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    Summary
    EudraCT Number:2017-000640-18
    Sponsor's Protocol Code Number:NANT2015-02
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2018-03-27
    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 ConcernedUK - MHRA
    A.2EudraCT number2017-000640-18
    A.3Full title of the trial
    NANT 2015-02: PHASE 1 STUDY OF LORLATANIB (PF-06463922), AN ORAL SMALL MOLECULE INHIBITOR OF ALK/ROS1, FOR PATIENTS WITH RELAPSED OR REFRACTORY NEUROBLASTOMA
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of the drug lorlatinib for children and young people with relapsed neuroblastoma that has changes in the ALK gene.
    A.3.2Name or abbreviated title of the trial where available
    NANT/Pfizer Lorlatinib Study
    A.4.1Sponsor's protocol code numberNANT2015-02
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03107988
    A.5.4Other Identifiers
    Name:Royal Marsden numberNumber:CCR4437
    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 SponsorNANT Operations Centre
    B.1.3.4CountryUnited States
    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 supportSolving Kids Cancer
    B.4.2CountryUnited States
    B.4.1Name of organisation providing supportRoyal Marsden Hospital Biomedical Research Centre
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportPfizer
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRoyal Marsden NHS Foundation Trust
    B.5.2Functional name of contact pointBev Wharram
    B.5.3 Address:
    B.5.3.1Street AddressDowns Road
    B.5.3.2Town/ citySutton
    B.5.3.3Post codeSM2 5PT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number02086613634
    B.5.5Fax number02086613617
    B.5.6E-mailbeverly.wharram@rmh.nhs.uk
    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 No
    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 nameLorlatinib (PF-0643922)
    D.3.2Product code n/a
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Relapsed or refractory high risk neuroblastoma
    E.1.1.1Medical condition in easily understood language
    Patients with a paediatric cancer called neuroblastoma that has returned after treatment or for whom treatment has proven to be ineffective.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. To determine the recommended phase 2 dose of lorlatanib administered orally to children and adolescents with ALK mutated, fusion protein or amplification relapsed or refractory neuroblastoma.
    2. To describe the toxicities of lorlatinib in the population
    3. To characterize the pharmacokinetics of single agent lorlatinib in the children and adolescents with relapsed/refractory neuroblastoma
    4. To define and describe the toxicities of lorlatinib in combination with topotecan and cyclophosphamide in children and adolescents with with ALK mutated, fusion protein or amplification relapsed or refractory neuroblastoma.
    5. To characterize the pharmacokinetics of lorlatinib when combined with topotecan and cyclophosphamide in the children and adolescents with relapsed/refractory neuroblastoma
    E.2.2Secondary objectives of the trial
    1. To preliminarily evaluate the anti-tumour activity of lorlatinib within the confines of a Phase I study in children and adolescents with relapsed/refractory neuroblastoma harbouring confirmed ALK alterations.

    EXPLORATORY RESEARCH AIMS
    a. To describe the toxicities, pharmacokinetics, and anti-tumor activity of lorlatinib in the larger adolescent and adult population with relapsed or refractory neuroblastoma who have tumor harboring a genetic change in ALK.
    b. To prospectively determine the frequency of circulating tumor cell-free DNA (ctDNA) in these patients, and any other acquired mutations in plasma from peripheral blood at study entry and at each anti-tumor evaluation time point.
    c. To describe the heterogeneity and evolution of genetic changes in ALK and other gene changes in relapsed neuroblastoma genomes by comparing DNA from matched tumor samples (diagnosis and recurrence).
    d. To assess tumor burden with a test of gene-expression, prior to and during treatment with lorlatini
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Patients must be equal to or greater than 12 months of age at the time of enrollment on the study.
    2. Diagnosis of neuroblastoma with histological verfication and/or tumour cells in the bone marrow with increased urinary catecholmines.
    3. Patients must have a confirmed ALK aberration: a) an ALK activating mutation b) ALK amplification c) Presence of any ALK fusion protein that arises from a chromosomal translocation.
    4. Patients must have high risk neuroblastoma according to COG classification. Patients who were initially low/intermediate risk but are then reclassified to high risk are eligible.
    5. Patients must have one of the following:
    a) recurrent/progressive disease
    b) refractory/persistent disease
    6. Sites of disease. Patients must have at least one of the following:
    a) bone sites
    b) bone marrow (tumour in)
    c) soft tissue sites
    6. Lansky or Karnofsky performance score of 50 or above
    7. Informed consent
    E.4Principal exclusion criteria
    1. Patients must not be receiving other anti-cancer agents or radiotherapy
    2. Concurrent use of known strong CYP3A4 inhibitors, inducers or substrates within 12 days prior to 1st dose of IMP.
    3. Abide by protocol defined wash out periods for other therapies.
    4. Adequate renal, hepatic and haematological function as defined in the protocol.
    5. Adequate neurophsychological function
    6. Adequate cardiac function
    7. Pregnancy, breast-feeding or an unwillingness to use effective contraception
    8. Prior allogeneic stem cell transplant
    9. Active or uncontrolled infection
    10.Does not consent to take part
    E.5 End points
    E.5.1Primary end point(s)
    1. To determine a recommended phase 2 dose of lorlatinib administered orally to children and adolescents with relapsed or refractory neuroblastoma who have tumour containing a confirmed pathogenic ALK fusion protein, ALK mutation or ALK amplification.
    2. To describe the toxicities of lorlatinib when administered to the population.
    3. To characterise the pharmacokinetics of single agent lorlatinib in children and adolescents with relapsed/refractory neuroblastoma.
    4. To define and describe the toxicities of lorlatinib in combination with topotecan and cyclophosamide in children and adolescents with relapsed or refractory neuroblastoma who have tumour containing a confirmed pathogenic ALK fusion protein, ALK mutation or ALK amplification administered on this schedule.
    5. To characterise the pharmacokinetics of lorlatinib when combined with topetecan and cyclophosphamide in children and adolescents with relapsed/refractory neuroblastoma.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Toxicities will be reviewed and defined at each cycle with a dose reduction/stopping protocol in place for safety.
    Laboratory testing for both statutory and optional biology studies will be done at baseline, with each disease evaluation and then every 4 cycles of treatment.
    E.5.2Secondary end point(s)
    To assess anti-tumor activity (within the confines of a phase 1 trial), both tumor response and event-free survival (EFS) will be measured. The tumor response (using the NANT response criteria), will be recorded for each patient and will be used to estimate the response rate of Lorlatinib as a single agent, at the RP2D, for the treatment of children with relapsed/refractory neuroblastoma harboring a confirmed ALK fusion protein, ALK mutation or ALK amplification. In addition, EFS will be calculated as the time from start of treatment with Lorlatinib until disease progression, death due to any cause or development of a second malignancy, whichever occurs first. Patients who are alive at their last follow-up without evidence of progression or development of another cancer, will be censored at that time.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Anti-tumour activity will be assessed at baseline (as a comparator), the end of cycles 2,4,6,8 and 12.
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    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) No
    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 No
    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.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    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 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
    Canada
    France
    United States
    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
    LVLS
    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 months9
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months11
    E.8.9.2In all countries concerned by the trial days1
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 6
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 1
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 4
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 1
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 0
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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 No
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Children under the age of 8 will be able to assent. Parental/guardian consent will be sought for children under the age of 8 years.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 10
    F.4.2.2In the whole clinical trial 48
    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)
    Patients will continue on treatment for as along as it proves beneficial or for as long as side effects are tolerable.

    Once the patient comes off study they may be eligible for other clinical trials, if available.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Royal Marsden NHS Foundation Trust
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-05-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-08-13
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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