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    Summary
    EudraCT Number:2018-001957-29
    Sponsor's Protocol Code Number:Brigatinib-3001
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-08-14
    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 ConcernedFrance - ANSM
    A.2EudraCT number2018-001957-29
    A.3Full title of the trial
    A Phase 3 Randomized Open-label Study of Brigatinib (ALUNBRIGTM) Versus Alectinib (ALECENSA®) in Advanced Anaplastic Lymphoma Kinase-Positive
    on–Small-Cell Lung Cancer Patients Who Have Progressed on Crizotinib (XALKORI®)
    Étude de phase III, randomisée, menée en ouvert visant à évaluer le brigatinib (ALUNBRIGTM) par rapport à l’alectinib (ALECENSA®) chez des patients atteints de cancer du poumon non à petites cellules avancé, avec mutation de la kinase du lymphome anaplasique (ALK), ayant progressé sous crizotinib (XALKORI®)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3 Randomized Open-label Study of Brigatinib Versus Alectinib in Advanced ALK-positive Non–Small-Cell Lung Cancer Patients Who Have Progressed on Crizotinib
    Étude de phase III, randomisée, menée en ouvert visant à évaluer le brigatinib par rapport à l’alectinib chez des patients atteints de cancer du poumon non à petites cellules avancé, avec mutation ALK+, ayant progressé sous crizotinib
    A.4.1Sponsor's protocol code numberBrigatinib-3001
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02737501
    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 SponsorARIAD Pharmaceuticals, Inc.(a wholly-owned subsidiary of Takeda Pharmaceutical Ltd.)
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportARIAD Pharmaceuticals, Inc.(a wholly-owned subsidiary of Takeda Pharmaceutical Ltd.)
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTakeda Pharmaceuticals Inc.
    B.5.2Functional name of contact pointAshwata Pokhrel
    B.5.3 Address:
    B.5.3.1Street Address40 Landsdowne Street
    B.5.3.2Town/ cityCambridge
    B.5.3.3Post codeMA 02139
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1617444 3168
    B.5.5Fax number+1617551 3742
    B.5.6E-mailashwata.pokhrei@takeda.com
    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 namebrigatinib
    D.3.2Product code AP26113
    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 INNBRIGATINIB
    D.3.9.1CAS number 1197953-54-0
    D.3.9.2Current sponsor codeAP26113
    D.3.9.3Other descriptive nameAP26133
    D.3.9.4EV Substance CodeSUB184911
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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.IMP: 2
    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 namebrigatinib
    D.3.2Product code AP26113
    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 INNBRIGATINIB
    D.3.9.1CAS number 1197953-54-0
    D.3.9.2Current sponsor codeAP26113
    D.3.9.3Other descriptive nameAP26133
    D.3.9.4EV Substance CodeSUB184911
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number90
    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.IMP: 3
    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 namebrigatinib
    D.3.2Product code AP26113
    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 INNBRIGATINIB
    D.3.9.1CAS number 1197953-54-0
    D.3.9.2Current sponsor codeAP26113
    D.3.9.3Other descriptive nameAP26133
    D.3.9.4EV Substance CodeSUB184911
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number180
    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.IMP: 4
    D.1.2 and D.1.3IMP RoleComparator
    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 Alecensa
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    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 namealectinib
    D.3.2Product code RO5424802/F03
    D.3.4Pharmaceutical form Capsule, hard
    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 INNALECTINIB
    D.3.9.1CAS number 1256580-46-7
    D.3.9.2Current sponsor codeRO5424802
    D.3.9.3Other descriptive nameALK INHIBITOR
    D.3.9.4EV Substance CodeSUB178557
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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
    ALK positive Locally Advanced or Metastatic Non-small Cell Lung Cancer
    Cancer du poumon non à petites cellules localement avancé ou métastatique, avec mutation de la kinase du lymphome anaplasique (ALK)
    E.1.1.1Medical condition in easily understood language
    Metastatic or locally advanced non-small cell lung cancer
    Cancer du poumon non à petites cellules localement avancé ou métastatique
    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 10059515
    E.1.2Term Non-small cell lung cancer metastatic
    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
    To compare the efficacy of brigatinib to that of alectinib in patients with ALK+ locally advanced or metastatic NSCLC who have progressed on crizotinib as evidenced by PFS as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
    Comparer l’efficacité de brigatinib à celle de l’alectinib chez des patients atteints de CPNPC ALK+ localement avancé ou métastatique, ayant progressé sous crizotinib, en évaluant la survie sans progression (SSP) selon les critères d'évaluation de la réponse dans les tumeurs solides (RECIST, Response Evaluation Criteria in Solid Tumors) v1.1.
    E.2.2Secondary objectives of the trial
    1. To compare the efficacy in the CNS of brigatinib to that of alectinib as evidenced by iORR, iDOR, and iPFS as assessed by modified RECIST criteria.
    2. To compare the efficacy of brigatinib to that of alectinib as evidenced by confirmed ORR, time to response, DOR (all as assessed by RECIST v1.1), and overall survival (OS).
    3. To assess the safety and tolerability of brigatinib in comparison with alectinib.
    4. To collect plasma concentration-time data for brigatinib to contribute to population pharmacokinetic (PK) analyses.
    5. To assess patient-reported symptoms and health-related quality of life (HRQoL) with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) (v3.0) and its Quality of Life Lung Cancer Module (QLQ-LC13), in patients treated with brigatinib compared with those treated with alectinib.
    1. Comparer l’efficacité du brigatinib à celle de l’alectinib sur le système nerveux central, en évaluant le taux de réponse objective intracrânienne, la durée de la réponse intracrânienne et la survie sans progression intracrânienne, selon les critères RECIST modifiés.
    2. Comparer l’efficacité du brigatinib à celle de l’alectinib, en évaluant par le taux de réponse objective, le délai jusqu’à la réponse, la durée de la réponse (selon les critères RECIST v1.1) et la survie globale.
    3. Évaluer la sécurité d’emploi et la tolérance du brigatinib par rapport à l’alectinib.
    4. Recueillir des données sur les concentrations plasmatiques/temps pour le brigatinib afin de contribuer aux analyses de pharmacocinétique de population.
    5. Évaluer les symptômes rapportés par les patients et la qualité de vie liée à la santé à l’aide du questionnaire principal de l’EORTC sur la qualité de vie QLQ C30 et de son module QLQ-LC13, chez les patients traités par brigatinib versus alectinib.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Adult patients aged 18 years and older.
    2. Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
    3. Have histologically or cytologically confirmed stage IIIB (locally advanced or recurrent) or stage IV NSCLC.
    4. Must meet one of the following criteria:
    a) Have documentation of ALK rearrangement by a positive result from the Vysis ALK Break-Apart fluorescence in situ hybridization (FISH) Probe Kit or the Ventana ALK (D5F3) CDx Assay or Foundation Medicine’s FoundationOne CDx.
    b) Have documented ALK rearrangement by a different test and be able to provide tumor sample to the central laboratory. (Note: central laboratory ALK rearrangement testing results are not required to be obtained before randomization.)
    5. Had PD while on crizotinib, as assessed by the investigator or treating physician. (Note: crizotinib does not need to be the last therapy a patient received. The patient may have received chemotherapy as his/her last therapy.)
    6. Treatment with crizotinib for at least 4 weeks before progression.
    7. Have had no other ALK inhibitor other than crizotinib.
    8. Have had no more than 2 prior regimens of systemic anticancer therapy in the locally advanced or metastatic setting.
    9. Have at least 1 measurable (ie, target) lesion per RECIST v1.1.
    10. Have recovered from toxicities related to prior anticancer therapy to NCI CTCAE v4.03 grade ≤1. (Note: treatment-related alopecia or peripheral neuropathy that are grade >1 are allowed, if deemed irreversible.)
    11. Have adequate organ function, as determined by:
    a) Total bilirubin ≤1.5 times the upper limit of normal (ULN).
    b) Estimated glomerular filtration rate ≥30 mL/minute/1.73 m2, using the modification of diet in renal disease equation.
    c) Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤2.5 × ULN; ≤5 × ULN is acceptable if liver metastases are present.
    d) Serum lipase ≤1.5 × ULN.
    e) Platelet count ≥75 ×109/L.
    f) Hemoglobin ≥9 g/dL.
    g) Absolute neutrophil count ≥1.5 × 109/L.
    12. Suitable venous access for study-required blood sampling (ie, including PK and laboratory safety tests).
    13. Have the willingness and ability to comply with scheduled visits and study procedures.
    14. For female patients of childbearing potential, have a negative pregnancy test documented before randomization.
    15. For female and male patients who are fertile, agree to use a highly effective form of contraception with their sexual partners during the dosing period and for a period of at least 120 days after the end of treatment with either study brigatinib or alectinib.
    16. Female patients who are postmenopausal for at least 1 year before the screening visit, or are surgically sterile, or if they are of childbearing potential, agree to practice:
    a) One highly effective method of contraception, and
    b) One additional effective (barrier) method at the same time, from the time of signing the informed consent through 1 month (whichever is longer) after the last dose of study drug, or
    c) Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
    17. Male patients, even if surgically sterilized (ie, status postvasectomy), who:
    a) Agree to practice effective barrier contraception during the entire study treatment period and through 120 days (or if the drug has a very long half-life, for 90 days plus five half lives) after the last dose of study drug, or
    b) Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
    c) Do not donate semen or sperm during treatment and for 90 days after the last dose of study therapy.
    18. Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
    (Note: Given that, globally, the patient population who has received crizotinib as the sole ALK inhibitor is decreasing, Takeda reserves the right to amend the inclusion criteria to include crizotinib intolerant patients and/or patients who have progressed on or been found intolerant to ALK inhibitors other than crizotinib, brigatinib, or alectinib.)
    1. Patients adultes âgés de 18 ans et plus.
    2. Avoir un score ECOG de 0 à 2;
    3. Présenter un CPNPC de stade IIIB (localement avancé ou récurrent) ou IV confirmé par examen histologique ou cytologique.
    3. Remplir l’un des critères suivants :
    a) Documentation prouvant le réarrangement de l'ALK par un résultat positif au kit d’hybridation in situ en fluorescence (FISH) Vysis avec sonde de séparation (Break-Apart) ou au dosage Ventana ALK (D5F3) CDx, ou encore FoundationOne CDx de Foundation Medicine.
    b) Documentation du réarrangement ALK par un test différent et capacité à fournir un échantillon tumoral au laboratoire central. (Remarque : il n’est pas obligatoire d’obtenir les résultats des tests de réarrangement ALK du laboratoire central avant la randomisation.)
    5. Avoir connu une progression de la maladie sous crizotinib, évaluée par l’investigateur ou le médecin traitant. (Remarque : le crizotinib ne sera pas obligatoirement le dernier traitement reçu par le patient. Le patient peut avoir reçu une chimiothérapie comme dernier traitement anticancéreux systémique.)
    6. Traitement par crizotinib pendant au moins 4 semaines avant la progression.
    7. N’avoir reçu aucun autre inhibiteur d’ALK que le crizotinib.
    8. N’avoir pas reçu plus de 2 schémas thérapeutiques anticancéreux systémiques antérieurs, pour le cancer localement avancé ou métastatique.
    9. Au moins une lésion mesurable (c’est-à-dire cible), selon les critères RECIST v1.1.
    10. S’être rétabli(e) de toxicités liées au traitement anticancéreux antérieur avec un retour à un grade ≤ 1 selon les critères communs de terminologie pour les événements indésirables version 4.03 du National Cancer Institute (NCI CTCAE). (Remarque : l’alopécie liée au traitement ou la neuropathie périphérique de grade > 1 sont autorisées si elles sont jugées irréversibles.)
    11. Fonction adéquate des organes, déterminée par :
    a) Bilirubine totale 1,5 fois la limite supérieure de la normale (LSN).
    b) Débit de filtration glomérulaire estimé ≥ 30 ml/min/1,73 m2, en utilisant la modification de régime pour l'équation de maladie rénale.
    c) Une alanine aminotransférase/aspartate aminotransférase ≤ 2,5 × LSN ; ≤ 5 × LSN est acceptable en cas de métastases hépatiques.
    d) Lipase sérique ≤ 1,5 × LSN.
    e) Numération plaquettaire ≥ 75 × 109/l.
    f) Hémoglobine ≥ 9 g/dl.
    g) Numération absolue de neutrophiles ≥ 1,5 x 109/l.
    12. Accès veineux adéquat pour les prélèvements sanguins nécessaires pendant l’étude (c’est-à-dire, y compriscomprenant les analyses de PK et analyses biologiques de sécurité).
    13. Volonté et capacité de respecter le calendrier des visites et des procédures de l’étude.
    14. Pour les femmes en âge de procréer, test de grossesse négatif documenté avant la randomisation.
    15. Pour les patients fertiles, hommes et femmes, accepter d’utiliser un moyen de contraception très efficace avec leurs partenaires sexuels pendant la période d’administration et pendant une durée d’au moins 120 jours après la fin du traitement par brigatinib ou alectinib.
    16. Les patientes qui sont ménopausées depuis au moins un an avant la visite de sélection, ou qui sont chirurgicalement stériles ou qui sont en âge de procréer, acceptent d'utiliser:
    a) Une méthode très efficace de contraception, et
    b) Une autre méthode efficace (barrière) en même temps, à partir de la signature du consentement éclairé jusqu'à 1 mois (selon la période la plus longue) après la dernière dose du médicament à l'étude, ou
    c) Accepter de pratiquer une véritable abstinence, si cela correspond au mode de vie préféré et habituel de la patiente. Les préservatifs féminins et masculins ne doivent pas être utilisés ensemble.)
    17. Patients de sexe masculin, même s'ils sont stérilisés chirurgicalement, doivent:
    a) Accepter de pratiquer une contraception de barrière efficace pendant toute la durée du traitement à l'étude et pendant 120 jours (ou si le médicament a une demi-vie très longue, pendant 90 jours plus cinq demi-vies) après la dernière dose du médicament à l'étude, ou
    b) Accepter une véritable abstinence,si cela correspond au mode de vie préféré et habituel du sujet. Les préservatifs féminins et masculins ne doivent pas être utilisés ensemble.)
    c) De ne pas donner de sperme pendant le traitement et pendant les 90 jours qui suivent la dernière dose du traitement à l'étude.
    18. Le consentement écrit volontaire doit être donné avant l'exécution de toute procédure liée à l'étude ne faisant pas partie des soins médicaux standard, étant entendu que le consentement peut être retiré par le patient à tout moment, sans préjudice des soins médicaux futurs.
    (Note: Étant donné que globalement, la population de patients ayant reçu le crizotinib comme seul inhibiteur de l'ALK est en baisse, Takeda se réserve le droit de modifier les critères d'inclusion pour inclure les patients intolérants au crizotinib et / ou les patients intolérants au Inhibiteurs de l'ALK autres que le crizotinib, le brigatinib ou l'alectinib.)
    E.4Principal exclusion criteria
    1. Participation in the control (crizotinib) arm of Study AP26113-13-301 (ALTA 1L).
    2. Received crizotinib within 7 days of randomization.
    3. Have a history or presence at baseline of pulmonary interstitial disease, drug-related pneumonitis, or radiation pneumonitis.
    4. Have uncontrolled hypertension. Patients with hypertension should be under treatment for control of blood pressure upon study entry.
    5. Received systemic treatment with strong cytochrome P-450 (CYP) 3A inhibitors, strong CYP3A inducers, or moderate CYP3A inducers within 14 days before randomization.
    6. Treatment with any investigational systemic anticancer agents within 14 days or 5 half-lives, whichever is longer, before randomization.
    7. Received chemotherapy or radiation therapy within 14 days of randomization except for stereotactic radiosurgery (SRS) or stereotactic body radiation therapy.
    8. Received antineoplastic monoclonal antibodies within 30 days of randomization.
    9. Had major surgery within 30 days of randomization. Minor surgical procedures, such as catheter placement or minimally invasive biopsies, are allowed.
    10. Have symptomatic CNS metastases (parenchymal or leptomeningeal) at screening (patients with asymptomatic brain metastases or patients who have stable symptoms and did not require an increased dose of corticosteroids to control symptoms within 7 days before randomization will be enrolled). Note: If a patient has worsening neurological symptoms or signs due to CNS metastasis, the patient needs to complete local therapy and be neurologically stable (with no requirement for an increasing dose of corticosteroids or use of anticonvulsants) for 7 days before randomization.
    11. Have current spinal cord compression (symptomatic or asymptomatic and detected by radiographic imaging). Patients with leptomeningeal disease and without cord compression are allowed.
    12. Have significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to the following:
    a) Myocardial infarction within 6 months before randomization.
    b) Unstable angina within 6 months before randomization.
    c) New York Heart Association Class III or IV heart failure within 6 months before randomization.
    d) History of clinically significant atrial arrhythmia (including clinically significant bradyarrhythmia), as determined by the treating physician.
    e) Any history of clinically significant ventricular arrhythmia.
    13. Had cerebrovascular accident or transient ischemic attack within 6 months before first dose of study drug.
    14. Have malabsorption syndrome or other gastrointestinal illness or condition that could affect oral absorption of the study drug.
    15. Have an ongoing or active infection, including but not limited to, the requirement for intravenous antibiotics.
    16. Have a known history of HIV infection. Testing is not required in the absence of history.
    17. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection.
    18. Any serious medical condition or psychiatric illness that could, in the investigator’s opinion, potentially compromise patient safety or interfere with the completion of treatment according to this protocol.
    19. Have a known or suspected hypersensitivity to brigatinib or alectinib or their excipients.
    20. Life-threatening illness unrelated to cancer.
    21. Female patients who are lactating and breastfeeding.
    22. Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.
    1. Participation au bras témoin (crizotinib) de l’étude AP26113-13-301 (ALTA 1L).
    2. Avoir reçu du crizotinib dans les 7 jours précédant la randomisation.
    3. Antécédents ou présence à la visite de référence de maladie pulmonaire interstitielle, de pneumopathie d’origine iatrogène ou radique.
    4. Hypertension non contrôlée. Les patients hypertendus doivent être sous traitement pour contrôler l’hypertension lors de l’admission à l’étude.
    5. Traitement antérieur par inhibiteurs puissants du cytochrome P-450 (CYP) 3A, inducteurs puissants ou modérés du CYP3A au cours des 14 jours précédant la randomisation.
    6. Traitement par agent anticancéreux systémique expérimental au cours des 14 jours, ou des 5 demi-vies, la durée la plus longue prévalant, précédant la randomisation.
    7. Traitement par chimiothérapie ou radiothérapie au cours des 14 jours précédant la randomisation, sauf radiochirurgie stéréotaxique ou radiothérapie stéréotaxique du corps entier.
    8. Traitement par anticorps monoclonaux antinéoplasiques au cours des 30 jours précédant la randomisation.
    9. Intervention chirurgicale majeure dans les 30 jours précédant la randomisation. Les interventions chirurgicales mineures, telles que la pose d’un cathéter ou les biopsies peu invasives, sont autorisées.
    10. Métastases symptomatiques du SNC (métastases parenchymateuses ou leptoméningées) à la visite de sélection (les patients avec des métastases cérébrales asymptomatiques ou qui ont des symptômes stables ne nécessitant pas une augmentation de dose des corticoïdes pour contrôler les symptômes au cours des 7 jours précédant la randomisation seront inclus).
    Remarque : si un patient a des symptômes neurologiques qui s’aggravent ou des signes dus aux métastases du SNC, le patient doit achever un traitement local et être stable au plan neurologique [pas besoin d’augmenter la dose de corticoïdes ou d’utiliser des anticonvulsivants] pendant les 7 jours précédant la randomisation.
    11. Compression de la moelle épinière en cours (symptomatique ou asymptomatique et décelée par radiographie). Les patients ayant une atteinte leptoméningée mais pas de compression de la moelle épinière sont autorisés dans l’étude.
    12. Présence de pathologie cardiovasculaire significative, non contrôlée, ou active, en particulier mais non limité à:
    a) Infarctus du myocarde dans les 6 mois précédant la randomisation.
    b) Angor instable dans les 6 mois précédant la randomisation.
    c) Insuffisance cardiaque de classe III ou IV selon les critères de la New York Heart Association, dans les 6 mois précédant la randomisation.
    d) Antécédents d’arythmies auriculaires cliniquement significatives (notamment bradycardie cliniquement significative), déterminées par le médecin traitant.
    e) Antécédents d’arythmies ventriculaires cliniquement significatives.
    13. Antécédent d’accident vasculaire cérébral ou d’accident ischémique transitoire dans les 6 mois précédant la première dose du médicament à l’étude.
    14. Syndrome de malabsorption ou autre pathologie ou affection gastro-intestinale qui pourrait gêner l’absorption orale du médicament à l’étude.
    15. Infection en cours ou active, notamment mais non limité à celles nécessitant des antibiotiques par voie intraveineuse.
    16. Antécédent connu d’infection au VIH. Le dépistage n’est pas obligatoire en l’absence d’antécédent.
    17. Positivité connue à l’antigène de surface du virus de l’hépatite B, ou infection active connue ou suspectée par l’hépatite C.
    18. Toute affection médicale ou psychiatrique grave qui pourrait, de l’avis de l’investigateur, potentiellement compromettre la sécurité du patient ou perturber la réalisation du traitement conformément à ce protocole.
    19. Hypersensibilité connue ou suspectée au brigatinib, à l’alectinib ou à leurs excipients.
    20. Maladie engageant le pronostic vital sans lien avec le cancer.
    21. Femmes allaitantes.
    22. Admission ou preuve d'usage de drogues illicites, d'abus de drogues ou d'abus d'alcool.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is progression free survival (PFS) as assessed by the blinded Independent Review Committee (BIRC) per RECIST v1.1.
    Le critère d’évaluation principal est la SSP, telle qu’évaluée par le BIRC (comité indépendant d’examen en aveugle), selon les critères RECIST v1.1.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Time interval from the date of randomization until the first date at which disease progression is objectively documented by RECIST, or death due to any cause.
    The interim analysis will be preformed after the first 115 events have been observed; the final analysis will be preformed after 164 events have been observed
    Intervalle de temps entre la date de la randomisation et la première date à laquelle la progression de la maladie est objectivement documentée par RECIST, ou le décès dû à une cause quelconque.
    L'analyse intermédiaire sera effectuée après que les 115 premiers événements auront été observés; l'analyse finale sera effectuée après que 164 événements aient été observés
    E.5.2Secondary end point(s)
    Key Secondary Endpoints:
    1. Intracranial Progression Free Survival (iPFS), as assessed by the BIRC per modified RECIST v1.1.
    2. Overall survival (OS).
    Other Secondary Endpoints:
    1. ORR, as assessed by the investigator and BIRC per RECIST v1.1.
    2. Time to response, as assessed by the investigator and BIRC.
    3. DOR, as assessed by the investigator and BIRC.
    4. iORR, as assessed by BIRC per modified RECIST v1.1 (as described in protocol and BIRC charter).
    5. iDOR, as assessed by the BIRC per modified RECIST v1.1.
    6. HRQoL assessed with the global health status/quality of life and other function and symptom domains from EORTC QLQ-C30 (v3.0) and EORTC QLQ-LC13.
    1. TRO évalué par l’investigateur et le BIRC, selon les critères RECIST version 1.1.
    2. Survie globale (SG)

    Autres critères secondaires :
    1. TRO évalué par l’investigateur et le BIRC, selon les critères RECIST version 1.1.
    2. Temps jusqu’à la réponse, évalué par l’investigateur et le BIRC.
    3. DDR évaluée par l’investigateur et le BIRC.
    4. TROi, évalué par le BIRC selon les critères RECIST modifiés v1.1 (comme décrit dans le protocole et la charte du BIRC).
    5. DDRi, évaluée par le BIRC selon les critères RECIST modifiés v1.1.
    6. QdVs évaluée d’après l’état de santé général/qualité de vie et d’autres domaines de fonctions et symptômes par les questionnaires EORTC QLQ-C30 (v3.0) et EORTC QLQ-LC13.
    E.5.2.1Timepoint(s) of evaluation of this end point
    For the key secondary endpoints formal statistical tests will be performed only once, when PFS per BIRC is statistically significant.
    Pour les principaux critères secondaires, les tests statistiques formels ne seront effectués qu'une seule fois, lorsque la survie sans progression par BIRC est statistiquement significative.
    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 Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned13
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA56
    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
    Argentina
    Austria
    Brazil
    Canada
    Chile
    China
    France
    Germany
    Greece
    Hong Kong
    Hungary
    Italy
    Korea, Republic of
    Mexico
    Romania
    Russian Federation
    Spain
    Sweden
    Taiwan
    Thailand
    United States
    E.8.7Trial has a data monitoring committee Yes
    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
    Last patient Last visit (LVLS)
    La dernière visite du dernier patient
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days17
    E.8.9.2In all countries concerned by the trial years5
    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: 166
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 80
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 115
    F.4.2.2In the whole clinical trial 246
    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)
    Subjects can continue treatment with the study drug at the doctor's discretion after the disease progression if they are still benefiting from it as determined by the investigator and after signing the new ICF.
    A la discrétion du médecin, les patients peuvent poursuivre le traitement avec le médicament à l'étude après la progression de la maladie s'ils peuvent en tirer bénéfice de l'avis de l'investigateur et après avoir signé un nouveau consentement éclairé.
    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 Decision2018-09-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-12-13
    P. End of Trial
    P.End of Trial StatusOngoing
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