Lung Cancer in Women Treated With Anti-oestrogens anD Inhibitors of EGFR (LADIE)

Phase II Randomised Clinical Trial Evaluating an EGFR Tyrosine Kinase Inhibitor (EGFR-TKI) Versus an EGFR-TKI Combined With an Anti-oestrogen Treatment (Fulvestrant) in Women With Advanced Stage Non-squamous Lung Cancer

Lung Cancer is to become the first cause of death related to cancer in France as it's already the case in United States. At Present, Lung Cancer in women and in men is treated similarly. Nevertheless, numerous studies shows that lung cancer in women has specificities : at the time of the diagnosis female patients are younger, there are less clinical signs, clinical stages are earlier, histology is often adenocarcinoma. The link with tabagism is weaker . Sensitivity to tabagism is higher (more cancer in women with the same tabagism). Response rate to chemotherapy is better. Prognosis is better

Numerous hypotheses have been put forward to account for the specific characteristics of female lung cancer described above.

• One hypothesis is that there are different genetic anomalies in women. Some studies show an increase of EGFR mutation and HER2 expression and a decrease of expression of repair enzymes (ERCC1, RRM1, BRCA) which can explain the increase sensitivity to tabagism and to chemotherapy.
• Another hypothesis is that hormones play a role in oncogenesis. Indeed, lung cancer presents hormonal risk factors : pre-menopause, less than 3 kids, short menstrual cycle, hormone replacement therapy. Estrogens would have a deleterious effect on cancer incidence and on survival of lung cancer in women. Cellular and animal models show that ER pathway is activated in lung cancer and participates in oncogenesis.
• Moreover an interaction between RE and EGFR pathway has been demonstrated on lung cancer cell lines and mouse models.

EGFR-TKI have shown benefit in women with wild type EGFR or unknown status (with erlotinib) and in women with EGFR mutations (with gefitinib). In this study, the use of these two treatment will be in accordance with their market authorisations.

The objective of this study is to test the addition of an anti-estrogen (fulvestrant) to EGFR-TKI. Fulvestrant is a pure anti-oestrogen that binds to ER, blocks it and accelerates its breakdown. It has a market authorisation in breast cancer. Furthermore the association between EGFR-TKI and anti-estrogen could have a synergetic effect due to interaction between RE and EGFR pathways .

Study Overview

• Status: Completed
• Conditions: Stage IV Lung Cancer
• Intervention / Treatment: Drug: Gefitinib; Drug: Fulvestrant; Drug: Erlotinib

• Study Type: Interventional
• Enrollment (Actual): 379
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Ambilly, France, 74100
    • Annemasse - CH
  • Amiens, France
    • Clinique de l'Europe
  • Angers, France, 49000
    • Angers - CHU
  • Bayonne, France
    • CH de la Cote Basque
  • Besancon, France, 25000
    • CHU Besancon - Pneumologie
  • Bobigny, France, 93000
    • BOBIGNY - Hôpital Avicenne
  • Boulogne, France
    • Hôpital Ambroise Paré - Pneumologie
  • Bron, France
    • HCL Hopital Louis Pradel
  • Béziers, France, 34525
    • Béziers - CH
  • Caen, France, 14000
    • Caen - Centre François Baclesse
  • Caen, France, 14000
    • Caen - CHU Côte de Nacre
  • Cahors, France, 46000
    • Cahors - CH
  • Chambéry, France
    • Chambéry - CH
  • Chauny, France
    • Centre Hospitalier
  • Cholet, France
    • Hôpital de Cholet - Pneumologie
  • Clamart, France, 92140
    • Clamart - Hôpital Percy
  • Clermont-Ferrand, France
    • CHU
  • Colmar, France
    • CH
  • Cornebarrieu, France
    • Clinique des Cèdres
  • Créteil, France, 94000
    • Créteil - CHI
  • Dax, France
    • CH de Dax
  • Dijon, France, 21000
    • Dijon - CAC
  • Grenoble, France, 38000
    • Grenoble - CHU
  • Le Coudray, France, 28630
    • Chartres - CH
  • Le Mans, France, 72000
    • Centre Hospitalier - Pneumologie
  • Lille, France, 59000
    • CHU (Hôpital Calmette) - Pneumologie
  • Longjumeau, France
    • CH
  • Marseille, France
    • Institut Paoli Calmette
  • Marseille, France
    • Hôpital Nord - Oncologie Multidisciplinaire & Innovations Thérapeutiques
  • Maubeuge, France
    • Polyclinique du Val de Sambre
  • Mont de Marsan, France, 40000
    • Mont de Marsan - CH
  • Mulhouse, France, 68000
    • Mulhouse - CH
  • Nancy, France
    • CHU Nancy
  • Nantes, France, 44805
    • Nantes - Centre René Gauducheau
  • Nevers, France, 58033
    • Nevers - CH
  • Nice, France
    • Centre Antoine Lacassagne
  • Paris, France, 75020
    • Hopital Tenon - Pneumologie
  • Paris, France
    • HIA Val-de-Grâce
  • Paris, France
    • Hopital Bichat - Claude - Bernard
  • Paris, France
    • Hôpital Européen Georges Pompidou
  • Paris, France
    • Hôpital Saint-Joseph
  • Paris, France
    • Paris - Curie
  • Pau, France, 64046
    • Pau - CH
  • Perpignan, France, 66046
    • Perpignan - Ch
  • Pierre Bénite, France, 69495
    • HCL - Lyon Sud (Pneumologie)
  • Rambouillet, France
    • Centre Hospitalier
  • Reims, France
    • CHU de Reims
  • Reims, France
    • Institut Jean Godinot
  • Rouen, France, 76000
    • Rouen - CHU
  • Saint Quentin, France, 02100
    • Saint Quentin - CH
  • Strasbourg, France, 63000
    • Strasbourg - NHC
  • Suresnes, France, 92151
    • Suresnes - Hopital Foch
  • Toulon, France
    • Centre Hospitalier Intercommunal
  • Toulouse, France
    • Toulouse - CHU Larrey
  • Toulouse, France
    • Clinique Pasteur
  • Tourcoing, France, 59208
    • Tourcoing - CH
  • Tours, France
    • CHU Tours - Pneumologie
  • Versailles, France, 78157
    • Versailles - CH
  • Vesoul, France
    • CHI de la Haute-Saône - Pneumologie
  • Villefranche, France
    • CH de Villefranche - Pneumologie
  • Villejuif, France, 94800
    • Institut Gustave Roussy

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Histologically confirmed predominant non-squamous, non-small cell lung cancer
• The presence of analysable tissue for the research of EGFR activating mutation. Analysis must be performed in INCa-labelled laboratories or platforms according to a validated technique
• Not suitable for radiation, inoperable stage III or stage IV
• Patients with an EGFR mutation must never have taken chemotherapy or must be in progression after only one previous line of chemotherapy (including maintenance). Patients without an EGFR mutation must have received one or two lines of chemotherapy beforehand. Maintenance chemotherapy is not considered to be a treatment line. Adjuvant chemotherapy is not considered to be a first line of treatment if it dates back to over a year
• Female
• Menopausal: older than 60 years of age or history of ovariectomy or younger than 60 years old with amenorrhoea for more than 12 months or an FSH rate that corresponds to a post-menopausal rate (according to the laboratory)

Exclusion Criteria:

• History of cancer except for skin cancer or cancer dating from over five years ago and considered to be cured
• Known or suspected Cerebral metastases or spinal cord compression unless they are asymptomatic without treatment or stable after being treated by surgery and/or radiation therapy. Corticosteroid treatments for symptoms must have discontinued for more than four weeks
• Pregnancy and breast-feeding
• Patient taking hormone replacement therapy for menopause that has not been stopped two weeks before the start of the trial treatment
• A change in bone marrow, kidney and liver functions inconsistent with treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Gefinitib + Fulvestrant (patient with EGFR mutations)	Drug: Gefitinib; 250 mg per day (oral); Drug: Fulvestrant; 500 mg (2 x 250 mg), IV by month with an additional 500 mg dose two weeks after the initial dose
Active Comparator: Erlotinib (wild type patients)	Drug: Erlotinib; 150 mg per day (oral)
Experimental: Erlotinib + Fulvestrant (wild type patients)	Drug: Fulvestrant; 500 mg (2 x 250 mg), IV by month with an additional 500 mg dose two weeks after the initial dose; Drug: Erlotinib; 150 mg per day (oral)
Active Comparator: Gefinib (patient with EGFR mutations)	Drug: Gefitinib; 250 mg per day (oral)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
progression-free survival	From date of randomization until the date of first progression for EGFR mutated patient	Around nine months
Progression free survival	From date of randomization until the date of first progression for EGFR wild type patients	Around three months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
toxicity of EGFR-TKI and fulvestrant	The number of patients for whom at least an adverse event will have been reported, the number of events, according to the relation to the treatment, the intensity, and the cycle of appearance for EGFR WT patients	Around three months
Response rate	For EGFR WT patients	Around three months
Overall survival	For all patients	Up to 18 months
toxicity of EGFR-TKI and fulvestrant	The number of patients for whom at least an adverse event will have been reported, the number of events, according to the relation to the treatment, the intensity, and the cycle of appearance for EGFR mutated patients	Around Nine months
Response rate	For EGFR-Mutated patients	Around nine months

Collaborators and Investigators

• Sponsor: Intergroupe Francophone de Cancerologie Thoracique
• Investigators: Principal Investigator: Julien MAZIERES, MD, PhD, University Hospital, Toulouse

Publications and helpful links

General Publications

• Mazieres J, Barlesi F, Rouquette I, Molinier O, Besse B, Monnet I, Audigier-Valette C, Toffart AC, Renault PA, Fraboulet S, Hiret S, Mennecier B, Debieuvre D, Westeel V, Masson P, Madroszyk-Flandin A, Pichon E, Cortot AB, Amour E, Morin F, Zalcman G, Moro-Sibilot D, Souquet PJ. Randomized Phase II Trial Evaluating Treatment with EGFR-TKI Associated with Antiestrogen in Women with Nonsquamous Advanced-Stage NSCLC: IFCT-1003 LADIE Trial. Clin Cancer Res. 2020 Jul 1;26(13):3172-3181. doi: 10.1158/1078-0432.CCR-19-3056. Epub 2020 Mar 6.

Helpful Links

• IFCT official website

Study record dates

Study Major Dates

• Study Start (Actual): May 15, 2012
• Primary Completion (Actual): May 15, 2018
• Study Completion (Actual): June 17, 2020

Study Registration Dates

• First Submitted: March 8, 2012
• First Submitted That Met QC Criteria: March 15, 2012
• First Posted (Estimate): March 16, 2012

Study Record Updates

• Last Update Posted (Actual): January 8, 2021
• Last Update Submitted That Met QC Criteria: January 6, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: lung cancer; women
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protein Kinase Inhibitors; Hormone Antagonists; Estrogen Antagonists; Estrogen Receptor Antagonists; Erlotinib Hydrochloride; Fulvestrant; Gefitinib
• Other Study ID Numbers: IFCT-1003

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No