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    Summary
    EudraCT Number:2018-003120-36
    Sponsor's Protocol Code Number:IMC-C103C-101
    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:2019-11-11
    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 number2018-003120-36
    A.3Full title of the trial
    A Phase 1/2 First-in-human Study of the Safety and Efficacy of IMC-C103C as a Single Agent and in Combination with Atezolizumab in HLA-A*0201-positive Patients with Advanced MAGE-A4-positive Cancer
    Primer estudio en humanos de fase I/II de la seguridad y eficacia del IMC-C103C en monoterapia y en combinación con atezolizumab en pacientes con HLA-A*0201 positivo y cáncer positivo para MAGE-A4 avanzado.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An open-label study in patients with advanced cancer
    Un estudio abierto en pacientes con cáncer avanzado.
    A.4.1Sponsor's protocol code numberIMC-C103C-101
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03973333
    A.5.4Other Identifiers
    Name:INDNumber:137,164
    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 SponsorImmunocore Limited
    B.1.3.4CountryUnited Kingdom
    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 supportImmunocore Limited
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationImmunocore, Ltd.
    B.5.2Functional name of contact pointEric Phillips
    B.5.3 Address:
    B.5.3.1Street AddressSix Tower Bridge, 181, Washington Street, Ste 540
    B.5.3.2Town/ cityConshohocken, PA
    B.5.3.3Post code19428
    B.5.3.4CountryUnited States
    B.5.4Telephone number+12673313302
    B.5.6E-maileric.phillips@immunocore.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 nameIMC-C103C
    D.3.2Product code IMC-C103C
    D.3.4Pharmaceutical form 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 INNIMC-C103C
    D.3.9.2Current sponsor codeIMC-C103C
    D.3.9.3Other descriptive nameIMC-C103C
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.2
    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 Yes
    D.2.1.1.1Trade name Tecentriq
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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 nameAtezolizumab
    D.3.2Product code 1380723-44
    D.3.4Pharmaceutical form 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 INNATEZOLIZUMAB
    D.3.9.3Other descriptive nameAtezolizumab
    D.3.9.4EV Substance CodeSUB178312
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1200
    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
    Patients with metastatic/unresectable tumors of interest which include NSCLC, esophageal carcinoma, gastric carcinoma, HNSCC, urothelial carcinoma, ovarian carcinoma and synovial sarcoma
    Pacientes con tumores metastásicos/irresecables de interés como, CPNM, carcinoma esofágico, carcinoma gástrico, CECC, carcinoma urotelial, carcinoma ovárico y sarcoma sinovial.
    E.1.1.1Medical condition in easily understood language
    Patients with advanced non-small cell lung cancer, head and neck cancer, esophageal cancer, gastric, bladder cancer (also called urothelial cancer), ovarian cancer and synovial sarcoma
    Pacientes con cáncer de pulmón no microcítico avanzado, cáncer de cuello y cabeza, cáncer esofágico, gástrico, cáncer de vejiga (también llamado cáncer urotelial), cáncer de ovario y sarcoma sinovial.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10062006
    E.1.2Term HLA marker study
    E.1.2System Organ Class 10022891 - Investigations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10030155
    E.1.2Term Oesophageal 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 20.1
    E.1.2Level LLT
    E.1.2Classification code 10017770
    E.1.2Term Gastric 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 20.0
    E.1.2Level LLT
    E.1.2Classification code 10064467
    E.1.2Term Urothelial 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 21.1
    E.1.2Level LLT
    E.1.2Classification code 10033131
    E.1.2Term Ovarian 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 20.0
    E.1.2Level PT
    E.1.2Classification code 10042863
    E.1.2Term Synovial sarcoma
    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 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 21.0
    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.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase I:
    To identify the MTD and/or RP2D of IMC-C103C as a single agent administered Q1W (Arm A1) and administered Q1W in combination with Q3W atezolizumab (Arm A2).
    Phase II:
    To assess the preliminary anti-tumor activity of IMC C103C in one or more selected indications, as a single agent administered Q1W (Arm B1) and administered Q1W in combination with Q3W atezolizumab (Arm B2).
    Fase I:
    Identificar la DMT y/0 DRFIl de IMC-C103C como agente único administrado una vez por semana (grupo A1) y administrado C1S en combinación con atezolizumab C3S (grupo A2).
    Fase II:
    Evaluar la actividad antitumoral preliminar que IMC-C103C ofrece en una o en más enfermedades seleccionadas, como agente único administrado C1S (grupo B1) y administrado C1S en combinación con atezolizumab C3S (grupo B2).
    E.2.2Secondary objectives of the trial
    - Phase II: To assess the safety and tolerability of IMC-C103C as a single agent administered Q1W (Arm A1) and administered Q1W in combination with Q3W atezolizumab (Arm A2)
    - To assess the preliminary anti-tumor activity of IMC C103C in one or more selected indications, as a single agent administered Q1W (Arm B1) and administered Q1W in combination with Q3W atezolizumab (Arm B2)
    - To characterize the PK profile of IMC-C103C as monotherapy and in combination with atezolizumab
    - Arms A2 and B2: To characterize the PK profile of atezolizumab in combination with IMC-C103C
    - To evaluate the preliminary incidence of anti IMC C103C antibody formation following multiple infusions of IMC-C103C as a monotherapy and in combination with atezolizumab
    - Arms A2 and B2: To evaluate the preliminary incidence of anti atezolizumab antibody formation following multiple infusions IMC-C103C in combination with atezolizumab
    - To determine pharmacodynamic changes following treatment with IMC-C103C
    -Fase II: Evaluar la seguridad y tolerabilidad de IMC-C103C como agente único administrado C1S (grupo A1) y administrado C1S en combinación con atezolizumab C3S (grupo A2)
    -Valorar actividad antitumoral preliminar que IMC C103C ofrece en 1 o en más enfermedades seleccionadas, como agente único administrado C1S (grupo B1) y administrado C1S en combinación con atezolizumab C3S (grupo B2)
    -Describir perfil FC de IMC-C103C administrado en monoterapia y combinación con atezolizumab
    -Grupos A2 y B2: Determinar el perfil FC del atezolizumab en combinación con IMC-C103C
    -Evaluar incidencia preliminar de formación de anticuerpos contra IMC-C103C tras múltiples infusiones de IMC-C103C en monoterapia y combinación con atezolizumab
    -Grupos A2 y B2: Evaluar la incidencia preliminar de formación de anticuerpos contra el atezolizumab tras múltiples infusiones de IMC-C103C en combinación con atezolizumab
    -Determinar cambios farmacodinámicos que se producen después del tratamiento con IMC-C103C
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age ≥ 18 years at time of informed consent
    2. Ability to understand and provide written informed consent prior to undergoing any study procedures
    3. Life expectancy of at least 3 months as estimated by the Investigator
    4. Eastern Cooperative Oncology Group (ECOG) status of 0 or 1 at start of treatment
    5. In the opinion of the Investigator, all other relevant medical conditions must be stable and well-managed for at least 28 days prior to first drug administration
    6. HLA-A*02:01 positive (testing by central laboratory)
    7. MAGE-A4-positive tumor (testing by central laboratory)
    8. Patients enrolling in biomarker backfill cohorts must have disease that is amenable to biopsy and consent to undergo biopsies during Screening and on treatment
    9. Patients must have measurable disease according to RECIST v1.1
    a. A previously irradiated lesion may be followed as a target lesion only if there was documented progression of the lesion following completion of radiotherapy
    b. A lesion that will be biopsied on study may be followed as a target lesion only if it is > 2 cm in diameter and the biopsy will not significantly impact its diameter
    10. Patients with metastatic/unresectable NSCLC, esophageal, gastric, urothelial, HNSCC, ovarian, or synovial sarcoma are eligible. Patients must meet the indication-specific histology and biomarker testing requirements specified in the protocol
    11. There is no maximum limit on the number of prior therapies. Patients must be relapsed from, refractory to, or intolerant of all therapies listed in the protocol for their indication and study phase. These therapies must have been given for unresectable / metastatic disease or given in the adjuvant setting if disease progression occurred during or within 6 months of completing adjuvant therapy.
    12. Male and female patients who are sexually active with a non-sterilized partner must agree to use highly effective methods of birth control from the trial screening date until 6 months after the final dose of the investigational product; cessation of birth control after this point should be discussed with a responsible physician. Highly effective methods of contraception are described in Section 6.4.4.
    • Pregnant or lactating women are prohibited from enrolling
    • Male patients are not allowed to donate sperm from the time of enrolment until 6 months post-administration of study drugs
    1. Edad >=18 años en el momento del consentimiento informado
    2. Capacidad para entender y dar el consentimiento informado antes de someterse a cualquier procedimiento del estudio
    3. Esperanza de vida de al menos 3 meses a juicio del investigador
    4. Estado según el Grupo Oncológico Cooperativo de la Costa Este (ECOG) de 0 o 1 al inicio del tratamiento
    5. En opinión del investigador, todas las demás afecciones médicas relevantes deben ser estables y estar bien controladas durante al menos 28 días antes de la administración de la primera dosis del medicamento
    6. HLA-A*0201 positivo (pruebas realizadas por el laboratorio central)
    7. Tumor positivo para MAGE-A4 (pruebas realizadas por el laboratorio central)
    8. Los pacientes incluidos en las cohortes de relleno de biomarcadores deben tener una enfermedad evaluable mediante biopsia y aceptar someterse a biopsias durante la fase de selección y tratamiento
    9. La enfermedad de los pacientes debe ser mensurable según los criterios RECIST v1.1
    a. Se podrá hacer el seguimiento de una lesión irradiada previamente como lesión indicadora solo si existen pruebas documentadas de una progresión de la lesión después de finalizar la radioterapia
    b. Se podrá hacer el seguimiento de una lesión que se someterá a biopsia durante el estudio como lesión indicadora solo si tiene un diámetro > 2 cm y la biopsia no disminuirá significativamente su diámetro
    10. Los pacientes con CPNM metastásico/irresecable, esofágico, gástrico, urotelial, CECC, ovárico o sarcoma sinovial pueden participar en el estudio. Los pacientes deben cumplir con la histología específica de la enfermedad y los requisitos de las pruebas de biomarcadores especificados en el protocolo.
    11. No existe ningún límite máximo en cuanto al número de tratamientos previos. Los pacientes tienen que haber recaído, ser resistentes o intolerantes a todos los tratamientos detallados en el protocolo para su enfermedad y fase del estudio. Estos tratamientos tienen que haberse administrado para una enfermedad irresecable/metastásica, o bien haberse administrado como tratamiento adyuvante si se ha producido una progresión de la enfermedad durante o en los 6 meses necesarios para completar el tratamiento adyuvante.
    12. Los pacientes de ambos sexos que sean activos sexualmente con una pareja no esterilizada deben acceder a usar métodos anticonceptivos altamente efectivos desde la fecha de selección del ensayo hasta 6 meses después de la dosis final del producto en investigación; el cese de la anticoncepción después de este momento deberá comentarse con el médico responsable. Los métodos anticonceptivos altamente eficaces se describen en la sección 6.4.4.
    • Las mujeres embarazadas o en periodo de lactancia no se pueden incluir en el estudio.
    • Los pacientes de sexo masculino no pueden donar esperma desde el momento de la inclusión hasta 6 meses después de la administración de los medicamentos del estudio.
    E.4Principal exclusion criteria
    1. Presence of untreated or symptomatic central nervous system (CNS) metastases, leptomeningeal disease, or cord compression. NOTE: patients with treated CNS lesions may enroll provided ALL the following apply:
    • Treated CNS lesions must be radiographically stable for ≥ 4 weeks after intervention (surgery and/or radiation)
    • Patients must be neurologically stable off systemic corticosteroids for receiving systemic corticosteroids or have received systemic corticosteroids within 3 weeks prior to enrollment
    2. Presence of NCI CTCAE ≥ Grade 2 toxicity due to prior cancer therapy (excepting Grade 2 alopecia, Grade 2 stable peripheral neuropathy, Grade 2 endocrine disorder [on stable replacement doses], Grade 2 hypophosphatemia [on appropriate replacement therapy], and Grade 2 ototoxicity).
    3. Patients enrolling in Arm A2 or Arm B2 with prior immunotherapy exposure must not have experienced immune-mediated AE (imAE) meeting any of the following criteria:
    • Grade 4 imAE
    • imAE resulting in the discontinuation of any prior immunotherapy
    • imAE requiring immunosuppressive treatments other than corticosteroids
    • imAE that recurred upon rechallenge
    • Any neurological or ocular imAE
    4. Receipt of anti-cancer therapy for the disease under study within the following times prior to the first planned dose of study drug:
    • Cellular therapies (eg, CAR-T): 90 days. Please refer to the NOTE added in the clinical study protocol Section 5.3.
    • Immunotherapies (eg, atezolizumab, pembrolizumab, ipilimumab): 28 days
    • HER2-targeted antibodies (eg, trastuzumab): 28 days
    • All other systemic therapies: 14 days
    • Radiotherapy: 14 days (excepting palliative radiotherapy to a limited field, which is permitted at any time)
    5. Patient with an out-of-range Screening laboratory values defined as shown below
    • Creatinine clearance (calculated using Cockcroft-Gault formula, or measured) < 50 mL/min
    • Total bilirubin > 1.5 × ULN (patients with Gilbert’s syndrome are excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 × ULN)
    • ALT > 3 × ULN
    • AST > 3 × ULN
    • Absolute neutrophil count < 1.0 × 109/L
    • Absolute lymphocyte count < 0.5 × 109/L
    • Platelet count < 75 × 109/L
    • Hemoglobin < 8 g/dL
    6. History of interstitial lung disease or severe chronic obstructive pulmonary disease (forced expiratory volume in less than 1 second ≤ 50% of predicted)
    7. Clinically significant cardiac disease or impaired cardiac function, including any of the following:
    • Uncontrolled hypertension (systolic blood pressure [BP] > 160 mmHg or diastolic BP > 110 mmHg despite treatment with appropriate anti-hypertensive treatment)
    •History of ventricular arrhythmia currently requiring medical treatment or uncontrolled atrial fibrillation
    • Ejection fraction < 50% on Screening echocardiogram
    • QTcF > 470 msec on Screening ECGs or congenital prolonged QT syndrome
    • Cardiac troponin T > ULN at Screening
    • Acute myocardial infarction or unstable angina pectoris ≤ 6 months prior to Screening
    8. Active autoimmune disease requiring treatment, including inflammatory bowel disease (ulcerative colitis or Crohn’s disease), within five years of Screening
    9. Systemic treatment with steroids or any other immunosuppressive drug use within 4 weeks of the planned first dose of study drug, with the exceptions listed in the protocol
    10. Patients with prior solid organ or bone marrow transplant
    11. Chronic viral infections as indicated below
    • Known history of HIV infection
    • HBV infection, unless on stable anti-viral therapy for > 4 weeks prior to the planned first dose of study drug and viral load confirmed as undetectable during Screening
    • HCV infection. History of HCV is not exclusionary if the patient has received curative treatment and viral load was confirmed as undetectable during Screening
    12. History of malignant disease other than those being treated in this study. See protocol for additional details which malignancies are allowed
    13. Pregnant, likely to become pregnant, or lactating (where pregnancy is defined as the state of a female after conception and until the termination of gestation)
    14. Any medical condition that is poorly controlled or that would, in the Investigator’s or Sponsor’s judgement, prevent the patient’s participation in the clinical study due to safety concerns, compliance with clinical study procedures, or interpretation of study results
    15. Patients requiring systemic antibiotics (IV or oral) for infection within 2 weeks prior to the planned first dose of study treatment
    16. Use of any live or non-live vaccines against infectious diseases within 4 weeks of the first planned administration of study drug
    17. Any major surgical procedure (as judged by the Principal Investigator) within 2 weeks of the first planned administration of study drug
    18. Hypersensitivity to IMC-C103C or its excipients (all Arms), or Hypersensitivity to atezolizumab or its excipients (Arms A2 and B2 only)
    1.Presencia de metástasis no tratadas o sintomáticas en SNC, enfermedad leptomeníngea o compresión medular.NOTA: los pacientes con lesiones tratadas del SNC pueden incluirse si cumplen TODOS los criterios siguientes
    •Lesiones tratadas del SNC deben ser radiográficamente estables durante>= 4 semanas después de la intervención (cirugía o irradiación)
    •Pacientes deben estar neurológicamente estables para ser tratados con corticoesteroides sistémicos o después de haber recibido corticoesteroides sistémicos en las 3 semanas previas a inclusión
    2.Presencia de una toxicidad de grado>=2 según criterios NCI CTCAE debido a tratamiento previo para cáncer (excepto alopecia de grado 2, neuropatía periférica estable de grado 2, trastorno endocrino de grado 2[con dosis estables de reposición], hipofosfatemia de grado 2[con el tratamiento de reposición adecuado] y ototoxicidad de grado 2)
    3.Pacientes incluidos en grupo A2 o B2 tratados previamente con inmunoterapia no deben haber experimentado AA inmunitarios al cumplir con criterios siguientes
    •AA inmunitario: de grado 4, que haya obligado a suspender cualquier inmunoterapia previa, que requiere tratamiento con inmunodepresores distintos a corticoesteroides, con recidiva con reexposición. Cualquier AA inmunitario neurológico u ocular
    4.Recibir tratamiento antineoplásico para enfermedad mientras el paciente participa en el estudio en los siguientes periodos de tiempo antes de recibir la primera dosis prevista del medicamento del estudio:
    •Tratamientos celulares (p. ej., tratamiento con linfocitos T-CAR):90 días. Consulte NOTA del protocolo Sección 5.3
    •Immunoterapias (p. ej., atezolizumab, pembrolizumab, ipilimumab):28 días
    •Anticuerpos dirigidos contra HER2 (p. ej., trastuzumab):28 días
    •Los demás tratamientos sistémicos:14 días
    •Radioterapia:14 días (excepto radioterapia paliativa en zona delimitada, que está siempre permitida)
    5.Pacientes con valores analíticos fuera del intervalo en selección de acuerdo a valores siguientes
    •Aclaramiento de creatinina (calculado según la fórmula Cockcroft-Gault o medido) <50 ml/min
    •Bilirrubina total>1,5 veces el LSN (excepto en los pacientes con síndrome de Gilbert, que están excluidos si la bilirrubina total es >3,0 veces el LSN o la bilirrubina directa es >1,5 veces LSN)
    •ALT>3 veces LSN
    •AST>3 veces LSN
    •Cifra absoluta neutrófilos<1,0 × 109/l
    •Cifra absoluta linfocitos<0,5 x 109/l
    •Recuento plaquetario<75 x 109/l
    •Hemoglobina<8 g/dl
    6.Antecedentes de enfermedad pulmonar intersticial o pulmonar obstructiva crónica grave (volumen espiratorio forzado en menos de 1 segundo<=50% previsto)
    7.Enfermedad cardíaca clínicamente significativa o función cardíaca alterada, incluido cualquiera de los trastornos siguientes
    •Hipertensión no controlada (presión arterial [PA] sistólica>160 mmHg o diastólica>110 mmHg, a pesar del tratamiento con los antihipertensores adecuados)
    •Antecedentes de arritmia ventricular que actualmente requiere tratamiento médico o fibrilación auricular descontrolada
    •Fracción de eyección<50 % en el ecocardiograma de la selección
    •QTcF>470 ms en ECG de la selección o síndrome del QT prolongado congénito
    •Troponina cardíaca T>LSN en selección
    •Infarto agudo de miocardio o angina de pecho inestable<=6 meses antes de selección
    8.Enfermedad autoinmunitaria activa que requiere tratamiento, como una enfermedad inflamatoria intestinal (colitis ulcerosa o enfermedad de Crohn) en 5 años previos a selección.
    9.Tratamiento sistémico con corticoesteroides u otro medicamento inmunodepresor en las 4 semanas previas a primera dosis prevista del medicamento del estudio, con excepciones enumeradas en protocolo
    10.Pacientes con trasplante previo de médula ósea u órgano sólido
    11.Infecciones víricas crónicas como se indica a continuación
    •Antecedentes de infección por VIH
    •Infección por VHB (véase protocolo)
    •Infección por VHC (véase protocolo)
    12.Antecedentes de cáncer distinto al tratado en el estudio. Véase protocolo para más detalle
    13.Mujeres embarazadas, que tienen intención de quedarse embarazadas o están en periodo de lactancia
    14.Cualquier afección médica que esté mal controlada o que, a criterio del investigador o el promotor, impidiera la participación del paciente en el estudio clínico debido a problemas para seguridad, cumplimiento de procedimientos del estudio o interpretación de los resultados del estudio
    15.Pacientes que necesitan antibióticos sistémicos (orales o intravenosos) para infección en 2 semanas antes de la primera dosis prevista del medicamento del estudio
    16.Uso de vacunas elaboradas con microbios vivos o muertos contra enfermedades infecciosas en 4 semanas previas a primera dosis del medicamento del estudio
    17.Cualquier procedimiento de cirugía mayor (a juicio del IP) en 2 semanas anteriores a primera administración prevista del medicamento del estudio
    18.Hipersensibilidad a IMC-C103C o excipientes(todos los grupos) o a atezolizumab o sus excipientes (solo A2 y B2)
    E.5 End points
    E.5.1Primary end point(s)
    Phase I:
    - Incidence of dose-limiting toxicities (DLT)
    - Incidence and severity of AE and SAE
    - Changes in safety laboratory parameters, vital signs, and electrocardiogram (QTcF)
    - Dose interruptions, reductions, and discontinuations

    Phase II:
    Best overall response as determined by RECIST v1.1
    Fase I:
    - Incidencia de toxicidades limitantes de la dosis (TLD)
    - Incidencia y gravedad de AA o de AAG
    - Cambios en los parámetros de seguridad de laboratorio, las constantes vitales y los electrocardiogramas (QTcF)
    - Interrupciones, reducciones y suspensiones de la dosis
    Fase II:
    La mejor respuesta global determinada según los criterios RECIST v1.1.
    E.5.1.1Timepoint(s) of evaluation of this end point
    DLT:
    The DLT observation period is 21 days for fixed-dose regimens, 28 days for 1-step escalation, and 35 days for 2-step escalation.

    Tumor responses will be determined per local investigators assessment, according to RECIST v1.1. Individual lesion measurements and objective response assessments will be listed by patient and assessment date. Best overall response per RECIST v1.1 will be listed and tabulated. Best overall change in tumor size for individual patients will be shown in waterfall plots.
    TLD:
    El periodo de observación de la TLD es de 21 días para los tratamientos a dosis fija, 28 días para el aumento escalonado de la dosis de 1 paso y 35 días para el aumento escalonado de la dosis de dos pasos.

    La respuesta tumoral se determinará en función de la evaluación de los investigadores locales, según RECIST v1.1. Las mediciones de lesiones individuales y las evaluaciones de la respuesta objetiva se enumerarán por paciente y fecha de evaluación. La mejor respuesta global según los RECIST v1.1 se enumerará y tabulará. El mejor cambio global en el tamaño tumoral de los pacientes individuales se mostrará en gráficos en cascada.
    E.5.2Secondary end point(s)
    - Phase II: Incidence and severity of AE and SAE,
    - Changes in safety laboratory parameters, vital signs, and electrocardiogram (QTcF)
    - Dose interruptions, reductions, and discontinuations
    - Phase I: BOR, PFS, and DOR by RECIST v1.1; OS
    - Phase II: PFS and DOR by RECIST v1.1; OS
    - IMC-C103C serum PK parameters (eg, AUC, Cmax, Tmax, t1/2) after single and multiple doses
    - Arms A2 and B2: Atezolizumab serum PK parameters (eg, AUC, Cmax, Tmax, t1/2) after single and multiple doses
    - Incidence of anti-IMC-C103C antibody formation and its impact on PK
    - Arms A2 and B2: Incidence of anti-atezolizumab antibody formation and its impact on PK
    - Changes in lymphocyte counts over time
    - Changes in serum cytokines over time
    - Fase II: - Incidencia y gravedad de AA o de AAG
    - Cambios en los parámetros de seguridad de laboratorio, las constantes vitales y los electrocardiogramas (QTcF)
    - Interrupciones, reducciones y suspensiones de la dosis
    - Fase I: MRG, SSP y DR según RECIST v1.1; SG
    - Fase II: SSP y DR según RECIST v1.1; SG
    - los parámetros FC séricos de IMC-C103C (por ejemplo, ABC, Cmáx, Tmáx, t1/2) después de una y varias dosis
    - Grupos A2 y B2: Los parámetros FC séricos de atezolizumab (por ejemplo, ABC, Cmáx, Tmáx, t1/2) después de una y varias dosis
    - Frecuencia en la formación de anticuerpos contra el IMC-C103C y cómo influyen en la FC
    - Grupos A2 y B2: - Frecuencia en la formación de anticuerpos contra el atezolizumab y cómo influyen en la FC
    - Cambios en el recuento de linfocitos en el transcurso del tiempo
    - Cambios en el recuento de citocinas séricas en el transcurso del tiempo
    E.5.2.1Timepoint(s) of evaluation of this end point
    Tumor responses will be determined per local investigators assessment, according to RECIST v1.1. Individual lesion measurements and objective response assessments will be listed by patient and assessment date. Best overall response per RECIST v1.1 will be listed and tabulated. Best overall change in tumor size for individual patients will be shown in waterfall plots.
    La respuesta tumoral se determinará en función de la evaluación de los investigadores locales, según RECIST v1.1. Las mediciones de lesiones individuales y las evaluaciones de la respuesta objetiva se enumerarán por paciente y fecha de evaluación. La mejor respuesta global según los RECIST v1.1 se enumerará y tabulará. El mejor cambio global en el tamaño tumoral de los pacientes individuales se mostrará en gráficos en cascada.
    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 Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans 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 No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the 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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA9
    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
    Spain
    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
    Última visita del último paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days8
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days1
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 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: 170
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 4
    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 43
    F.4.2.2In the whole clinical trial 174
    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
    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 Decision2020-01-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-11-22
    P. End of Trial
    P.End of Trial StatusOngoing
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