Status: Unknown
• First Posted: January 22, 2014
• Last Update Posted: August 30, 2017
• Sponsor: Jewish General Hospital
• Collaborators: Pfizer; Quebec Clinical Research Organization in Cancer; PeriPharm; Personalized Medicine Partnership for Cancer
• Information provided by (Responsible Party): Dr. Jason Agulnik, Jewish General Hospital

Study Description

Brief Summary:

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.

Condition or disease
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 Design

• Study Type: Observational
• Actual Enrollment: 29 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: 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
• Study Start Date: January 2014
• Estimated Primary Completion Date: March 2018
• Estimated Study Completion Date: June 2018

Groups and Cohorts

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)

Outcome Measures

Primary Outcome Measures :

1. The pharmacoeconomic impact of using personalized medicine for the treatment of ALK+ lung cancer. [ Time Frame: From the date of registration until date of death from any cause, assessed up to 60 months. ]
   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

Secondary Outcome Measures :

1. Type of resistance mechanisms identified in crizotinib-resistant tumors [ Time Frame: At progression of disease, an expected average of 24 months. ]
   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.
2. Change in blood-based biomarkers of response to crizotinib. [ Time Frame: From the date of registration until the date of treatment discontinuation, an expected average of 24 months. ]
   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.
3. Number of participants with adverse events related to the biopsy procedure. [ Time Frame: Up to 4 years. ]
   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

Biospecimen Retention:   Samples With DNA

The study will collect plasma, platelet-depleted plasma, tumor tissue (biopsy of a metastatic site that has acquired resistant to treatment) and primary archived tissue.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• 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.

Criteria

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.

Contacts and Locations

Locations

Canada, Ontario

Ottawa Hospital

Ottawa, Ontario, Canada, K1H 8L6

Princess Margaret Hospital

Toronto, Ontario, Canada, M5G 2M9

Canada, Quebec

McGill University Health Center (JGH, St-Mary's, MGH, RVH)

Montreal, Quebec, Canada, H3T 1E2

Centre hospitalier de l'Université de Montréal

Montreal, Quebec, Canada

Hôpital du Sacré-Coeur de Montréal

Montréal, Quebec, Canada, H4J 1C5

CSSS Rimouski

Rimouski, Quebec, Canada, G5L 5T1

Centre Hospitalier Universitaire de Sherbrooke

Sherbrooke, Quebec, Canada, J1H 5N4

Canada

Institut Universitaire de cardiologie et de pneumonologie

Quebec, Canada, G1V 4G5

Sponsors and Collaborators

Jewish General Hospital

Pfizer

Quebec Clinical Research Organization in Cancer

PeriPharm

Personalized Medicine Partnership for Cancer

Investigators

• Principal Investigator: Jason Agulnik, MD; Jewish General Hospital
• Principal Investigator: Victor Cohen, MD; Jewish General Hospital

More Information

Publications:

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.

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.

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Dr. Jason Agulnik, Principal Investigator, Jewish General Hospital
• ClinicalTrials.gov Identifier: NCT02041468
• Other Study ID Numbers: Q-CROC-05
• First Posted: January 22, 2014
• Last Update Posted: August 30, 2017
• Last Verified: August 2017

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

Keywords provided by Dr. Jason Agulnik, Jewish General Hospital:

ALK-positive

Additional relevant MeSH terms:

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms