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    Summary
    EudraCT Number:2016-003970-41
    Sponsor's Protocol Code Number:CRU3
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-06-17
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2016-003970-41
    A.3Full title of the trial
    A PHASE 2 OPEN LABEL STUDY OF ORAL LORLATINIB (PF-06463922) IN PATIENTS WITH RELAPSED ALK POSITIVE LYMPHOMA PREVIOUSLY TREATED WITH ALK INHIBITORS
    STUDIO DI FASE 2 IN APERTO CON LORLATINIB (PF-06463922) IN PAZIENTI AFFETTI DA LINFOMA ALK POSITIVO, RECIDIVATI E PRECEDENTEMENTE TRATTATI CON INIBITORI DI ALK
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical trial with the drug lorlatinib in patients affected by a lymphoma that expresses the protein ALK, previously treated with ALK inhibitors but for whom the therapy is not anymore effective
    Sperimentazione clinica con il farmaco lorlatinib in pazienti affetti da linfoma che esprime la proteina ALK, che sono stati precedentemente trattati con altri farmaci contro ALK ma che non rispondono più alla terapia
    A.3.2Name or abbreviated title of the trial where available
    Phase 2 study of lorlatinib in ALK+ lymphoma patients
    Studio di fase 2 con lorlatinib in pazienti affetti da linfoma ALK+
    A.4.1Sponsor's protocol code numberCRU3
    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 SponsorUNIVERSITÀ DEGLI STUDI MILANO BICOCCA
    B.1.3.4CountryItaly
    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 supportPfizer
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversità degli Studi di Milano-Bicocca
    B.5.2Functional name of contact pointProf. Carlo Gambacorti Passerini -
    B.5.3 Address:
    B.5.3.1Street Addressvia Cadore, 48
    B.5.3.2Town/ cityMonza
    B.5.3.3Post code20900
    B.5.3.4CountryItaly
    B.5.4Telephone number+390392339553
    B.5.5Fax number+390392333539
    B.5.6E-mailcarlo.gambacorti@unimib.it
    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 namePF-06463922
    D.3.2Product code [lorlatinib]
    D.3.4Pharmaceutical form 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 INNPF-06463922
    D.3.9.2Current sponsor codePF-06463922
    D.3.9.3Other descriptive namePF-06463922 form (anhydrous form 7)
    D.3.9.4EV Substance CodeSUB12819
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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
    Anaplastic Large Cells Lymphoma (ALCL) ALK+
    Linfoma anaplastico a grandi cellule (ALCL) ALK +
    E.1.1.1Medical condition in easily understood language
    ALCL is a lymphoma associated with the formation of the protein NPM-ALK that determines the abnormal production of white cells
    ALCL è un linfoma associato alla formazione della proteina NPM-ALK che determina una produzione anomala di globuli bianchi.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10073478
    E.1.2Term Anaplastic large-cell lymphoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Define the objective response rates (ORR) of PF-06463922 in subjects with ALK+ lymphomas resistant or refractory to ALK inhibitors.
    Definire il tasso di risposta oggettiva (ORR) di PF-06463922 in soggetti con linfoma ALK+ resistente o refrattario ad altri inibitori di ALK.
    E.2.2Secondary objectives of the trial
    - Define the Progression Free Survival (PFS) in subjects with ALK+ lymphomas resistant or refractory to ALK inhibitors.
    - Define the overall survival (OS) in ALK+ lymphoma patients treated with PF-06463922, that are resistant or refractory to ALK inhibitors.
    - Determine the toxicity profile of PF-06463922 in ALK+ lymphoma patients resistant or refractory to ALK inhibitors.
    - Determine the Quality of Life (QoL) in this population of patients using the EORTC–C30 Quality of Life questionnaire.
    - Study the mutational status of ALK pre/post PF-06463922 treatment through next-generation sequencing (NGS).
    - Definire la sopravvivenza libera da progressione (PFS) nei soggetti con linfoma ALK+ resistente o refrattario ad altri inibitori di ALK;
    - definire la sopravvivenza globale (OS) in soggetti con linfoma ALK+ resistente o refrattario ad altri inibitori di ALK;
    - determinare il profilo di tossicità di PF-06463922 in soggetti con linfoma ALK+ resistente o refrattario ad altri inibitori di ALK;
    - determinare la qualità di vita (QoL) in questa popolazione di pazienti con il questionario EORTC-C30;
    - studiare lo stato mutazionale di ALK pre/post trattamento con PF-06463922 tramite il sequenziamento di nuova generazione (NGS).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Signed and dated Informed Consent approved by Local Ethical Committee before any protocol-specific screening procedures.
    2) ALK+ Lymphoma diagnosed by IHC or FISH.
    3) Refractory disease or relapse after at least one prior chemotherapy regimen (typically a minimum of 6 cycles of CHOP) and at least one ALK inhibitor; presence of measurable disease by physical examination, CT or CT-PET scan.
    4) Any prior antitumor medical treatment or major surgeries must have been completed at least 14 days prior to initiation of study medication. This could not be respected if there is clear evidence of disease progression, manifested as growing pain attributable to the tumour, fever, growing tumour lesions, increasing LDH values. Systemic anti-cancer therapy completed within a minimum of 5 half-lives of study entry.
    5) Able to take oral therapy.
    6) Female or male, 18 years of age or older.
    7) ECOG performance status 0-3.
    8) Adequate organ function as defined by the following criteria:
    - Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) = 2.5 x upper limit of normal (ULN) or AST and ALT = 5 x ULN if liver function abnormalities are due to underlying malignancy
    - Total serum bilirubin 1.5 x ULN (except patients with documented Gilbert’s syndrome
    - Creatinine = 1.5 x ULN.
    9) Adequate bone marrow function:
    - Absolute neutrophil count (ANC) = 1000/µL
    - Platelets = 50.000/µL
    - Hemoglobin = 9.0 g/dL
    The hematological values will not be considered in case of bone marrow involvement.
    10) Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
    11) Female and male patients who are of childbearing potential must agree to use an effective form of contraception (2 forms of contraception) with their partners throughout participation in this study and for at least 90 days after the last dose of treatment.
    1) consenso informato approvato dal Comitato Etico locale firmato e datato prima di qualsiasi procedura di screening specifica del protocollo.
    2) Diagnosi di linfoma ALK+ diagnosticato tramite immunoistochimica o FISH.
    3) Sviluppo di una recidiva o resistenza dopo almeno un precedente regime chemioterapico (tipicamente un minimo di 6 cicli di CHOP) ed almeno un inibitore di ALK; presenza di malattia misurabile tramite esame fisico, CT o CT-PET.
    4) Precedenti chemioterapie o importanti interventi chirurgici devono essere completati almeno 14 giorni prima dell'inizio del farmaco in studio. Ciò potrebbe non essere rispettato se vi è una chiara evidenza di progressione della malattia, caratterizzata da dolore crescente attribuibile al tumore, febbre, aumento delle lesioni tumorali, aumento dei valori di LDH. Un eventuale terapia sistemica anti-neoplastica deve essere completata con un minimo di 5 emivite dall'ingresso nello studio.
    5) Paziente in grado di assumere una terapia orale.
    6) Maschio o femmina, di età uguale o maggiore di 18 anni.
    7) ECOG performance status 0-3.
    8) Adeguata funzionalità degli organi, definita dai seguenti criteri:
    - Aspartato Aminotransferasi sierica (AST) e Alanina Aminotransferasi sierica (ALT) = 2.5 volte il limite superiore del valore normale (ULN) o AST e ALT = 5 x ULN se le alterazioni della funzionalità epatica sono dovute al tumore;
    - Bilirubina totale sierica 1.5 x ULN (ad eccezione dei pazienti con sindrome di Gilbert documentata);
    - Creatinina = 1,5 x ULN.
    9) Adeguata funzionalità del midollo osseo:
    - conta assoluta dei neutrofili (ANC) = 1000 / ml
    - piastrine = 50.000 / mL
    - emoglobina = 9,0 g / dl
    I valori ematologici non saranno presi in considerazione in caso di coinvolgimento del midollo osseo.
    10) Disponibilità e capacità di rispettare le visite programmate, i piani di trattamento, gli esami di laboratorio e altre procedure dello studio.
    11) Uomini e donne che sono in età fertile devono accettare di utilizzare una forma efficace di contraccezione (2 forme di contraccezione) con i loro partner durante la partecipazione a questo studio e per almeno 90 giorni dopo l'ultima dose di trattamento.
    E.4Principal exclusion criteria
    1) Current treatment on another therapeutic clinical trial.
    2) Clinically significant cardiovascular disease (that is, active or <3 months prior to enrollment): cerebral vascular accident/stroke, myocardial infarction, unstable angina, congestive heart failure (New York Heart Association Classification Class = II)
    3) Ongoing cardiac dysrhythmias of NCI CTCAE Grade =2: second-degree or third-degree AV block (unless paced) or any AV block with PR >220 msec, uncontrolled atrial fibrillation of any grade, bradycardia defined as <50 bpm (unless patient is otherwise healthy such as long-distance runners, etc.), machine-read ECG with QTc >470 msec, or congenital long QT syndrome.
    4) Pregnancy or breastfeeding.
    5) Use of drugs or foods that are known strong or moderate CYP3A4 inhibitors, inducers and substrates; drugs that are CYP2C9 substrates; drugs that are strong CYP2C19 inhibitors; drugs that are strong CYP2C8 inhibitors; and drugs that are P-gp substrates.
    6) Prior malignancy other than basal cell carcinoma , if original diagnosis happened in the last 5 years.
    7) Patients with predisposing characteristics for acute pancreatitis according to investigator judgment (e.g. uncontrolled hyperglycemia, current gallstone disease, alcoholism).
    8) Hypertriglyceridemia = grade 1.
    9) Active and clinically significant bacterial, fungal, or viral infection including hepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS) related illness.
    10) Other severe acute or chronic medical or psychiatric conditions, or laboratory abnormalities that would impart, in the judgment of the investigator and/or sponsor, excess risk associated with study participation or study drug administration.
    1) contemporanea partecipazione ad un altro studio clinico.
    2) Patologie cardiovascolari clinicamente significative (attive o < 3 mesi prima dell'arruolamento): ictus, infarto del miocardio, angina instabile, insufficienza cardiaca congestizia (classificata in base alla New York Heart Association Classification = II)
    3) Aritmie cardiache in corso di grado NCI CTCAE =2: blocco AV di secondo o terzo grado (a meno che non stimolato) o qualsiasi blocco AV con PR > 220 msec, fibrillazione atriale non controllata di qualsiasi grado, bradicardia definita come < 50 bpm (a meno che il paziente sia in buona salute, come i corridori di lunga distanza), ECG con QTc > 470 msec, o sindrome del QT lungo congenito.
    4) Gravidanza o allattamento.
    5) Uso di farmaci o alimenti che sono forti o moderati inibitori, induttori o substrati del CYP3A4; farmaci che sono substrati del CYP2C9; farmaci che sono forti inibitori del CYP2C19; farmaci che sono forti inibitori del CYP2C8; farmaci che sono substrati della P-gp.
    6) Precedente neoplasia diversa dal carcinoma basocellulare, solo se la diagnosi è avvenuta negli ultimi 5 anni.
    7) I pazienti con una predisposizione per pancreatite acuta (ad esempio pazienti con iperglicemia incontrollata, colelitiasi, alcolismo…).
    8) Ipertrigliceridemia = grado 1.
    9) Infezioni batteriche, fungine o infezioni virali compresa quella da virus dell'epatite B (HBV), virus dell’epatite C (HCV), virus dell’HIV, o sindrome da immunodeficienza acquisita (AIDS), attive e clinicamente significative.
    10) Altre condizioni severe acute o croniche mediche o psichiatriche, o anomalie di laboratorio che potrebbero impartire, a giudizio dello sperimentatore e/o sponsor, eccesso di rischio associato alla partecipazione allo studio o alla somministrazione del farmaco in studio.
    E.5 End points
    E.5.1Primary end point(s)
    ORR
    Tasso di risposta oggettiva
    E.5.1.1Timepoint(s) of evaluation of this end point
    After 4 weeks from the date of the first dose of PF-06463922, at 12 weeks and then every 12 weeks. After 1 year of treatment every 6 months until M24, then only if clinically indicated and at the end of the study.
    Dopo 4 settimane dall'inizio del trattamento con PF-06463922, a 12 settimane e succesivamente ogni 12 settimane. Dopo 1 anno di trattamento, ogni 6 mesi fino all'M24, poi solo se clinicamente indicato e alla fine dello studio.
    E.5.2Secondary end point(s)
    PFS; OS; Toxicity; QoL; Mutational analysis
    Sopravvivenza senza progressione; Sopravvivenza globale; Tossicità; Qualità di vita; Analisi mutazionale
    E.5.2.1Timepoint(s) of evaluation of this end point
    PFS will be evaluated continuosly for the entire study duration; OS will be evaluated continuosly for the entire study duration; Toxicity will be evaluated continuosly for the entire study duration; QoL will be evaluated at screening, M3, M12, M24, M30, M36 and at the end of the study; The analysis will be performed at screening, M3 and at the end of the study
    La sopravvivenza è valutata in modo continuo per tutta la durata dello studio; La sopravvivenza è valutata in modo continuo per tutta la durata dello studio; La tossicità è valutata in modo continuo per tutta la durata dello studio; La qualità di vita verrà valutata allo screening, M3, M12, M24, M30, M36 e alla fine dello studio; L'analisi verrà effettuata allo screening, M3 e alla fine dello studio
    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 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 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.8.2.4Number 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 No
    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 Information not present in EudraCT
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    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: 11
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1
    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 state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 12
    F.4.2.2In the whole clinical trial 12
    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 be treated as per local clinical practice
    I pazienti saranno trattati secondo la normale pratica clinica
    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 Decision2017-02-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-07-06
    P. End of Trial
    P.End of Trial StatusOngoing
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