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    Summary
    EudraCT Number:2011-004903-20
    Sponsor's Protocol Code Number:ABR-38376
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2012-02-20
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2011-004903-20
    A.3Full title of the trial
    Hydroxychloroquine as an anti-autophagy and chromatin modulating drug in combination with erlotinib in non-small cell lung cancer (NSCLC) patients: a single-center single arm open-label phase II trial
    Hydroxychloroquine als een anti-autofagie en chromatine modulerend medicijn in combinatie met erlotinib in patienten met niet-kleincellig longcarcinoom: een single-center single arm open-label fase II studie
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Treatment with hydroxychloroquine and erlotinib in patients with non-small-cell lung cancer
    Therapie met hydroxychloroquine en erlotinib in patienten met niet-kleincellig longcarcinoom
    A.3.2Name or abbreviated title of the trial where available
    Hydroxychloroquine and erlotinib in NSCLC
    Hydroxychloroquine en erlotinib in NSCLC
    A.4.1Sponsor's protocol code numberABR-38376
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    D. IMP Identification
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients with histologically confirmed stage IV non-squamous non-small-cell lung cancer (NSCLC)
    • with an activating EGFR mutation who progressed on erlotinib or gefitinib monotherapy.
    OR
    • who failed after at least one line of platinum based doublet chemotherapy and who are EGFR TKI naïve.
    Patienten met histologisch bewezen stadium IV niet-plaveiselcel NSCLC.
    • met een activerende EGFR mutatie die progressief zijn onder erlotinib of gefitinib monotherapie.
    OF
    • welke progressieve ziekte hebben na eerdere behandeling met ten minste een lijn platinum doublet based chemotherapie en welke EGFR TKI naief zijn.
    E.1.1.1Medical condition in easily understood language
    Patients with stage IV non-small-cell lung cancer who have either progressive disease after erlotinib or gefitinib therapy or after treatment with platinum based chemotherapy.
    Patienten met stadium IV niet-kleincellig longkanker die ziekte progressie hebben na te zijn behandeld met erlotinib of gefitinib of na te zijn behandeld met op platina gebaseerde chemotherapie.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of the drug combination.
    Het evalueren van de effectiviteit van HCQ en erlotinib combinatie therapie.
    E.2.2Secondary objectives of the trial
    Translational work is aimed to explore pharmacodynamic, predictive and surrogate endpoint biomarkers in tumor tissue and blood.
    Translationeel onderzoek is gericht op het exploreren van pharmacodynamische, predictieve en surrogaat-eindpunt biomarkers in tumorweefsel en bloed.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Histologically confirmed stage IV non-squamous NSCLC patients.
    • Patients:
    with an activating EGFR mutation who progressed on erlotinib or gefitinib monotherapy.
    OR
    who failed after at least one line of platinum based doublet chemotherapy and who are EGFR TKI naïve.
    • At least one measurable disease site, defined as a lesion of ≥ 1 cm in at least one dimension on CT-scan.
    • WHO performance status 0-2.
    • No symptomatic brain metastases.
    • Absolute neutrophil count of at least 1500/μl, platelet count of at least 100000/μl and hemoglobin level at least 6 mmol/l.
    • Calculated creatinine clearance of at least 60 ml/min.
    • Adequate hepatic function: Total bilirubin ≤ 1.5 x upper limit of normal (ULN); ALT, AST, and alkaline phosphatase ≤ 2.5 x ULN (in case of liver metastases ≤ 5 x ULN).
    • Willing and able to comply with the study prescriptions
    • 18 years or older.
    • Not pregnant or breast feeding and willing to take adequate contraceptive measures during the study.
    • Ability to give and having given written informed consent before patient registration.
    • No recent (< 3 months) severe (NYHA class >1) cardiac disease (congestive heart failure, infarction). No history of cardiac arrythmia (multifocal premature ventricular contractions, uncontrolled atrial fibrillation, bigeminy, trigeminy, ventricular tachycardia) which is symptomatic and requiring treatment (CTC AE 4.0), or asymptomatic sustained ventricular tachycardia. Asymptomatic atrial fibrillation controlled on medication is allowed.
    • No cardiac conduction disturbances or medication potentially causing them: congenital long QT-syndrome or unexplained sudden death of first degree relative under 40 years of age, QT interval > 480 msec (note: when this is the case on screening ECG, the ECG may be repeated twice. If the average QT-interval of these 3 measurements remains below 480 msec, patient is eligible). Patients on medication potentially prolonging the QT-interval are excluded if the QT-interval is > 460 msec. Medication that might cause QT-prolongation or Torsades de pointes tachycardia is not allowed. Drugs with a risk of prolonging the QT-interval that cannot be discontinued are allowed, however, under close monitoring by the treating physician.
    • No uncontrolled infectious disease.
    • No clinically significant gastrointestinal abnormalities.
    • No other active malignancy.
    • No major surgery (excluding diagnostic procedures like e.g. mediastinoscopy or VATS biopsy) in the previous 4 weeks.
    • No treatment with investigational drugs in the 4 weeks prior to or during this study that are thought or known to interact with autophagy or the EGFR axis.
    • No known G6PD deficiency.
    • No psoriasis or porphyria.
    • No known hypersensitivity to 4-aminoquinoline compound.
    • No retinal or visual field changes from prior 4-aminoquinoline compound use.
    • No known prior hypersensitivity to erlotinib, HCQ or any of their components.
    • Histologisch bewezen stadium IV non-squamous NSCLC patienten.
    • Patienten:
    • met een activerende EGFR mutatie die progressief zijn onder erlotinib of gefitinib monotherapie.
    OF
    • welke progressieve ziekte hebben na eerdere behandeling met ten minste een lijn platinum doublet based chemotherapie en welke EGFR TKI naief zijn.
    • Ten minste een meetbare laesie, gedefinieerd als een laesie van ≥ 1 cm in ten minste een dimensie op CT-scan.
    • WHO performance status 0-2.
    • Geen symptomatische hersenmetastasen.
    • Absolute neutrofielen count van ten minste 1500/μl, bloedplaatjes van ten minste 100000/μl en hemoglobine gehalte van ten minste 6 mmol/l.
    • Berekende creatinine klaring van ten minste 60 ml/min.
    • Voldoende leverfunctie: totaal bilirubine ≤ 1.5 x maximale normaalwaarde; ALT, AST, and alkaline phosphatase ≤ 2.5 x maximale normaalwaarde (in geval van levermetastasen ≤ 5 x).
    • Bereid en geschikt om deel te nemen aan de studie.
    • 18 jaar of ouder.
    • Niet zwanger, geen borstvoeding en bereid om anticoncpetie te nemen tijdens de studie indien in de vruchtbare leeftijd.
    • Mogelijkheid en bereidheid om "written informed consent" te geven voor de studie.
    • Geen recente (< 3 maanden) ernstige (NYHA klasse >1) cardiale ziekte (congestief hartfalen, hartinfarct). Geen voorgeschiedenis van hartritmestoornissen (multifocale PVCs, instabiel boezemfibrilleren, bigeminie, trigeminie, ventriculaire tachycardie) welke symptomatisch is en behandeling behoeft (CTC AE 4.0), of asymptomatisch sustained VT. Asymptomatisch boezemfibrilleren, onder controle met medicatie, is toegestaan.
    • Geen cardiale geleidingsstoornis of medicatie dat hiertoe leidt: congenitaal QT-syndroom of onverklaarde plotse hartdood van eerste graads familielid onder de leeftijd van 40 jaar, QT interval > 480 msec.
    Patienten met medicatie dat de QT tijd kan verlengen worden niet geincludeerd indien het QT-interval > 460 msec is. Medicatie met risico op verlenging van het QT tijdsinterval die niet kan worden gestaakt is toegestaan onder goede controle van de behandelend specialist.
    • Geen actieve infectie.
    • Geen klinisch significante gastrointestinale ziekte.
    • Geen andere actieve maligniteit.
    • Geen grote chirurgie (dit betreft niet diagnostische procedures zoals mediastinoscopie of VATS biopsie) in de voorafgaande vier weken.
    • Geen behandeling met studiemedicamenten in de vier voorafgaande weken die bekend staan om interactie met autofagie of de EGFR as.
    • Geen bekende G6PD deficientie.
    • Geen bekende psoriasis of porphyrie.
    • Geen bekende overgevoeligheid voor 4-aminoquinoline producten.
    • Geen bekende retina of gezichtsveld pathologie door eerdere 4-aminoquinoline producten.
    • Geen bekende overgevoeligheid voor erlotinib, HCQ of een van hun bestandsdelen.
    E.4Principal exclusion criteria
    We refer to the inclusion criteria
    Zie inclusie criteria
    E.5 End points
    E.5.1Primary end point(s)
    The difference in metabolic activity of the tumor after one week of treatment as compared to the baseline value, measured with 18F-FDG PET using predefined PET response criteria.
    Verschil in metabole activiteit van de tumor na een week behandeling ten opzichte van de baseline waarde, gemeten met 18F-FDG PET volgens vooraf vastgelegde PET respons criteria.
    E.5.1.1Timepoint(s) of evaluation of this end point
    After one week of treatment.
    Na een week behandeling.
    E.5.2Secondary end point(s)
    • To assess the disease control rate (DCR) according to the response evaluation criteria in solid tumors (RECIST v1.1) with CT-Thorax, performance free survival (PFS) after six months of treatment and overall survival (OS) after one year of treatment.
    • To assess the level of autophagy at baseline and the inhibition of autophagy during treatment in peripheral blood and tumor samples.
    • Upon progression, a rebiopsy will be taken to analyse EGFR mutation and autophagy status and to analyse mechanisms of secondary resistance to erlotinib/hydroxychloroquine treatment.
    • Disease control rate (DCR) volgens RECIST v1.1 met CT-Thorax, progressie-vrije overleving (PFS) na zes maanden behandeling en overall survival (OS) na een jaar behandeling.
    • Bepalen van de mate van autofagie op baseline en de remming van autofagie tijdens behandeling in bloed en tumor samples.
    • Bij progressie zal opnieuw een tumorbiopt worden genomen om de EGFR mutatie status en de mate van autofagie te evalueren ter analyse van secundaire resistentie mechanismen tegen erlotinib/hydroxychloroquine behandeling.
    E.5.2.1Timepoint(s) of evaluation of this end point
    After one week, every six weeks from baseline and upon disease progression
    Na een week, elke zes weken na baseline en op het moment van ziekte progressie
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.5.1Number of sites anticipated in the EEA1
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The last visit of the last subject undergoing the trial.
    Op het moment van het laatste bezoek van de laatste patient in de studie.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 136
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2012-02-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-05-09
    P. End of Trial
    P.End of Trial StatusOngoing
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