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    Summary
    EudraCT Number:2019-002013-20
    Sponsor's Protocol Code Number:ALKS4230-001
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-01-15
    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 number2019-002013-20
    A.3Full title of the trial
    A Phase 1/2 Study of ALKS 4230 Administered Subcutaneously
    as Monotherapy and in Combination With Pembrolizumab in
    Subjects With Advanced Solid Tumors
    (ARTISTRY-2)
    Étude de phase 1/2 sur l’ALKS 4230 administré par voie sous-cutanée en monothérapie et en association avec le pembrolizumab à des sujets présentant des tumeurs solides à un état avancé - ARTISTRY-2 (001)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 1/2 Study of ALKS 4230 Administered Subcutaneously
    as Monotherapy and in Combination With Pembrolizumab in
    Subjects With Advanced Solid Tumors
    (ARTISTRY-2)
    Étude de phase 1/2 sur l’ALKS 4230 administré par voie sous-cutanée en monothérapie et en association avec le pembrolizumab à des sujets présentant des tumeurs solides à un état avancé - ARTISTRY-2 (001)
    A.3.2Name or abbreviated title of the trial where available
    ARTISTRY-2
    A.4.1Sponsor's protocol code numberALKS4230-001
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03861793
    A.5.4Other Identifiers
    Name:INDNumber:128,159
    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 SponsorAlkermes, Inc.
    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 supportAlkermes, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSyneos Health
    B.5.2Functional name of contact pointMelanie Owen
    B.5.3 Address:
    B.5.3.1Street Address4277 Cider Mill Dr.
    B.5.3.2Town/ cityCincinnati
    B.5.3.3Post codeOhio 45245
    B.5.3.4CountryUnited States
    B.5.4Telephone number1513763 1937
    B.5.6E-mailmelanie.owen@syneoshealth.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.3.2Product code ALKS 4230
    D.3.4Pharmaceutical form Lyophilisate for suspension for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNALKS 4230
    D.3.9.2Current sponsor codeALKS 4230
    D.3.9.3Other descriptive nameALKS 4230
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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.3.2Product code ALKS 4230
    D.3.4Pharmaceutical form Lyophilisate for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNALKS 4230
    D.3.9.2Current sponsor codeALKS 4230
    D.3.9.3Other descriptive nameALKS 4230
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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.3.2Product code ALKS 4230
    D.3.4Pharmaceutical form Lyophilisate for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNALKS 4230
    D.3.9.2Current sponsor codeALKS 4230
    D.3.9.3Other descriptive nameALKS 4230
    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 No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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 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 Keytruda
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme B.V.
    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 namepembrolizumab
    D.3.4Pharmaceutical form Concentrate and solvent for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPEMBROLIZUMAB
    D.3.9.3Other descriptive nameKeytruda
    D.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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 No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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
    Advanced Solid Tumors
    Tumeurs solides à stade avancé
    E.1.1.1Medical condition in easily understood language
    Advanced Solid Tumors
    Tumeurs solides à stade avancé
    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.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10041067
    E.1.2Term Small cell lung cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10073071
    E.1.2Term Hepatocellular carcinoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10060121
    E.1.2Term Squamous cell carcinoma of head and neck
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10041823
    E.1.2Term Squamous cell carcinoma
    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 characterize the safety and tolerability and to identify the recommended Phase 2 dose (RP2D) of ALKS 4230 administered subcutaneously (SC) as lead-in monotherapy and in combination with pembrolizumab in subjects with advanced solid tumors (Phase 1)
    - To characterize the safety profile of SC ALKS 4230 at the RP2D in combination with pembrolizumab in subjects with advanced solid tumors (Phase 2)
    - To estimate the clinical activity of combination treatment with ALKS 4230 and pembrolizumab in terms of objective response rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) guidelines version 1.1 separately for non–small-cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), squamous tumor agnostic, hepatocellular carcinoma (HCC), and small-cell lung cancer (SCLC) (Phase 2)
    - Caractériser l’innocuité et la tolérabilité et identifier la dose recommandée en phase 2 (RP2D) d’ALKS 4230 administré par voie sous-cutanée (SC) en monothérapie et en association avec le pembrolizumab à des sujets présentant des tumeurs solides à un état avancé (Phase 1)
    - Caractériser le profil d’innocuité de l’ALKS 4230 sous-cutané à la dose RP2D administrée en association avec le pembrolizumab à des sujets atteints de tumeurs solides à l’état avancé (phase 2)
    - Évaluer l’activité clinique du traitement associant l’ALKS 4230 et le pembrolizumab en termes de taux de réponse objective (ORR) évalué selon les directives RECIST critères d’évaluation de la réponse dans les tumeurs solides, version 1.1 séparément pour le cancer du poumon non à petites cellules (CPNPC), le carcinome épidermoïde de la tête et du cou (CETC), les tumeurs épidermoïdes agnostiques, le carcinome hépatocellulaire (CHC) et le cancer du poumon à petites cellules (CPPC) (Phase 2)
    E.2.2Secondary objectives of the trial
    - To describe dose-limiting toxicity (DLT) for SC ALKS 4230 lead-in monotherapy (Phase 1)
    - To characterize the pharmacokinetics (PK), clinical pharmacodynamics (PD), and immunogenicity of SC ALKS 4230 as lead-in monotherapy (Phase 1) and in combination with pembrolizumab (Phase 1 and Phase 2)
    - To describe antitumor activity observed with SC ALKS 4230 as lead-in monotherapy and in combination with pembrolizumab (Phase 1)
    - To evaluate antitumor efficacy in subjects treated with SC ALKS 4230 in combination with pembrolizumab (Phase 2)
    - Décrire la toxicité limitant la dose (TLD) de la monothérapie introductive de l’ALKS 4230 sous-cutané (Phase 1)
    - Caractériser la pharmacocinétique (PK), la pharmacodynamique clinique (PD) et l’immunogénicité de l’ALKS 4230 sous-cutané en monothérapie introductive (Phase 1) et en association avec le pembrolizumab (Phase 1 et Phase 2)
    - Décrire l’activité antitumorale observée avec l’ALKS 4230 sous-cutané en monothérapie et en association avec le pembrolizumab (Phase 1)
    - Évaluer l’efficacité antitumorale chez les sujets traités avec l’ALKS 4230 sous-cutané en association avec le pembrolizumab (Phase 2)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Eligible subjects must be aged ≥18 years.
    - For Phase 1, subjects must have an advanced solid tumor (including lymphoma) and progressive disease following at least 1 line of therapy.
    - For Phase 2, subjects will be enrolled into 1 of 5 cohorts based on the subject’s tumor type and specific histology: NSCLC, SCCHN , squamous tumor agnostic, HCC, and SCLC.
    - All study subjects in Phase 1 and Phase 2 must have measurable disease based on RECIST and an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1. Subjects must have adequate hematologic reserves and adequate hepatic and renal function.
    - Les sujets admissibles doivent être âgés de ≥ 18 ans.
    - Pour participer à la phase 1, les sujets doivent présenter une tumeur solide à un état avancé (notamment un lymphome) et une maladie évolutive après au moins une ligne de traitement.
    - Pour participer à la phase 2, les sujets seront inclus dans l’une des cinq cohortes en fonction de leur type de tumeur et de leur histologie spécifique : CPNPC, CETC, tumeurs épidermoïdes agnostiques, CHC et CPPC.
    - Tous les sujets participant à l’étude des phases 1 et 2 doivent être atteints d’une maladie mesurable selon les critères RECIST et un score d’état général de l’Eastern Cooperative Oncology Group (ECOG PS) égal à 0 ou 1. Les sujets doivent présenter des réserves hématologiques suffisantes et une fonction hépatique et rénale adéquate.
    E.4Principal exclusion criteria
    1. Subject is currently pregnant or breastfeeding or is planning to become pregnant during the study period.
    2. Subject is employed by Alkermes, Syneos Health, the Investigator, the study center (including permanent or temporary contact workers and designees responsible for the conduct of the study), or other affiliate of this study or is immediate family of an employee of Alkermes, Syneos Health, the Investigator, the study center, or other affiliate. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
    3. Subject has an active infection or a fever ≥38.5°C (≥101°F) within 3 days of the first scheduled day of dosing for the monotherapy lead-in or Cycle 1 of Phase 2.
    4. Subject has known hypersensitivity (Grade ≥3) to any components of ALKS 4230, to pembrolizumab, or any of its excipients.
    5. Subjects with mean QT interval corrected by the Fridericia Correction Formula values of >470 msec (in females) or >450 msec (in males) following a standard 12-lead electrocardiogram (ECG); subjects who are known to have congenital prolonged QT syndromes; or subjects who are on medications known to cause prolonged QT interval on ECG.
    6. Subject has developed autoimmune disorders while on prior immunotherapy, including pneumonitis, nephritis, and neuropathy. Subject was discontinued from prior treatment with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX40, or CD137) due to a Grade 3 or higher immune-related AE.
    Subjects who developed other autoimmune disorders of Grade ≤3 may enroll if the disorder has resolved and the subject is off steroids for 2 weeks. Subjects who experienced autoimmune colitis as a toxicity of prior immunotherapy must undergo or must have been evaluated by colonoscopy to rule out ongoing inflammation.
    7. Subjects must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis.
    8. Subject has active or symptomatic central nervous system metastases unless the metastases have been treated by surgery and/or radiation therapy, the subject has been dose, and the subject is neurologically stable.
    9. Subject has an active autoimmune disease that has required systemic treatment in the past 2 years (ie, with the use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
    10. Subject is known to be positive for human immunodeficiency virus and/or history of hepatitis B, or C infections or is known to be positive for hepatitis B antigen (HBsAg)/hepatitis B virus (HBV) DNA or hepatitis C antibody (Hep C Ab) or RNA.
    1. La personne actuellement enceinte ou qui allaite ou prévoit de devenir enceinte pendant la période de l'étude.
    2. Le sujet est employé par Alkermes, Syneos Health, l'investigateur, le centre d’étude (y compris les agents permanents ou temporaires et les représentants chargés de la conduite de l’étude), ou autre affiliés à cette étude, ou les membres de la famille immédiate d’un employé d’Alkermes, Syneos Health, l'investigateur, le centre d’étude ou tout autre affiliation. La famille immédiate est définie comme un conjoint, un parent, un enfant ou un frère ou une soeur, biologique ou légalement adopté.
    3. Le sujet a une infection active ou une fièvre ≥ 38,5 ° C (≥ 101 ° F) dans les 3 jours suivant le premier jour de traitement prévu pour la monothérapie ou le cycle 1 de la phase 2.
    4. Le sujet présente une hypersensibilité connue (grade ≥3) à l'un des composants de ALKS 4230, au pembrolizumab ou à l'un de ses excipients.
    5. Sujets avec intervalle QT moyen corrigé par les valeurs de la formule de correction de Fridericia supérieures à 470 ms (chez les femmes) ou> 450 ms (chez les hommes) à la suite d'un électrocardiogramme standard à 12 dérivations (ECG); les sujets qui sont connus pour avoir des syndromes QT prolongés congénitaux; ou les sujets qui prennent des médicaments connus pour causer un intervalle QT prolongé sur l’ECG.
    6. Le sujet a développé des troubles auto-immuns lors d'une immunothérapie antérieure, notamment une pneumonite, une néphrite et une neuropathie. Le sujet a du interrompre un traitement antérieur par un agent anti-PD-1, anti-PD-L1 ou anti-PD-L2 ou par un agent dirigé contre un autre récepteur des cellules T stimulant ou co-inhibiteur (par exemple, CTLA-4, OX40 ou CD137) en raison d'un EI lié au système immunitaire de grade 3 ou supérieur.
    Les sujets qui ont développé d'autres troubles auto-immuns de grade ≤ 3 peuvent participer si le trouble est résolu et que le sujet n'a pas de stéroïdes pendant 2 semaines. Les sujets ayant présenté une colite auto-immune en tant que toxicité d'une immunothérapie antérieure doivent subir ou doivent avoir été évalués par coloscopie pour exclure une inflammation en cours.
    7. Les sujets doivent avoir récupéré de toutes les toxicités liées aux radiations, ne pas avoir besoin de corticostéroïdes et ne pas avoir eu de pneumonite par radiation.
    8. Le sujet a des métastases actives ou symptomatiques du système nerveux central, à moins que les métastases n'aient été traitées par une intervention chirurgicale et / ou une radiothérapie, une dose administrée et que le sujet soit neurologiquement stable.
    9. Le sujet a une maladie auto-immune active qui a nécessité un traitement systémique au cours des 2 dernières années (c'est-à-dire avec l'utilisation d'agents modificateurs de la maladie, de corticostéroïdes ou de médicaments immunosuppresseurs). Le traitement substitutif (par exemple, la thyroxine, l'insuline ou le traitement physiologique de remplacement des corticostéroïdes en cas d'insuffisance surrénalienne ou hypophysaire) n'est pas considéré comme une forme de traitement systémique et est autorisé.
    10. Le sujet est connu pour être infecté par le virus de l’immunodéficience humaine et / ou par des antécédents d’hépatite B ou C ou par l’antigène de l’hépatite B (AgHBs) / du virus de l’hépatite B (VHB) ou par un anticorps anti-hépatite C (Hep C Ab) ou ARN.
    E.5 End points
    E.5.1Primary end point(s)
    - The incidence and severity of treatment-emergent AEs (Phase 1 and Phase 2)
    - ORR based on RECIST 1.1 (Phase 2)
    - Incidence et gravité des événements indésirables (EI) apparus sous traitement (Phase 1 et Phase 2)
    - ORR basé sur les critères RECIST 1.1 (Phase 2)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Treatment-emergent AEs will be evaluated during every visit at the clinic.

    Antitumor activity will be determined by the measurement of extent of
    known disease at baseline and approximately every 9 weeks. After Cycle 10, this should be reduced to every 12 weeks.
    Les événements indésirables (EI) apparus sous traitement seront évalués lors de chaque visite à la clinique.

    L'activité antitumorale sera déterminée par la mesure de l'étendue de
    maladie connue au départ et toutes les 9 semaines environ. Après le cycle 10, il devrait être réduit à toutes les 12 semaines.
    E.5.2Secondary end point(s)
    - The incidence of DLTs from the first dose through the end of the DLT observation period (Phase 1)
    - Serum concentrations of ALKS 4230 and descriptive PK parameters using noncompartmental analysis (Phase 1)
    - Detection of presence of anti-ALKS 4230 antibodies in serum (Phase 1)
    - Numbers of circulating cluster of differentiation (CD)8 T cells, T regulatory cells (Tregs), and natural killer cells in peripheral blood (Phase 1)
    - Serum levels of interleukin-6 and other cytokines (Phase 1)
    - ORR, Disease Control Rate (DCR), Duration of Response (DOR), Time to Response (TTR),and Progression-free Survival (PFS) per RECIST 1.1 (Phase 1)
    - Immune ORR (iORR), immune DCR (iDCR), immune DOR (iDOR), immune TTR (iTTR), and immune PFS (iPFS) per Immune RECIST (iRECIST) (Phase 1)
    - DCR, DOR, TTR, and PFS, per RECIST 1.1 (Phase 2)
    - iORR, iDCR, iDOR, iTTR, and iPFS, per iRECIST (Phase 2)
    - Overall Survival (OS) (Phase 2)
    - Incidence des toxicités limitant la dose (TLD), de la première dose à la fin de la période d’observation des TLD (Phase 1)
    - Concentrations sériques d’ALKS 4230 et paramètres pharmacocinétiques descriptifs par analyse non compartimentale (Phase 1)
    - Détection de la présence d’anticorps anti-ALKS 4230 dans le sérum (Phase 1)
    - Nombre de cellules T en circulation du marqueur de différenciation (CD)8, de cellules T régulatrices (Tregs) et de cellules tueuses naturelles dans le sang périphérique (Phase 1)
    - Taux sériques d’interleukine-6 et autres cytokines (Phase 1)
    - ORR, taux de contrôle de la maladie (DCR), durée de la réponse (DOR), délai avant réponse (TTR) et survie sans progression (PFS) selon les critères RECIST 1.1 (Phase 1)
    - ORR immun (iORR), DCR immun (iDCR), DOR immun (iDOR), TTR immun (iTTR) et PFS immun (iPFS) selon les critères RECIST immun (iRECIST) (Phase 1)
    - DCR, DOR, TTR et PFS selon les critères RECIST 1.1 (Phase 2)
    - iORR, iDCR, iDOR, iTTR et iPFS selon les critères iRECIST (Phase 2)
    - Survie globale (OS) (Phase 2)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Serum samples for evaluation of ALKS 4230 PK and patient immunogenicity will be obtained from each subject at predetermined time points.

    Antitumor activity will be determined by the measurement of extent of
    known disease at baseline and approximately every 9 weeks. After Cycle 10, this should be reduced to every 12 weeks.
    Des échantillons de sérum pour l'évaluation de ALKS 4230 PK et l'immunogénicité du patient seront obtenus de chaque sujet à des moments prédéterminés.

    L'activité antitumorale sera déterminée par la mesure de l'étendue de
    maladie connue au départ et toutes les 9 semaines environ. Après le cycle 10, il devrait être réduit à toutes les 12 semaines.
    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 Yes
    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
    Immunogenicity
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    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 Yes
    E.8.1.7.1Other trial design description
    sequential groups
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA21
    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
    France
    Germany
    Korea, Republic of
    Netherlands
    Spain
    Taiwan
    United Kingdom
    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 years5
    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 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: 180
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 77
    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 state14
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 73
    F.4.2.2In the whole clinical trial 257
    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)
    None. Once a patient has completed study treatment, their treating physician can discuss standard of care or other alternative options available to them.
    Aucun. Une fois qu'un patient a terminé son traitement à l'étude, son médecin traitant peut discuter du traitement standard ou des autres options possibles.
    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 Decision2020-03-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-12-11
    P. End of Trial
    P.End of Trial StatusCompleted
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