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    Summary
    EudraCT Number:2018-002551-15
    Sponsor's Protocol Code Number:8951-CL-5201
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-11-23
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2018-002551-15
    A.3Full title of the trial
    A Phase 2, Open-Label, Randomized Study to Assess the Antitumor Activity and Safety of Zolbetuximab (IMAB362) in Combination with Nab-Paclitaxel and Gemcitabine (Nab-P + GEM) as First Line Treatment in Subjects with Claudin 18.2 (CLDN18.2) Positive, Metastatic Pancreatic Adenocarcinoma
    Estudio en fase II, aleatorizado y abierto para evaluar la actividad antitumoral y la seguridad de zolbetuximab (IMAB362) en combinación con nab paclitaxel y gemcitabina (Nab-P + GEM) como tratamiento de primera línea en pacientes con adenocarcinoma de páncreas metastásico con presencia de claudina-18.2 (CLDN18.2)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial to evaluate a new medicine (Zolbetuximab) for the treatment of pancreatic cancer
    Un ensayo clínico para evaluar un nuevo medicamento (Zolbetuximab) para el tratamiento del cancer pancreatico.
    A.4.1Sponsor's protocol code number8951-CL-5201
    A.5.4Other Identifiers
    Name:INDNumber:129598
    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 SponsorAstellas Pharma Global Development, Inc. (APGD)
    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 supportAstellas Pharma Global Development, Inc. (APGD)
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstellas Pharma Europe B.V.
    B.5.2Functional name of contact pointService Desk - Global Clinical Dev.
    B.5.3 Address:
    B.5.3.1Street AddressSylviusweg 62
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333 BE
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31715455878
    B.5.5Fax number+31715455224
    B.5.6E-mailcontacts@nl.astellas.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/13/1177
    D.3 Description of the IMP
    D.3.1Product nameZolbetuximab
    D.3.2Product code IMAB362
    D.3.4Pharmaceutical form Powder for concentrate 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 INNZolbetuximab
    D.3.9.1CAS number 1496553-00-4
    D.3.9.2Current sponsor codeIMAB362
    D.3.9.3Other descriptive nameIMAB362
    D.3.9.4EV Substance CodeSUB190351
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number105
    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 Yes
    D.3.11.13.1Other medicinal product typeMonoclonal Antibody
    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 Yes
    D.2.1.1.1Trade name N/A
    D.2.1.1.2Name of the Marketing Authorisation holderN/A
    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 nameNab-Paclitaxel
    D.3.4Pharmaceutical form Powder 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 INNPACLITAXEL
    D.3.9.1CAS number 33069-62-4
    D.3.9.4EV Substance CodeSUB09583MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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 Yes
    D.3.11.13.1Other medicinal product typeThe IMP contains an excipient of biological origin, albumin, a non-active stabilizing agent. It is derived from human blood subject to approved donor screening and product manufacturing processes
    D.IMP: 3
    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 N/A
    D.2.1.1.2Name of the Marketing Authorisation holderN/A
    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 namegemcitabine
    D.3.4Pharmaceutical form Powder 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 INNGEMCITABINE
    D.3.9.1CAS number 95058-81-4
    D.3.9.4EV Substance CodeSUB07892MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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
    First Line Treatment in Subjects with Claudin 18.2 (CLDN18.2) Positive, Metastatic Pancreatic Adenocarcinoma
    Tratamiento de primera línea en pacientes con adenocarcinoma de páncreas metastásico con presencia de claudina-18.2 (CLDN18.2)
    E.1.1.1Medical condition in easily understood language
    Pancreatic cancer
    Cáncer de páncreas.
    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 LLT
    E.1.2Classification code 10033599
    E.1.2Term Pancreatic adenocarcinoma metastatic
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    -To confirm the recommended phase 2 dose (RP2D) of zolbetuximab in combination with Nab-P + GEM for subjects with CLDN18.2 positive, metastatic pancreatic adenocarcinoma (Safety Lead-in Phase)
    -To determine antitumor activity of zolbetuximab measured by the OS in combination with Nab-P + GEM for subjects with CLDN18.2 positive, metastatic pancreatic adenocarcinoma (Randomization Phase)
    -To assess the safety and tolerability of zolbetuximab in combination with Nab-P + GEM
    -Confirmar la dosis recomendada para la fase II (DRF2) de zolbetuximab en combinación con Nab-P + GEM en pacientes con adenocarcinoma de páncreas metastásico con presencia de CLDN18.2 (fase de preinclusión de seguridad).
    -Determinar la actividad antitumoral de zolbetuximab, medida a partir de la supervivencia global (SG), en combinación con Nab-P + GEM en pacientes con adenocarcinoma de páncreas metastásico con presencia de CLDN18.2 (fase de aleatorización).
    -Evaluar la seguridad y la tolerabilidad de zolbetuximab en combinación con Nab-P + GEM.
    E.2.2Secondary objectives of the trial
    Key Secondary:
    ● To evaluate additional antitumor activities of zolbetuximab in combination with Nab-P + GEM measured by PFS and ORR (Randomization Phase)
    Secondary:
    ● To evaluate pharmacokinetics of Nab-P + GEM in combination with zolbetuximab (Randomization Phase)
    ● To evaluate additional antitumor activities measured by disease control
    rate (DCR) and duration of response (DOR) (Randomization Phase)
    ● To evaluate the change in serum CA19-9 (Randomization Phase)
    ● To evaluate pharmacokinetics and immunogenicity of zolbetuximab in
    combination with Nab-P + GEM
    -Evaluar otras actividades antitumorales de zolbetuximab en combinación con Nab-P + GEM, medidas a partir de la supervivencia sin progresión (SSP) y la tasa de respuesta objetiva (TRO) (fase de aleatorización).
    -Evaluar la farmacocinética de Nab-P + GEM en combinación con zolbetuximab (fase de aleatorización)
    -Evaluar otras actividades antitumorales medidas a partir de la tasa de control de la enfermedad (TCE) y la duración de la respuesta (DdR) (fase de aleatorización).
    -Evaluar la respuesta del CA19-9 sérico (fase de aleatorización).
    -Evaluar la farmacocinética y la inmunogenicidad de zolbetuximab en combinación con Nab-P + GEM.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent and privacy language as per national regulations (e.g., Health Insurance Portability and Accountability Act Authorization for United States sites) must be obtained from the subject or legally authorized representative prior to any study related procedures (including withdrawal of prohibited medication, if applicable).
    2. Subject is considered an adult according to local regulation at the time of signing informed consent.
    3. Subject agrees not to participate in another interventional study while
    receiving study drug in present study.
    4. A female subject is eligible to participate if she is not pregnant or lactating and at least 1 of the following conditions applies:
    ● Not a woman of childbearing potential (WOCBP) as defined in the Protocol.
    OR
    ● WOCBP who agrees to follow the contraceptive guidance as defined in the Protocol throughout the treatment period and for at least 6 months after the final study drug administration.
    5. Female subject must agree not to breastfeed starting at screening and
    throughout the study period, and for 6 months after the final study drug administration.
    6. Female subject must not donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration.
    7. A male subject with female partner(s) of child-bearing potential must agree to use contraception as detailed in the Protocol during the treatment period and for at least 6 months after the final study drug administration.
    8. A male subject must not donate sperm during the treatment period and for at least 6 months after the final study drug administration.
    9. Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy or time partner is breastfeeding throughout the study period and for 6 months after the final study drug administration.
    Disease Specific Criteria
    10. Subject has histologically or cytologically confirmed adenocarcinoma of pancreas.
    11. Subjects must have metastatic pancreatic cancer that has not been previously treated with chemotherapy.
    ● Prior treatment with 5-FU or GEM administered as a radiation sensitizer during
    and up to 4 weeks after radiation therapy is allowed (if there is lingering toxicity,
    then the sponsor should be consulted).
    ● If a subject received therapy in the adjuvant setting, tumor recurrence or disease progression must have occurred at least 6 months after completing the
    last dose of adjuvant therapy.
    12. Subject has a measurable lesion(s) on at least 1 metastatic site based on RECIST 1.1 within 28 days prior to the first dose of study treatment. For subjects
    with only 1 measureable lesion and prior radiotherapy, the lesion must be outside the field of prior radiotherapy or must have documented progression following radiation therapy.
    13. Subject's tumor sample has CLDN18.2 expression in ≥ 75% of tumor cells
    demonstrating moderate to strong membranous staining as determined by central IHC testing.

    Physical or Laboratory Findings
    14. Subject has ECOG performance status of 0 or 1.
    15. Subject has predicted life expectancy ≥ 12 weeks in the opinion of the investigator.
    16. Subject must meet all of the following criteria on the laboratory tests 16. Subject must meet all of the following criteria on the laboratory tests that will be
    analyzed centrally within 14 days prior to the first dose of study drug. In case of multiple laboratory data within this period, the most recent data should be used.
    •Hemoglobin ≥ 9 g/dl (no transfusion within 14 days of start of study treatment)
    •Absolute neutrophil count ≥ 1.5 x 109 /L
    •Platelets ≥ 100 x 109 /L
    •Albumin ≥ 2.5 g/dL
    •Total bilirubin ≤ 1.5 x upper limit of normal (ULN)
    •Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x ULN without liver metastases (≤ 5 x ULN if liver metastases are present)
    •Estimated creatinine clearance ≥ 30 mL/min
    •Prothrombin time/international normalized ratio and partial thromboplastin time ≤ 1.5 x ULN (except for subjects receiving anticoagulation therapy)
    1. Antes de que se lleve a cabo cualquier procedimiento relacionado con el estudio (incluida la retirada de los medicamentos prohibidos, si procede) el paciente o su representante legal deberán firmar un consentimiento informado por escrito, aprobado por el Comité de ética independiente, y el texto sobre privacidad conforme con la normativa local (por ejemplo, autorización conforme con la Ley de transferencia y responsabilidad de los seguros médicos en el caso de los centros de Estados Unidos). 2. En el momento de la firma del consentimiento informado, el paciente debe ser considerado un adulto según la legislación local. 3. El paciente se debe comprometer a no participar en ningún otro estudio intervencionista mientras esté recibiendo el fármaco del estudio en el marco de este estudio. 4. Las pacientes podrán participar si no están embarazadas ni en periodo de lactancia [véase el Apéndice 12.3. Requisitos en materia de métodos anticonceptivos] y se cumple al menos una de las siguientes condiciones: -No ser una mujer potencialmente fértil (MPF) de acuerdo con el [Apéndice 12.3. Requisitos en materia de métodos anticonceptivos]. O BIEN - Si es una MPF, comprometerse a seguir las directrices sobre anticonceptivos definidas en el [Apéndice 12.3. Requisitos en materia de métodos anticonceptivos] durante todo el período de tratamiento y, como mínimo, en los 6 meses siguientes a haber recibido la última dosis del fármaco del estudio. 5. Las pacientes deberán comprometerse a no amamantar desde la selección, durante todo el período del estudio ni en los 6 meses siguientes a haber recibido la última dosis del fármaco del estudio. 6. Las pacientes no deben donar óvulos desde la selección, durante todo el período del estudio ni en los 6 meses siguientes a haber recibido la última dosis del fármaco del estudio. 7. Los pacientes varones con pareja(s) femenina(s) que sean potencialmente fértiles deben comprometerse a seguir las directrices sobre anticonceptivos definidas en el [Apéndice 12.3. Requisitos en materia de métodos anticonceptivos] durante el período de tratamiento del estudio y, como mínimo, en los 6 meses siguientes a haber recibido la última dosis del fármaco del estudio. 8. Los pacientes varones no deben donar espermatozoides durante el período de tratamiento ni en los 6 meses siguientes a haber recibido la última dosis del fármaco del estudio. 9. Los pacientes varones con parejas embarazadas o en periodo de lactancia deben comprometerse a practicar la abstinencia o a usar preservativo durante todo el embarazo o mientras su pareja esté amamantando. Estos requisitos deberán mantenerse durante todo el período del estudio y en los 6 meses siguientes a haber recibido la última dosis del fármaco del estudio. 10. El paciente presenta un adenocarcinoma pancreático confirmado histológica o citológicamente. 11. Los pacientes deben tener un cáncer pancreático metastásico que no haya sido tratado previamente con quimioterapia. -Se permite el tratamiento previo con 5-FU o gemcitabina (GEM) administrado como radiosensibilizador durante y hasta 4 semanas después de la radioterapia (si se ha producido toxicidad persistente, se deberá consultar al promotor). -En caso de que un paciente haya recibido tratamiento adyuvante, la recidiva tumoral o la progresión de la enfermedad deberá haberse producido al menos 6 meses después de haber recibido la última dosis de tratamiento adyuvante. 12. El paciente presenta lesión(es) cuantificable(s) en al menos un área metastásica según los criterios RECIST 1.1 durante los 28 días previos al tratamiento del estudio. En el caso de los pacientes que presenten una única lesión cuantificable y radioterapia previa, la lesión debe encontrarse fuera del campo de la radioterapia previa o deberán tener progresión documentada tras la radioterapia. 13. La muestra tumoral del paciente debe expresar CLDN18.2 en ≥75 % de las células tumorales con tinción membranosa entre moderada y fuerte según la determinación IHQ central. Hallazgos físicos o de las pruebas analíticas: 14. El paciente debe presentar un estado funcional ECOG de 0 o 1. 15. La esperanza de vida prevista para el paciente debe ser ≥12 semanas de acuerdo con la valoración del investigador.
    16. Ver criterio de inclusión en inglés.
    E.4Principal exclusion criteria
    Subject will be excluded from participation if any of the following apply:
    Prohibited Treatment or Therapies
    1. Subject has received other investigational treatment within 28 days
    prior to screening.
    2. Subject has received radiotherapy for metastatic pancreatic
    adenocarcinoma within 28 days prior to the first dose of study treatment. Subject who received palliative radiotherapy to peripheral bone metastases ≥ 14 days prior to first dose of study treatment and has recovered from all acute toxicities is eligible.
    3. Subject has received systemic immunosuppressive therapy, including systemic
    corticosteroids within 14 days prior to first dose of study treatment. Subject using a physiologic replacement dose of hydrocortisone or its equivalent (defined as up to 30 mg per day of hydrocortisone or up to 10 mg per day of prednisone) or a single dose of systemic corticosteriods is eligible.
    Medical History or Concurrent Disease
    4. Subject has prior severe allergic reaction or intolerance to known ingredients of zolbetuximab or other monoclonal antibody, including humanized or chimeric
    antibodies.
    5. Subject has known immediate or delayed hypersensitivity, intolerance or
    contraindication to any component of study treatment.
    6. Subject has a known history of a positive test for human immunodeficiency virus infection or known active Hepatitis B (positive HBs antigen [Ag]) or
    Hepatitis C infection. For subjects who are negative for HBs Ag, but Hepatitis B core antibody positive, a Hepatitis B virus DNA test will be performed and if positive, the subject will be excluded. Subjects with positive serology but negative Hepatitis C virus RNA test results are eligible.
    7. Subject has a history of interstitial pneumonia or pulmonary fibrosis.
    8. Subject has pleural effusion or ascites ≥ Grade 3 per CTCAE v 4.0.
    9. Subject has an active autoimmune disease that has required systemic treatment in the past 2 years.
    10. Subject has active infection requiring systemic therapy that has not completely resolved per investigator judgment within 14 days prior to first dose of study treatment.
    11. Subject has significant cardiovascular disease, including:
    ● Congestive heart failure (defined as New York Heart Association Class
    III or IV), myocardial infarction, unstable angina, coronary angioplasty, coronary stenting, coronary artery bypass graft, cerebrovascular accident or hypertensive
    crisis within 6 months prior to administration of first dose of study treatment;
    ● History of clinically significant ventricular arrhythmias (i.e., sustained ventricular tachycardia, ventricular fibrillation or Torsades de Pointes);
    ● QTc interval > 450 msec for male subjects; QTc interval > 470 msec for female
    subjects;
    ● Cardiac arrhythmias requiring anti-arrhythmic medications (Subjects with rate
    controlled atrial fibrillation for > 1 month prior to first dose of study treatment
    are eligible.)
    12. Subject has known active or treated central nervous system metastases and/or carcinomatous meningitis.
    13. Subject has known peripheral sensory neuropathy ≥ Grade 2 per CTCAE v.4.0 unless the absence of deep tendon reflexes is the sole neurological abnormality.
    14. Subject has had a major surgical procedure ≤ 28 days prior to the first dose of study drug.
    15. Subject without complete recovery from a major surgical procedure ≤ 14 days prior to the first dose of study treatment.
    16. Psychiatric illness or social situations that would preclude study compliance per investigator's judgment.
    17. Subject has another malignancy for which treatment is required per investigator's clinical judgment.
    18. Subject has any concurrent disease, infection or co-morbid condition that interferes with the ability of the subject to participate in the study, which places the subject at undue risk or complicates the interpretation of data in the opinion of the investigator.
    1. El paciente ha recibido otro tratamiento en investigación durante los 28 días previos a la selección. 2. El paciente ha recibido radioterapia para el adenocarcinoma de páncreas metastásico durante los 28 días previos a la primera dosis del tratamiento del estudio. Se considerarán aptos los pacientes que hayan recibido radioterapia paliativa para metástasis óseas periféricas ≥14 días antes de recibir la primera dosis del tratamiento del estudio y que se hayan recuperado de todas las toxicidades agudas. 3. El paciente ha recibido tratamiento inmunodepresor sistémico, incluidos los corticoides sistémicos, en
    los 14 días anteriores la primera dosis del tratamiento del estudio. Se considerarán aptos los pacientes que reciban una dosis de restitución fisiológica de hidrocortisona o su equivalente (definida como un máximo de 30 mg diarios de hidrocortisona o hasta 10 mg diarios de prednisona) o una dosis única de corticoides sistémicos. 4. El paciente ha sufrido previamente una reacción alérgica grave o intolerancia a los ingredientes conocidos de zolbetuximab u otro anticuerpo monoclonal, incluidos los anticuerpos humanizados o quiméricos. 5. El paciente presenta una contraindicación, intolerancia o hipersensibilidad inmediata o demorada conocida a alguno de los componentes del tratamiento del estudio. 6. El paciente tiene antecedentes conocidos de un resultado positivo en la prueba de detección de la infección por el virus de la inmunodeficiencia humana o hepatitis B activa (con antígeno [Ag] HBs positivo) o hepatitis C conocidas. En el caso de los pacientes con Ag HBs negativo pero anticuerpos nucleares de la hepatitis B positivos, se realizará una prueba de ADN del virus de la hepatitis B y, en caso de resultar positiva, se excluirá al paciente. Serán aptos los pacientes con serología positiva pero con un resultado negativo en la prueba de ARN del virus de la hepatitis C. 7. El paciente presenta antecedentes de neumonía intersticial o de fibrosis pulmonar. 8. El paciente presenta derrame pleural o ascitis de grado ≥3 de acuerdo con la versión 4.0 de los CTCAE. 9. El paciente sufre una enfermedad autoinmune activa que ha requerido la administración de tratamientsistémico durante los dos últimos años. 10. El paciente presenta una infección activa que requiere la administración de tratamiento sistémico y que, a criterio del investigador, no se ha resuelto completamente en los 14 días anteriores a la primera dosis del tratamiento del estudio. 11. El paciente sufre una enfermedad cardiovascular significativa, entre las que se incluyen: a. insuficiencia cardíaca congestiva (de clase III o IV según la clasificación de la New York Heart Association), infarto de miocardio, angina inestable, angioplastia coronaria, endoprótesis coronaria, injerto de revascularización de arteria coronaria, accidente cerebrovascular o crisis hipertensiva durante los 6 meses anteriores a la administración de la primera dosis del tratamiento del estudio; b. antecedentes de arritmias ventriculares clínicamente significativas (es decir, taquicardia ventricular continuada, fibrilación ventricular o taquicardia ventricular en entorchado); c. intervalo QTc >450 ms (varones); intervalo QTc >470 ms (mujeres); d. Arritmias cardíacas que requieran la administración de antiarrítmicos (se considerarán aptos los pacientes con fibrilación auricular de frecuencia controlada durante >1 mes antes de recibir la primera dosis del tratamiento del estudio). 12. Metástasis activas o tratadas del sistema nervioso central y/o meningitis carcinomatosa conocidas. 13. El paciente presenta una neuropatía sensorial periférica de grado ≥ 2 de acuerdo con la versión 4.0 de los CTCAE, salvo que la ausencia de reflejos tendinosos profundos constituya la única anomalía neurológica. 14. El paciente se ha sometido a una intervención quirúrgica mayor ≤28 días antes de recibir la primera dosis del fármaco del estudio. 15. El paciente no se ha recuperado completamente de una cirugía mayor ≤14 días antes de recibir la primera dosis del tratamiento del estudio. 16. Enfermedad psiquiátrica o situación social que, en opinión del investigador, impida cumplir con los requisitos del estudio. 17. El paciente presenta otra neoplasia maligna que, según el criterio del investigador, requiere tratamiento. 18. El paciente presenta una enfermedad concomitante, una infección o una comorbilidad que, en opinión del investigador, interfiere con su capacidad para participar en el estudio, le expone a un riesgo inadecuado o dificulta la interpretación de los datos.
    E.5 End points
    E.5.1Primary end point(s)
    Primary Endpoints
    ● Confirm RP2D as assessed by DLTs (Safety Lead-in Phase)
    ● Safety and tolerability as measured by AEs, laboratory test results,
    vital signs, ECGs and ECOG performance status.
    ● OS, defined as the time from the date of randomization until the date of death from any cause
    Criterios de valoración principales
    • Confirmar la DRF2, evaluada de acuerdo con las TLD (fase de preinclusión de seguridad)
    • Seguridad y tolerabilidad, determinada mediante los AA, resultados de las pruebas de laboratorio, constantes vitales, ECG y el estado funcional de la ECOG.
    • SG, definida como el tiempo entre la fecha de aleatorización y la fecha de la muerte por cualquier causa
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary endpoints will be evaluated at the time of interim analysis.
    All endpoints will be evaluated at primary analysis. A futility analysis will be conducted by the IDMC when 42 OS events are observed. The primary analysis will occur once 83 OS events have been observed.
    Los criterios de valoración principales se evaluarán en el momento de realizar el análisis intermedio.
    Todos los criterios de valoración se evaluarán en el análisis principal. El CISDI llevará a cabo un análisis de futilidad cuando se hayan observado 42 eventos de SG. El análisis principal se realizará cuando se hayan observado 83 eventos de SG.
    E.5.2Secondary end point(s)
    Key Secondary (Randomization):
    ● PFS, defined as the time from the date of randomization until the date of radiological PD per RECIST 1.1 by local investigator evaluation, or death from any cause, whichever is earliest
    ● ORR, defined as the proportion of subjects who have a best overall response of CR or PR as assessed by local investigator evaluation per RECIST 1.1
    Secondary:
    ● Pharmacokinetic parameters of zolbetuximab, Nab-P (measured as PTX) and GEM (AUCinf, AUCinf [%extrap], AUClast, Cmax, Ctrough, tmax, t1/2, , tlast,
    CL, Vz, as appropriate)
    ● DCR, defined as the proportion of subjects who have a best overall response of CR, PR or stable disease (SD) as assessed by local investigator evaluation per
    RECIST 1.1
    ● DOR, defined as the time from the date of the first response (CR/PR) until the date of PD as assessed by local investigator evaluation per RECIST 1.1 or date of
    death from any cause, whichever is earliest
    ● Serum CA19-9 change from baseline
    ● Immunogenicity of zolbetuximab as measured by the frequency of anti-drug antibody (ADA) positive subjects
    The primary and key secondary endpoints will be evaluated at the time of interim analysis.
    All endpoints will be evaluated at primary analysis.
    Criterios de valoración secundarios fundamentales (aleatorización):
    • SSP, definida como el tiempo desde la fecha de aleatorización hasta la fecha de PE determinada radiológicamente de acuerdo con los criterios RECIST 1.1, según la evaluación local realizada por el investigador, o la muerte por cualquier causa, lo que ocurra en primer lugar
    • TRG, definida como la proporción de sujetos que alcanzan una mejor respuesta global de RC o RP, según la evaluación local realizada por el investigador de acuerdo con los criterios RECIST 1.1
    Secundarios:
    • Parámetros farmacocinéticos de zolbetuximab, Nab-P (medido como PTX) y GEM (ABCinf, ABCinf [% extrap.], AUCfinal, Cmáx, Cmín, tmáx, t1/2, tfinal, CL, Vd, tal como proceda)
    • TCE, definida como la proporción de sujetos que presentan una mejor respuesta global de RC, RP o enfermedad estable (EE), según la evaluación local realizada por el investigador de acuerdo con los criterios RECIST 1.1
    • DR, definida como el tiempo desde la fecha de la primera respuesta (RC/RP) hasta la fecha de PE, según la evaluación local realizada por el investigador de acuerdo con los criterios RECIST 1.1, o bien la fecha de la muerte por cualquier causa, lo que suceda en primer lugar
    • Cambio en la concentración sérica de CA19-9 respecto al valor basal
    • Inmunogenia de zolbetuximab, determinada mediante la frecuencia de sujetos positivos para anticuerpos antifármaco (AFA).
    Los criterios de valoración principal y secundarios fundamentales se evaluarán en el momento de realizar el análisis intermedio. Todos los criterios de valoración se evaluarán en el análisis principal.
    E.5.2.1Timepoint(s) of evaluation of this end point
    The key secondary endpoints will be evaluated at the time of interim analysis.
    All endpoints will be evaluated at primary analysis. A futility analysis will be conducted by the IDMC when 42 OS events are observed. The primary analysis will occur once 83 OS events have been observed
    Los criterios de valoración secundarios fundamentales se evaluarán en el momento de realizar el análisis intermedio.
    Todos los criterios de valoración se evaluarán en el análisis principal. El CISDI llevará a cabo un análisis de futilidad cuando se hayan observado 42 eventos de SG. El análisis principal se realizará cuando se hayan observado 83 eventos de SG.
    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 Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity
    Inmunogenicidad
    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 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 Yes
    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 concerned9
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA44
    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
    Australia
    France
    Germany
    Ireland
    Italy
    Japan
    Korea, Republic of
    Spain
    Taiwan
    United Kingdom
    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
    The last visit or scheduled procedure for the last study participant in the study
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months4
    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: 47
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 94
    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 61
    F.4.2.2In the whole clinical trial 141
    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)
    Zolbetuximab may be made available after the conclusion of the study to subjects who are still receiving and benefiting from study treatment until study defined treatment discontinuation criterion is met.
    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 Decision2019-02-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-01-30
    P. End of Trial
    P.End of Trial StatusOngoing
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