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    Summary
    EudraCT Number:2019-003862-41
    Sponsor's Protocol Code Number:EORTC-1825-LCG
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-05-11
    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 number2019-003862-41
    A.3Full title of the trial
    Activity of Lorlatinib based on ALK resistance mutations on blood in ALK positive NSCLC patients previously treated with 2nd generation ALK inhibitor
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Activity of Lorlatinib based on ALK resistance mutations on blood in ALK positive NSCLC patients previously treated with 2nd generation ALK inhibitor
    A.3.2Name or abbreviated title of the trial where available
    ALKALINE
    A.4.1Sponsor's protocol code numberEORTC-1825-LCG
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04127110
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorEuropean Organisation for Research and Treatment of Cancer
    B.1.3.4CountryBelgium
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportEuropean Organisation for the Research and Treatment of Cancer
    B.4.2CountryBelgium
    B.4.1Name of organisation providing supportPfizer NV/SA
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEuropean Organisation for the Research and Treatment of Cancer
    B.5.2Functional name of contact pointRegulatory Affairs Department
    B.5.3 Address:
    B.5.3.1Street Address83/11 Avenue E. Mounier
    B.5.3.2Town/ cityBrussels
    B.5.3.3Post code1200
    B.5.3.4CountryBelgium
    B.5.4Telephone number+3227741521
    B.5.5Fax number+3227727063
    B.5.6E-mailregulatory@eortc.org
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Lorviqua
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Europe MA EEIG
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLorviqua
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLORLATINIB
    D.3.9.3Other descriptive nameLorlatinib
    D.3.9.4EV Substance CodeSUB181272
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    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
    Non-small cell lung cancer
    E.1.1.1Medical condition in easily understood language
    lung cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10061873
    E.1.2Term Non-small cell lung cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The main aim of this trial is to assess the progression-free survival rate at 12 months (PFSR12) to lorlatinib in ALK positive advanced NSCLC patients, who progressed on second generation ALKTKI with the presence of ALK resistance mutations on blood (liquid biopsies) by Independent Central Review (ICR) assessment per RECIST v1.1
    E.2.2Secondary objectives of the trial
    To evaluate:
    • Activity as measured by ORR, Central nervous system response rate (CNS ORR), Duration of the response (DOR), PFS, OS
    • Toxicity of lorlatinib in patients previously treated with 2nd generation ALK TKI
    • Patient reported outcomes (PRO) of global health-related quality of life (HRQOL), functioning and the impact of lorlatinib on disease/treatment-related symptoms of lung
    cancer.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Emergence of ALK and non ALK resistance mutation during response to second generation ALK TKI in blood
    E.3Principal inclusion criteria
    • Age ≥ 18 years old
    • Histologically or cytologically confirmed diagnosis of NSCLC with ALK rearrangement, assessed by FISH assay or by Immunohistochemistry approved by FDA. Liquid biopsy is an acceptable method for the
    diagnosis of ALK rearrangement in case there is no leftover
    biopsy/cytological specimen.
    • Stage III (not eligible for local therapy) or stage IV (according to UICC TNM staging v8.0)
    • WHO performance status of 0-2
    • Previous treatment with at least one 2nd-generation ALK inhibitor. The 2nd-generation ALK TKI (including but not limited to ceritinib, alectinib, brigatinib) should be the latest therapy.
    • Progressive disease during treatment with 2nd-generation ALK inhibitor prior to the
    administration of lorlatinib
    • Measurable disease according to RECIST version 1.1 by computed tomography or
    magnetic resonance imaging (MRI) of Chest/Abdomen/Pelvis and brain MRI performed within 28 days prior to study enrolment
    Note: At least one measurable extracranial lesion is required.
    • Collection of blood sample for cohort allocation.
    • Treated and/or untreated brain or leptomeningeal metastases will be allowed if asymptomatic and/or controlled (stable dose of steroids 7 days before the beginning of lorlatinib treatment)
    • Adequate bone marrow and organ function defined as following:
    • Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L;
    • Platelets ≥ 100 x 109/L;
    • Hemoglobin ≥ 9 g/dL;
    • Serum total amylase ≤ 1.5 ULN;
    • Serum lipase ≤1.5 ULN;
    • Serum creatinine ≤ 1.5 x ULN or estimated creatinine clearance > 30 mL/min as calculated
    using the MDRD formula for subject with serum creatinine levels > 1.5x institutional ULN;
    • Total serum bilirubin ≤ 1.5 x ULN or direct bilirubin ≤ ULN for patients with total bilirubin
    levels > 1.5 x ULN; for patients with Gilbert's disease total bilirubin may be > 1.5 x ULN,
    however direct bilirubin must be normal;
    • Aspartate Aminotransferase (SGOT) and Alanine Aminotransferase (SGPT) ≤ 2.5 x ULN
    (≤5.0 x ULN if there is liver metastases involvement);
    • Women of child bearing potential (WOCBP) must have a negative serum pregnancy test within 3 days prior to enrolment.
    • Women of childbearing potential must use a highly effective non-hormonal method of
    contraception during the study treatment period and for at least 35 days after the last dose of lorlatinib. If a hormonal method of contraception is unavoidable, then a condom must be used in
    combination with the hormonal method.
    • Male patients with female partners of childbearing potential must use effective contraception, including a condom, and male patients with pregnant partners must use condoms, during the study treatment period and for at least 14 weeks after the last dose of lorlatinib.
    • Female subjects who are breast feeding should discontinue nursing prior to the first dose of study treatment and until 7 days after the last dose of lorlatinib
    • Patient is willing and able to comply with the protocol for the duration of the study including
    undergoing treatment and scheduled visits and examinations including follow up
    • Before patient registration, written informed consent must be given according to ICH/GCP, and national/local regulations

    Patient selection criteria for the optional prospective sub-study:
    In the optional prospective sub-study, the patient could be enrolled during the ongoing response to second-generation ALK inhibitor if the following conditions are fulfilled:
    • Age ≥ 18 years old
    • The patient has received at least 6 months of second generation ALK-TKI therapy (if crizotinib-pretreated)
    OR
    • The patient has received at least 12 months of second generation ALK-TKI therapy (if
    crizotinib-naïve)
    • Patient is willing and able to comply with the sub-study requirements including scheduled
    visits and examinations
    • Before patient registration, written informed consent must be given according to ICH/GCP,
    and national/local regulations.
    If the patient enrolled in the prospective sub-study presents a PD by RECIST V1.1 while the
    recruitment in ALKALINE study is still ongoing and all the inclusion/exclusion criteria for the
    participation in the ALKALINE study are fulfilled, then the patient can be enrolled in the
    ALKALINE phase II study.
    E.4Principal exclusion criteria
    • Spinal cord compression. Patients who received adequate treatment (surgery or radiotherapy) and has adequate control of the pain and stabilization and/or recovery of neurological symptoms/function for the 3 weeks prior to study entry are allowed
    • Major surgery within 4 weeks prior to study enrolment. Complete wound healing from major surgery must have occurred 3 weeks before the first dose of study treatment.
    • Minor surgical procedures (including port insertion, uncomplicated tooth extractions) without complete wound healing at the latest 1 week before the first dose of study reatment.
    • Radiation therapy within 2 weeks of study entry. Exception are:
    • Palliative radiation (≤10 fractions) is allowed if completed at least 48 hours prior to study enrolment
    • Stereotactic or small field brain irradiation is allowed if completed at least 2 weeks prior to study enrolment
    • Whole brain radiation is allowed if completed at least 4 weeks prior to study enrolment
    • Any systemic anti-cancer therapy or an investigational drug treatment completed within 7 days prior to start lorlatinib (in case of clinically meaningful risk of tumour flare according to investigator's assessment, discussion with EORTC is required before enrolment)
    • Any unresolved toxicities from prior systemic therapy, including haematological toxicities,
    greater than CTCAE v5.0 grade 2 at the time of study enrolment
    • Active infection requiring therapy
    • Known active hepatitis B (HBV) or hepatitis C (HCV). Active Hepatitis B is defined as a known
    positive HBsAg result. Active Hepatitis C is defined by a known positive Hep C Ab result and known quantitative HCV RNA result greater than the lower limits of detection of the assay
    • Known human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome
    (AIDS)-related illness
    • Any of the following cardiac criteria:
    • Clinically significant cardiovascular disease (that is active or occurred <3 months prior to
    enrolment): cerebral vascular accident/stroke, myocardial infarction, unstable angina,
    congestive heart failure (New York Heart Association Classification Class ≥ II), second degree or third-degree AV block (unless paced) or any AV block with PR >220 msec
    • Ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2, uncontrolled atrial fibrillation of any grade, bradycardia defined as <50 bpm (unless patient is otherwise healthy such as longdistance runners, etc.)
    • Abnormal Left Ventricular Ejection Fraction (LVEF): LVEF <50% (assessed by MUGA or
    ECHO)
    • History of interstitial lung disease (ILD) or history of (non-infectious) pneumonitis that required oral or IV steroids (other than COPD exacerbation) or current pneumonitis or current evidence of interstitial lung disease. Patients with history of prior radiation pneumonitis are not excluded
    • Any serious or uncontrolled acute or chronic medical or psychiatric condition, including recent(within the past year) or active suicidal ideation or behaviour, chronic alcoholism, drug addiction, or laboratory abnormality that may increase the risk associated with study participation or investigational product dministration or may interfere with the interpretation of study results
    and, in the judgment of the investigator, would make the patient not eligible for this study
    • Hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption
    • Inability to swallow and/or retain oral tablets or impaired gastrointestinal function or disease that may significantly alter the absorption of lorlatinib (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption)
    • Evidence of active hematologic or primary solid tumour malignancy (other than completely resected non-melanoma skin cancer, successfully treated in situ carcinoma for example in situ cervical cancer, completely resected and successfully treated papillary thyroid cancer, or localized and presumed cured prostate cancer) within the last 3 years
    • History of hypersensitivity to excipients of Lorlatinib (please refer to Summary of Product
    Characteristics - SmPC)
    • Patients currently receiving (or unable to stop use at least 3 plasma half-lives of the strong CYP3A4/5 inducer before lorlatinib treatment is started) medications or herbal supplements known to be strong inducers of cytochrome P450 (CYP) 3A4/5
    • Any psychological, familial, sociological or geographical condition potentially hampering
    compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
    E.5 End points
    E.5.1Primary end point(s)
    PFS Rate at 12 months
    E.5.1.1Timepoint(s) of evaluation of this end point
    disease evaluation at 52 weeks (+/- 2 weeks) is required for all patients who are still alive and without progression
    E.5.2Secondary end point(s)
    Overall Survival (OS).
    • Progression Free Survival (PFS).
    • Overall Response Rate (ORR).
    • Duration of Response (DOR).
    • CNS Overall Response Rate (CNS-ORR)
    • Patient Reported Outcomes (PROs): as assessed by EORTC QLQ- C30, EORTC QLQ-LC13 and study specific Item List.
    • Safety profile according to NCI CTCAE v 5.0
    E.5.2.1Timepoint(s) of evaluation of this end point
    Follow the primary endpoint
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Biobanking, quality of life
    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 No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA24
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Jordan
    United Kingdom
    Belgium
    France
    Netherlands
    Norway
    Spain
    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
    End of study occurs when all of the following criteria have been
    satisfied:
    • All patients have reached the end of study.
    If a participant discontinues the follow-up for one of the following
    reasons: withdrawal of consent, loss to follow-up, or death, the end of
    study participation is defined as the time point when one of these
    events occurred.
    • The trial is mature for all analyses defined in the protocol and the
    database has been cleaned and frozen for these analyses.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months0
    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.1.2.1Number of subjects for this age range: 67
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 17
    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 Yes
    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 state45
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 72
    F.4.2.2In the whole clinical trial 84
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    According to the discretion of the treating physician.
    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 Decision2020-05-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-10-12
    P. End of Trial
    P.End of Trial StatusCompleted
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