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Evaluation of the Feasibility and Clinical Relevance of Liquid Biopsy in Patients With Suspicious Metastatic Lung Cancer (LIBELULE)

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ClinicalTrials.gov Identifier: NCT03721120
Recruitment Status : Recruiting
First Posted : October 26, 2018
Last Update Posted : May 30, 2019
Sponsor:
Information provided by (Responsible Party):
Centre Leon Berard

Brief Summary:

Lung cancer is diagnosed at metastatic stage in 60% of the cases. For these patients, first-line treatment is based on histology and molecular characterization of non-squamous non-small cell lung cancer (NSCLC). Thus, quality and quantity of tumor tissue are crucial to determine the appropriate treatment (targeted therapies, chemotherapy and immunotherapy).

However, in routine practice, tissue quality and quantity can be limited (25%), resulting in the need for tumor rebiopsy for molecular analysis. Therefore, lung cancer patients often experience substantial delays before treatment initiation that may be associated with worse patient experience of subsequent cancer care and poorer clinical outcomes.

"Liquid biopsies" (LB) are used to detect genomic alterations in cell-free circulating DNA (cfDNA). Since very recently, they are routinely used in reference centers for the detection of EGFR-mutations when tissue is not sufficient for molecular characterization. Importantly, the feasibility and clinical relevance of systematic liquid biopsies in routine practice has never been evaluated in patients with suspicious advanced lung cancer.

Investigators hypothesize that using systematic LB in patients with clinical suspicion of metastatic lung cancer may reduce time-to-treatment initiation and avoid tissue rebiopsy.

Investigators performed a retrospective study including 250 NSCLC patients treated in a tertiary Cancer Center and in the University Hospital of Lyon, France. The mean time-to-appropriate frontline treatment initiation (TTI) was 42+/-22.5 days. With the use of LB at the time of first consultation, the investigators believe it is possible to reduce the mean TTI down to 33 days (21% reduction in TTI) in the overall population with suspicious metastatic lung cancer, including a 50% and 40% reduction in TTI for EGFR/ALK/ROS1/BRAF V600E subgroups and KRAS/LKB1/ERBB2/c-MET/BRAF non V600E subgroups, respectively.

Investigators therefore designed a "real-life" randomized study to evaluate the feasibility and clinical relevance of LB to decrease the TTI, which may in turn improve patients' outcome. Genomic analyses of circulating cfDNA will be performed using a robust and highly sensitive technology (InVision®), that profiles the presence of genomic aberrations in a panel of 35 genes including mutations, insertion/deletions and rearrangements, including all actionable alterations required to initiate the appropriate first-line therapy (EGFR-, ALK-, ROS1 and BRAF V600E).


Condition or disease Intervention/treatment Phase
Metastatic Lung Cancer Diagnostic Test: InvisionFirst® molecular panel Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 286 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: A Randomized Phase III Clinical Trial to Evaluate the Feasibility and Clinical Relevance of Liquid Biopsy in Patients With Suspicious Metastatic Lung Cancer
Actual Study Start Date : April 10, 2019
Estimated Primary Completion Date : July 1, 2020
Estimated Study Completion Date : July 1, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Biopsy Lung Cancer

Arm Intervention/treatment
Experimental: Liquid biopsy
Liquid biopsy will be performed at the first visit using InVisionFirst®. Treatment will be determined by (i) genomic characterization in plasma for patients with druggable alteration in first-line, (ii) after pathology results (including assessment of PD-L1 level of expression by immunohistochemistry) for patients with an informative molecular characterization on plasma and no druggable alteration in first-line and (iii) after pathology results and tissue molecular characterization for the remaining patients.
Diagnostic Test: InvisionFirst® molecular panel

During the first visit, liquid biopsy will be performed using the InVisionFirst® panel. Cytological or histological sampling will be planned. According to InVisionFirst® results, treatment will be initiated:

  • regardless of cytological/histological and tissue molecular analysis in case of EGFR, BRAF V600E-mutation, ALK- or ROS1-rearrangement identified on InvisionFirst® panel.
  • regardless of molecular characterization performed on tissue sample in case of ERBB2-, BRAF non V600E-, c-MET-, KRAS- and LKB1- mutation on InVisionFirst® panel. Treatment will be based on pathology results and if appropriate on PD-L1 level of expression.
  • for patients with none of the previous alterations, treatment will be initiated after obtaining pathology results and genomic characterization from the tumor tissue analysis.

No Intervention: Cytological or histological sampling
During the first visit, cytological or histological sampling will be planned and treatment will be initiated according to European Society of Medical Oncology (ESMO) recommendations; in case of a tissue sample inadequate for genomic characterization, physicians may resort to liquid biopsy according to their usual practice and available technology.



Primary Outcome Measures :
  1. Time-to-appropriate Treatment Initiation (TTI) [ Time Frame: From date of randomisation to start date of appropriate treatment , assessed up to 12 months ]
    It is defined as the time between the date of randomization and the date of appropriate-treatment initiation (whatever the start date occurs before or after the biopsy results). As all the patients will receive an appropriate-treatment, no censored data are expected, thus the TTI will be analyzed as a continuous outcome. Appropriate treatment is defined as follow:- Based on contributive results on tissue OR liquid biopsy:-Presence of EGFR- and BRAF V600E-mutations, ALK- and ROS1- rearrangements: specific targeted therapies.-None of the four previous alterations: treatment according to investigator's choice (chemotherapy or immunotherapy based on pathology results and if appropriate on PD-L1 level of expression).- In case of non-contributive molecular results on tissue AND liquid biopsy: any treatment initiated by investigator (chemotherapy or immunotherapy based on pathology results and if appropriate on PD-L1 level of expression) will be considered as appropriate.


Secondary Outcome Measures :
  1. Rate of treatment initiated before molecular results [ Time Frame: From date of randomisation to 12 months ]
    Defined as the proportion of patients with a treatment initiated without any available molecular results (tissue and liquid biopsy)

  2. Time to availability of informative molecular pathology results [ Time Frame: From date of randomisation to date of molecular results, assessed up to 12 months ]
    Defined as the time from randomization to date of availability of informative molecular pathology results (positive or negative).

  3. Progression Free Survival (PFS) [ Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 30 months ]
    Defined as the time from randomization to the date of the first documented clinical or radiological progression (as per RECIST version 1.1.) or death due to any cause.Patients who have not progressed or died at the time of analysis will be censored at the time of the latest date of assessment.

  4. Incidence of diagnostic test-emergent adverse events [ Time Frame: From date of randomization to follow-up visit month 12 or death due to any cause, whichever came first, assessed up to 30 months ]
    Safety assessed according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version5

  5. The impact of cancer on the patient's quality of life using the European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life core questionnaire (QLQ-C30) [ Time Frame: At baseline, at Day 21 post-baseline, at the time of treatment initiation (within 6 weeks after baseline), at 8 weeks post treatment initiation and every 3 months post initiation of treatment until 12 months ]
    64 questions related to cancer impact on health and daily activities composed this questionnaire. Each item has to be graded from 1 to 4 (1 = not at all, 4= very much). More the score is high, worst the quality of life is.

  6. Evaluation of lung cancer symptoms impact on health and daily activities using the Lung Cancer Symptoms Scale (LCSS) questionnaire [ Time Frame: At baseline, at Day 21 post-baseline, at the time of treatment initiation (within 6 weeks after baseline), at 8 weeks post treatment initiation and every 3 months post initiation of treatment until 12 months ]
    10 questions related to lung cancer symptoms impact on health and daily activities composed this questionnaire. Each item has to be graded from 1 to 10. More the score is high, worst the quality of life is.

  7. Evaluation of anxiety and depression level using Hospital Anxiety and Depression (HAD)Scale [ Time Frame: At baseline, at Day 21 post-baseline, at the time of treatment initiation (within 6 weeks after baseline), and at 8 weeks post treatment initiation ]
    6 questions related to anxiety and 6 questions related to depression composed this questionnaire. Each item has to be graded from 0 to 3. More the score of anxiety or depression is high, worst the quality of life is.

  8. Concordance between molecular status on tissue and liquid biopsies in the experimental arm [ Time Frame: From date of randomization to follow-up visit month 12 or death due to any cause, whichever came first, assessed up to 30 months ]
    Evaluated by the proportion of discordances (error rates) between tissue and liquid biopsies for the mutational status.

  9. Biopsy avoidance rate in the experimental arm [ Time Frame: From date of randomization to follow-up visit month 12 or death due to any cause, whichever came first, assessed up to 30 months ]
    Be defined as the proportion of patients with an initial non-informative tissue biopsy and an informative liquid biopsy allowing appropriate treatment initiation without need for tissue rebiopsy.

  10. The cost analysis [ Time Frame: From date of randomization to follow-up visit month 12 or death due to any cause, whichever came first, assessed up to 30 months ]
    All costs items related to the stratégies and supported by the payers will be collected prospectively for each patient. Mean total costs will be calculated for the 2 stratégies and be compared between the arms.

  11. The effectiveness analysis using the EuroQoL 5 Dimensions 5 Levels (EQ-5D-5L) [ Time Frame: At baseline, at Day 21 post-baseline, at the time of treatment initiation (within 6 weeks after baseline), at 8 weeks post treatment initiation and every 3 months post initiation of treatment until 12 months ]
    Preferences will be measured using EuroQoL 5 Dimensions 5 Levels questionnaire. Five attributes will therefore be investigated: mobility, self-care, usual activity, pain/discomfort, and anxiety/depression. Each attributes having five levels (from "able to […]"/"no pain/discomfort/anxiety/depression" to "unable to […]"/ "extremely pain/discomfort/anxiety/depression"). More the patient is unable to doing daily activities and painful/anxious, worst the quality-adjusted life-year (QALYs) is.

  12. QALYS comparaison between 2 arms [ Time Frame: At baseline, at Day 21 post-baseline, at the time of treatment initiation (within 6 weeks after baseline), at 8 weeks post treatment initiation and every 3 months post initiation of treatment until 12 months ]
    Mean QALYs (based on EQ-5D-5L score) will be calculated for each arm and will be compared between the 2 arms.

  13. The budget impact analysis in experimental arm [ Time Frame: From date of randomization to follow-up visit month 12 or death due to any cause, whichever came first, assessed up to 30 months ]
    The Liquid biopsy using the InVisionFirst® cost, the evolution of market shares, the data pertaining to the target population, and the costs involved with treating the pathologies will be analysed to to estimate the budget impact on the French National Health Insurance of the generalization of innovative Liquid biopsy using the InVisionFirst® panel strategy.

  14. Exploratory objectives : Whole-exome sequencing [ Time Frame: At baseline, at the time of treatment initiation (within 6 weeks after baseline), at 8 weeks after the treatment initiation, and at the progression if occured within 12 month post-baseline. ]
    Additional mandatory 10 ml DNA STRECK tubes will be collected for patients signing study consent.

  15. Exploratory objectives : miRNA profiling [ Time Frame: At baseline, at the time of treatment initiation (within 6 weeks after baseline), at 8 weeks after the treatment initiation, and at the progression if occured within 12 month post-baseline. ]
    Additional mandatory 10 ml RNA STRECK tubes will be collected for patients signing study consent.



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

Inclusion Criteria:

  • Age ≥ 18 years;
  • Patients with clinico-radiological suspicious presentation of stage IV lung cancer;
  • No prior chemotherapy for locally advanced or metastatic NSCLC;
  • Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 (Appendix 2);
  • Life expectancy > 12 weeks;
  • No contraindication to systemic lung cancer treatment;
  • No planned or previous inclusion in another 1st line therapy study;
  • Covered by a medical insurance;
  • Signed informed consent prior to any study-specific procedure;
  • No prior biopsy or cytology for lung cancer diagnosis.

Exclusion Criteria:

  • Pregnant or breastfeeding women;
  • Patient concurrently using other approved or investigational antineoplastic agents;
  • Major concurrent disease affecting cardiovascular system, liver, kidneys, hematopoietic system or else considered as clinically important by the investigator and that could be incompatible with patient's participation in this trial or would likely interfere with study procedures or results;
  • Prior history of malignancies other than study disease (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix) unless the patient has been free of the disease for at least 3 years;
  • Patient requiring tutorship or curatorship.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03721120


Contacts
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Contact: Séverine METZGER +33478782786 severine.metzger@lyon.unicancer.fr
Contact: Maurice PEROL, MD +33426556761 maurice.perol@lyon.unicancer.fr

Locations
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France
Centre Hospitalier de Bayeux Not yet recruiting
Bayeux, France, 14400
Contact: Anne PEYTIER, MD    02-31-51-51-51 ext +33    a.peytier@sih-bessin.fr   
Hopital Louis Pradel Not yet recruiting
Bron, France, 69677
Contact: Michaël DURUISSEAUX, md    04.27.85.77.00 ext +33    michael.duruisseaux@chu-lyon.fr   
Centre Leon Berard Recruiting
Lyon, France, 69373
Contact: Maurice PEROL, MD    04.26.55.67.61 ext +33    maurice.perol@lyon.unicancer.fr   
Centre Hospitalier Annecy Genevois Not yet recruiting
Pringy, France, 74374
Contact: Stéphane HOMINAL, MD    04.50.63.66.03 ext +33    shominal@ch-annecygenevois.fr   
Sponsors and Collaborators
Centre Leon Berard

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Responsible Party: Centre Leon Berard
ClinicalTrials.gov Identifier: NCT03721120     History of Changes
Other Study ID Numbers: ET18-086 LIBELULE
First Posted: October 26, 2018    Key Record Dates
Last Update Posted: May 30, 2019
Last Verified: May 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases