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    Summary
    EudraCT Number:2019-001553-12
    Sponsor's Protocol Code Number:2SMALL
    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:2019-09-04
    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 number2019-001553-12
    A.3Full title of the trial
    Phase I-II Study to Assess the Safety, Tolerability and Efficacy of PM01183 and Atezolizumab in Patients with Advanced Small Cell Lung Cancer that Progressed Following Prior Therapy with Platinum-Based Chemotherapy
    Estudio de fase I-II para evaluar la seguridad, tolerabilidad y eficacia de PM01183 y atezolizumab en pacientes con cáncer de pulmón de células pequeñas avanzado que hayan progresado tras una quimioterapia previa de platino
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase I-II Study to Assess the Safety, Tolerability and Efficacy of PM01183 and Atezolizumab in Patients with Advanced Small Cell Lung Cancer that Progressed Following Prior Therapy with Platinum-Based Chemotherapy
    Estudio de fase I-II para evaluar la seguridad, tolerabilidad y eficacia de PM01183 y atezolizumab en pacientes con cáncer de pulmón de células pequeñas avanzado que hayan progresado tras una quimioterapia previa de platino
    A.4.1Sponsor's protocol code number2SMALL
    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 SponsorFundacion ONCOSUR
    B.1.3.4CountrySpain
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportFundación ONCOSUR
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFundación ONCOSUR
    B.5.2Functional name of contact pointFundación ONCOSUR
    B.5.3 Address:
    B.5.3.1Street AddressCamino del Molino, 2
    B.5.3.2Town/ cityFuenlabrada, Madrid
    B.5.3.3Post code28942
    B.5.3.4CountrySpain
    B.5.4Telephone number0034915608227
    B.5.5Fax number0034915608227
    B.5.6E-mailinfo@oncosur.org
    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 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.3.4Pharmaceutical 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.3.9.1CAS number 1380723-44-3
    D.3.9.4EV Substance CodeSUB178312
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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 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 typehumanized monoclonal antibody of genetically engineered immunoglobulin G1 Fc, anti-ligand programmed death receptor 1, produced in Chinese hamster ovarian cells by recombinant DNA technology
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePM01183
    D.3.4Pharmaceutical form Lyophilisate 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 INNlurbinectedin
    D.3.9.1CAS number 497871-47-3
    D.3.9.2Current sponsor codePM01183
    D.3.9.3Other descriptive nameLURBINECTEDIN
    D.3.9.4EV Substance CodeSUB31196
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    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
    Histologically or cytologically confirmed diagnosis of extensive or limited SCLC.
    Progression to first-line platinum-based chemotherapy.
    Measurable disease according to RECIST v.1.1.
    Diagnóstico confirmado histológica o citológicamente de SCLC extenso o limitado.
    Progresión a la quimioterapia de primera línea a base de platino.
    Progresión documentada de la enfermedad según RECIST v1.1
    E.1.1.1Medical condition in easily understood language
    diagnosis of small cell lung cancer,
    progression after treatment with other drugs
    diagnostico de cáncer de pulmón de células pequeñas,
    progresión tras tratamiento con otros medicamentos
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    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 determine the maximum tolerated dose (MTD) and the recommended dose for phase II studies (RD) of PM01183 in combination with atezolizumab in advanced SCLC patients progressing after platinum doublet chemotherapy.
    Phase II
    • To assess the efficacy of PM01183 in combination with atezolizumab in terms of confirmed tumor response rate according to Response Evaluation Criteria In Solid Tumors (RECIST) v.1.1 in patients with SCLC progressing after platinum doublet chemotherapy.
    Fase I
    •Determinar la dosis máxima tolerada (DMT) y la dosis recomendada para los estudios de fase II (DR) de PM01183 en combinación con atezolizumab en pacientes con CPCP avanzado que hayan progresado tras doble quimioterapia de platino.
    Fase II
    •Evaluar la eficacia de PM01183 en combinación con atezolizumab en términos de tasa de respuesta tumoral confirmada según los Criterios de Evaluación de Respuesta en Tumores Sólidos (RECIST) v1.1 en pacientes con CPCP que haya progresado tras doble quimioterapia de platino.
    E.2.2Secondary objectives of the trial
    Ph.I-Characterize comb safety profile&feasibility-Characterize PM01183 PK&detect major drug-drug PK interactions-Obtain preliminary inform on comb clinical antitumor activity-If DLTs being exclusively related to neutropenia,determine PM01183 in comb w/atezolizumab MTD&RD in patients w/advanced SCLC w/compulsory primary G-CSF prophylaxis-Evaluate PGt in germline DNA to identify factors that explain individual variability in main PK parameters-Evaluate PGx in tumor&blood samples to identify response &/or resistance potential markers
    Ph.II-Confirm comb safety profile&tolerability-Characterize comb antitumor activity in terms of DoR,clinical benefit[ORR/stable disease lasting≥3mos]PFS,OS&mid/long-term survival(12,18,24mos)-Characterize plasma PK of comb&detect major drug-drug PK interactions-Evaluate PGt in germline DNA to identify factors that explain individual variability in main PK parameters-Evaluate PGx in tumor&blood samples to identify response &/or resistance potential markers
    F.I-Caract perfil seguridad/viabilidad de la combin-Caract PK de PM01183,detect interac fármaco-fármaco import de PK-Obtener inform preliminar activ clínica antitumoral de la combin-Si TLD se relaciona con neutropenia,determ DMT/DR de PM01183+atezolizumab en pacientes con CPCP avanzado con G-CSF como profilaxis princ oblig-Evaluar PGt en ADN germinal para identif factores que expliquen variab indiv en parámetros princip de PK-Evaluar PGx en muestras tumorales/sangre para identif marcadores respuesta/resistencia
    F.II-Confirm perfil seguridad/tolerabilidad de la combin-Caract activ antitumoral de la combin en términos de DR,beneficio clínico [TRG o enfermedad estable≥3meses], SLP, SG medio/largo plazo en 12,18,24meses)-Caract PK en plasma de la combin,detectar interac fármaco-fármaco import de PK-Evaluar PGt en ADN germinal para identif factores expliquen variab indiv en parámetros principales de PK-Evaluar PGx en muestras tumorales/sangre para identif marcadores respuesta/resistencia
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Title: PGx sub-study,
    Objetive: Patients who voluntarily sign the ICF for the PGx sub-study will participate in an optional PGx sub-study with on treatment tumor samples from biopsy and/or blood samples (refusal will not affect patient participation in the clinical study).
    titulo: subestudio de PGx
    Objetivo: Los pacientes que firmen voluntariamente la HIP para el subestudio PGx participarán en un subestudio PGx opcional con muestras de tumor en tratamiento a partir de biopsias y/o muestras de sangre (el rechazo no afectará la participación del paciente en el estudio clínico).
    E.3Principal inclusion criteria
    -Voluntarily signed and dated written informed consent prior to any specific study procedure.
    -Age>18 years.
    -Histologically or cytologically confirmed diagnosis of extensive or limited SCLC.
    -Progression to first-line platinum-based chemotherapy. For phase II part: a chemotherapy-free interval (CTFI, time from the last dose of first-line chemotherapy to the occurrence of progressive disease)≥30 days.
    -Available tumor tissue blocks or slides from a previous surgery or biopsy.
    -Eastern Cooperative Oncology Group (ECOG) performance status (PS) score ≤1.
    -Measurable disease according to RECIST v.1.1. Note: irradiated lesions may qualify as target if progression has been documented.
    -At least three weeks since last prior anticancer treatment (including radiotherapy) and recovery to grade ≤ 1 from any adverse event (AE) related to previous anticancer treatment (excluding sensory neuropathy, anemia, asthenia and alopecia, all grade ≤ 2) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, v.5).
    -Adequate bone marrow, renal, hepatic, and metabolic function (assessed ≤7 days before inclusion in the study):
    a.Platelet count≥100 x 109/L, hemoglobin≥9.0g/dL and absolute neutrophil count (ANC)≥1.5x109/L.
    b.Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0 x the upper limit of normal (ULN), independently of the presence of liver metastases.
    c.Alkaline phosphatase (AP)≤2.5 x ULN.
    d.Total bilirubin≤1.5 x ULN or direct bilirubin≤ULN.
    e.International Normalized Ratio (INR) <1.5 (except if patient is on oral anticoagulation therapy).
    f.Calculated creatinine clearance (CrCL) ≥30 mL/minute (using Cockcroft and Gault´s formula).
    g.Creatine phosphokinase (CPK) ≤2.5 x ULN.
    h.Albumin ≥3.0 g/dL. Albumin infusion to fulfill the inclusion criterion is forbidden.
    i.Thyroid stimulating hormone (TSH) within institutional normal limits. If TSH is above the ULN, then a free T4 within institutional normal limits is acceptable.
    -Evidence of non-childbearing status for women of childbearing potential (WOCBP). Both women and men must agree to use a highly effective contraceptive measure during the trial, for at least five months after last atezolizumab dose, and for at least six weeks (women) or 4 months (men) after last PM01183 dose. Fertile male patients with WOCBP partners must agree to refrain from fathering a child or donating sperm during the trial and up to five months after treatment discontinuation. Acceptable methods of contraception include abstinence, intrauterine device (IUD), oral contraceptive, subdermal implant and/or double barrier.
    -Consentimiento informado firmado y fechado de manera voluntaria antes de cualquier procedimiento específico del estudio.
    -Edad >18 años.
    -Diagnóstico histológica o citológicamente confirmado de CPCP extensivo o limitado.
    -Progresión a quimioterapia de platino de primera línea. Para la fase II: un intervalo sin quimioterapia (ISQ, tiempo desde la última dosis de quimioterapia de primera línea hasta la progresión) ≥30 días.
    -Disponibilidad de bloques o cortes de tejido tumoral o de una cirugía o biopsia anterior.
    -Puntuación ≤1 del estado funcional (PS) del Grupo Cooperativo Oncológico del Este (ECOG).
    -Enfermedad medible según los criterios RECIST v.1.1. Nota: las lesiones irradiadas se pueden calificar como lesiones diana si se ha documentado la progresión.
    -Al menos tres semanas desde el último tratamiento previo contra el cáncer (incluyendo radioterapia) y recuperación a grado ≤1 de cualquier acontecimiento adverso (AA) relacionado con el tratamiento previo contra el cáncer (excluyendo neuropatía sensorial, anemia, astenia y alopecia, todos de grado ≤2) según los criterios de terminología común de acontecimientos adversos del National Cancer Institute (CTCAE del NCI, v.5).
    -Médula ósea y función renal, hepática y metabólica adecuadas (evaluadas ≤7 días antes de la inclusión en el estudio):
    a.Recuento de plaquetas ≥100 x 109/l, hemoglobina ≥9 g/dl y recuento absoluto de neutrófilos (RAN) ≥1,5 x 109/l.
    b.Aspartato aminotransferasa (AST) y alanino aminotransferasa (ALT) ≤3 x el límite superior de normalidad (LSN), independientemente de la presencia de metástasis hepáticas.
    c.Fosfatasa alcalina (FA) ≤ 2,5 x LSN.
    d.Bilirrubina total ≤1,5 x LSN o bilirrubina directa ≤LSN.
    e.Índice internacional normalizado (INR) <1,5 (excepto si el paciente está en tratamiento anticoagulante oral).
    f.Aclaramiento de creatinina calculada (CrCL) ≥30 ml/minuto (mediante la fórmula de Cockcroft-Gault).
    g.Creatinfosfoquinasa (CPK) ≤2,5 x LSN.
    h.Albúmina ≥3 g/dl. Se prohíbe la perfusión de albúmina para cumplir los criterios de inclusión.
    i.Hormona estimulante del tiroides (TSH) dentro de los límites normales del centro. En el caso de que la TSH esté por encima del LSN, se acepta T4 libre dentro de los límites normales del centro.
    10) Evidencia de estado de infertilidad en mujeres en edad fértil (MEF). Tanto hombres como mujeres deben aceptar utilizar un método anticonceptivo altamente eficaz durante el ensayo, durante al menos cinco meses después de la última dosis de atezolizumab y durante al menos seis semanas (mujeres) o 4 meses (hombres) después de la última dosis de PM01183. Los pacientes varones en edad fértil con parejas MEF deben abstenerse de engendrar o de donar esperma durante el ensayo y hasta cinco meses después de la discontinuación del tratamiento. Los métodos anticonceptivos aceptables incluyen abstinencia, dispositivo intrauterino (DIU), anticonceptivo oral, implante subdérmico o doble barrera.
    E.4Principal exclusion criteria
    -Active or untreated central nervous system (CNS) involvement. Treated CNS metastases have to show radiographic stability (defined as no CNS progression for at least three weeks from post-radiotherapy brain scan to brain scan performed prior study entry), and patients should not have neurologic sign/symptoms secondary to the brain metastases or RT. Any steroid treatment must be completed ≥ 14 days before first dose of study treatment
    -More than one prior chemotherapy-containing line (re-challenge with the same initial regimen is not allowed)
    -Patients with radiation therapy (RT) in more than 35% of the bone marrow
    -History of previous bone marrow and/or stem cell transplantation
    -Impending need for RT (e.g., painful bone metastasis and/or risk of spinal cord compression).
    -History of allergy or hypersensitivity to any of the study drugs or their excipients
    -Prior therapy with PM01183, antibodies against PD-1, PD-L1, PD-L2, CD137, or cytotoxic T lymphocyte associated antigen-4 (CTLA-4)
    -Live vaccines within 30 days prior to start of study treatment and while on treatment
    -History of other prior malignancy, with the exception of basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, in situ cervical cancer. Patients with other prior malignancies and no disease recurrence for 3 years are eligible
    -Concomitant diseases/conditions:
    1.History or presence of unstable angina, myocardial infarction, congestive heart failure defined as abnormal left ventricular ejection fraction (LVEF) < 50% assessed by multiple-gated acquisition scan (MUGA) or equivalent by ultrasound (US), or clinically significant valvular heart disease within 12 months prior first study dose
    2.Symptomatic arrhythmia or any uncontrolled arrhythmia requiring ongoing treatment.
    3.Ongoing chronic alcohol consumption, or cirrhosis with Child-Pugh score B or C
    4.Active uncontrolled infection. Serious non-healing wound, ulcer or bone fracture
    5.Diagnose of immunodeficiency or receiving systemic steroids therapy (more than a daily dose of 10 mg of prednisone or equivalent per day) or any other form of immunosuppressive therapy within 14 days prior to the first study dose
    6.Active autoimmune disease that required systemic treatment in the past two years (i.e., with disease-modifying agents, corticosteroids and immunosuppressive drugs). Patients with vitiligo or resolved childhood asthma/atopy are eligible, as well as patients who require intermittent use of bronchodilators or local steroid injections, patients with hypothyroidism stable on hormone replacement, patients with insulin-treated controlled type 1 diabetes or Sjogren's syndrome
    7.History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis or evidence of active pneumonitis on screening chest computed tomography (CT) scans. A history of radiation pneumonitis in radiation field (fibrosis) will be allowed if asymptomatic and not requiring steroids
    8.Known history of active tuberculosis (Mycobacterium tuberculosis)
    9.Ongoing treatment-requiring, non-neoplastic chronic liver disease of any origin. For hepatitis B, this includes positive tests for both Hepatitis B surface antigen (HBsAg) and quantitative Hepatitis B polymerase chain reaction (PCR). For hepatitis C, this includes positive tests for both Hepatitis C antibody and quantitative Hepatitis C PCR. Patients taking hepatitis-related antiviral therapy within 6 months prior to the first study dose will also be excluded
    10.Known human immunodeficiency virus (HIV) infection.
    11.Myopathy or any clinical situation that causes significant and persistent elevation of CPK (>2.5 x ULN in two different determinations performed one week apart)
    12.Limitation of the patient’s ability to comply with the treatment or follow-up procedures.
    13.Any other major illness that, in the Investigator’s judgment, will substantially increase the risk associated with the patient’s participation in this study
    -Afectación del sistema nervioso central (SNC) activa o no tratada. Las metástasis del SNC tratadas deben mostrar estabilidad radiográfica (definida como ausencia de progresión en el SNC durante al menos tres semanas desde la imagen cerebral posterior a la radioterapia hasta la imagen cerebral realizada antes de la entrada del estudio) y los pacientes no deben tener ningún signo/síntoma neurológico secundario a las metástasis cerebrales o RT. Cualquier tratamiento con esteroides debe completarse ≥14 días antes de la primera dosis del tratamiento del estudio.
    -Más de una línea previa de quimioterapia (no se permite volver a exponer al paciente a la misma pauta posológica inicial).
    -Pacientes con radioterapia (RT) en más del 35 % de la médula ósea.
    -Antecedentes de trasplante de médula ósea o células madre.
    -Necesidad inminente de RT (p. ej., metástasis ósea dolorosa o riesgo de compresión de la médula espinal).
    -Antecedentes de alergia o hipersensibilidad a alguno de los fármacos del estudio o sus excipientes.
    -Terapia previa con PM01183, anticuerpos contra PD-1, PD-L1, PD-L2, CD137, o antígeno 4 del linfocito T citotóxico(CTLA-4).
    -Vacunas vivas durante los 30 días anteriores al comienzo del tratamiento del estudio y durante el tratamiento.
    -Antecedentes de otra neoplasia previa, con la excepción de carcinoma basocelular de la piel, cáncer de vejiga superficial, carcinoma de células escamosas de la piel y cáncer de cuello uterino in situ. Son elegibles los pacientes con otras neoplasias previas y sin recurrencia de la enfermedad durante 3 años.
    -Enfermedades concomitantes:
    1.Antecedentes o presencia de angina inestable, infarto de miocardio, insuficiencia cardíaca congestiva definida como fracción de eyección del ventrículo izquierdo anormal (FEVI) <50 % evaluada mediante gammagrafía con adquisición sincronizada múltiple (MUGA) o el equivalente mediante ecografía, o cardiopatía valvular clínicamente significativa durante los 12 meses anteriores a la primera dosis del estudio.
    2.Arritmia sintomática o cualquier arritmia no controlada que requiera tratamiento continuo.
    3.Consumo crónico actual de alcohol o cirrosis de clase B o C en la escala de Child-Pugh.
    4.Infección activa no controlada. Herida no cicatrizada, úlcera o fractura ósea graves.
    5.Diagnóstico de inmunodeficiencia o en tratamiento sistémico con esteroides (más de una dosis diaria de 10 mg de prednisona o su equivalente al día) o cualquier otra forma de tratamiento inmunosupresor durante los 14 días anteriores a la primera dosis del estudio.
    6.Enfermedad autoinmune activa que ha requerido tratamiento sistémico durante los dos años anteriores (es decir, con fármacos modificadores de la enfermedad, corticosteroides y fármacos inmunosupresores). Son elegibles los pacientes con vitíligo o asma/atopía infantil resuelta, así como los pacientes que requieren el uso intermitente de broncodilatadores o inyecciones locales de esteroides; pacientes con hipotiroidismo estable con terapia hormonal sustitutiva, pacientes con diabetes de tipo 1 controlada tratada con insulina o con síndrome de Sjögren.
    7.Antecedentes de fibrosis pulmonar idiopática, neumonía organizativa, neumonitis inducida por fármacos, neumonitis idiopática o evidencia de neumonitis activa según la tomografía computarizada (TC) de tórax en la selección. Se permitirán antecedentes de neumonitis por radiación en el campo de radiación (fibrosis) si es asintomática y no requiere esteroides.
    8.Antecedentes de tuberculosis activa (Mycobacterium tuberculosis).
    9.Enfermedad hepática crónica no neoplásica de cualquier origen y en curso que requiera tratamiento. Para la hepatitis B, esto incluye antígeno de superficie de la hepatitis B (HBsAg) positivo y reacción de polimerasa en cadena (PCR) cuantitativa de la hepatitis B positiva. Para la hepatitis C, esto incluye anticuerpo de la hepatitis C positivo y PCR cuantitativa de la hepatitis C positiva. También se excluirá a los pacientes en tratamiento antiviral relacionado con la hepatitis durante los 6 meses anteriores a la primera dosis del estudio.
    10.Infección por virus de la inmunodeficiencia humana (VIH).
    11.Miopatía o cualquier situación clínica que cause un aumento significativo y persistente de la CPK (>2,5 x LSN en dos determinaciones diferentes realizadas con una semana de diferencia).
    12.Limitación de la capacidad del paciente de cumplir con los procedimientos del tratamiento o el seguimiento.
    13.Cualquier otra enfermedad mayor que, según el criterio del investigador, aumentará considerablemente el riesgo de la participación del paciente en este estudio.
    E.5 End points
    E.5.1Primary end point(s)
    Phase I
    Determination of MTD and RD:
    • The MTD will be the lowest dose level explored during dose escalation at which more than one third of evaluable patients experience a DLT during Cycle 1.
    • The RD will be the highest dose level explored during dose escalation at which less than one third of evaluable patients experience a DLT during Cycle 1.
    If the DLTs observed with the PM01183 and atezolizumab combination without G-CSF prophylaxis are exclusively related to neutropenia, the MTD and RD will also be determined with primary G-CSF prophylaxis.
    Phase II
    The primary objective of this phase is to assess the antitumor activity of the PM01183 and atezolizumab combination in terms of ORR, defined as the percentage of evaluable patients with confirmed response, either complete (CR) or partial (PR).
    The ORR will be assessed using the RECIST v.1.1 on a set of measurable lesions identified at baseline as target lesions or as non-target lesions (if any), and followed until PD by an appropriate method [e.g., helical CT-scan, magnetic resonance imaging (MRI)], using the same method throughout the study for each individual patient.
    Adequate CNS imaging (contrast enhanced-CT or MRI, if applicable) will be performed at baseline to document any disease involvement. This assessment will not be repeated routinely unless it is clinically indicated.
    Radiological tumor assessments will be performed at baseline, and every six weeks (+/- 2 weeks) until evidence of PD or start of a new antitumor therapy. If an objective response according to RECIST v.1.1 is observed, it must be confirmed by the same method at least four weeks after the date of the first documentation of response.
    Clinically stable patients with suspected pseudoprogression (i.e., tumor growth from treatment effect rather than true disease progression) and perceived clinical benefit by the Investigator, might continue treatment and radiological evaluations despite RECIST-defined progression.
    The date of response, the date of radiological or clinical PD, and the date of death will be registered and documented, as appropriate.
    Fase I
    Determinación de DMT y DR:
    •La DMT será el nivel de dosis menor explorado durante la escalada de dosis en la cual más de un tercio de los pacientes evaluables experimentan una TLD durante el ciclo 1.
    •La DR será el nivel de dosis mayor explorado durante la escalada de dosis en la cual menos de un tercio de los pacientes evaluables experimentan una TLD durante el ciclo 1.
    Si las TLD observadas con PM01183 y atezolizumab en combinación sin G-CSF como profilaxis están exclusivamente relacionadas con la neutropenia, la DMT y la DR también se determinarán con G-CSF como profilaxis principal.
    Fase II
    El objetivo principal de esta fase es evaluar la actividad antitumoral de PM01183 y la combinación de atezolizumab en términos de TRG, definida como el porcentaje de pacientes evaluables con respuesta confirmada, ya sea completa (RC) o parcial (RP).
    La TRG se evaluará según RECIST v.1.1 en un conjunto de lesiones medibles identificadas en la basal como lesiones diana o como lesiones no diana (si hubiera), y se seguirá hasta la EP por un método apropiado (p. ej., TC helicoidal, resonancia magnética [RM]), utilizando el mismo método durante todo el estudio en cada paciente.
    Se realizarán imágenes del SNC adecuadas (TC o RM con contraste, si procede) en la basal para documentar cualquier relación de la enfermedad. Esta evaluación no se repetirá rutinariamente a menos que se indique clínicamente. Las evaluaciones tumorales radiológicas se realizarán en la basal, y cada seis semanas (+/- 2 semanas) hasta la evidencia de EP o el comienzo de un nuevo tratamiento antitumoral. Si se observa una respuesta objetiva según RECIST v.1.1, se debe confirmar mediante el mismo método al menos cuatro semanas después de la fecha de la primera documentación de respuesta.
    Los pacientes clínicamente estables con sospecha de pseudoprogresión (es decir, el tumor crece por el efecto del tratamiento en lugar de una progresión real de la enfermedad) y en caso de que el investigador haya percibido beneficio clínico, pueden continuar el tratamiento y las evaluaciones radiológicas a pesar de la progresión definida por RECIST.
    Se registrará y documentará la fecha de respuesta, la fecha de EP radiológica o clínica, y la fecha de fallecimiento, según proceda.
    E.5.1.1Timepoint(s) of evaluation of this end point
    PhaseI
    The Sponsor or delegate will organize raw data review and discussion (e.g., a teleconference) with the Investigators as appropriate (e.g., monthly or after the first patient enrolled at a given dose level has completed the first cycle or when a dose level cohort has been completed)
    Fase I
    El Promotor o su delegado organizará una revisión y discusión de los datos brutos (por ejemplo, una teleconferencia) con los Investigadores según corresponda (por ejemplo, mensualmente o después de que el primer paciente incluido en un nivel de dosis determinado haya completado el primer ciclo o cuando se haya completado una cohorte de nivel de dosis).
    E.5.2Secondary end point(s)
    Both phases
    • Safety: patients will be evaluable for safety if they have received at least one partial infusion of atezolizumab and PM01183. AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.5.
    • Efficacy: antitumor activity of the combination will be evaluated in terms of:
    -Progression-free survival defined as the time from the date of registration to the date of documented progression per RECIST v.1.1 or death (regardless of the cause of death). If the patient receives further antitumor therapy or is lost to follow-up before PD, PFS will be censored at the date of last tumor assessment before the date of subsequent antitumor therapy.
    -Duration of response (DoR) will be calculated from the date of first documentation of response per RECIST v.1.1 (complete or partial response, whichever comes first) to the date of documented PD or death. The censoring rules defined above for PFS will be used for DoR.
    -Clinical benefit defined as percentage of evaluable patient with complete response, partial response or stable disease lasting ≥3 months, as defined by RECIST v1.1.
    -Overall survival (OS): calculated from the date of registration to the date of death (death event) or last contact (in this case, survival will be censored on that date).
    -Mid- and long-term survival (OS at 12, 18 and 24 months) will be the Kaplan-Meier estimates of the probability of being alive at these time points.
    • Pharmacokinetics: PK parameters will be evaluated in plasma by standard non-compartmental methods (compartmental modeling may be performed if appropriate).
    • Pharmacogenetics: factors that may help to explain individual variability in main PK parameters, the presence or absence of germline mutations or polymorphisms that may be involved in the metabolism and/or transport of PM01183 will be analyzed in leukocyte DNA extracted.
    • Pharmacogenomics: In order to determine predictive/prognostic markers of response and/or resistance to PM01183 and atezolizumab, tumor samples available at baseline will be evaluated in all patients. In addition, blood samples (Day 1 of every cycle and end-of-treatment) and on-treatment tumor sample from biopsy (4th to 6th weeks after treatment onset) will be obtained and evaluated for patients consenting to PGx sub-study.
    Ambas fases
    •Seguridad: los pacientes serán evaluables para la seguridad si han recibido al menos una perfusión parcial de atezolizumab y PM01183. Se clasificarán los AA según los Criterios de terminología común de acontecimientos adversos del National Health Institute (CTCAE del NCI) v.5.
    •Eficacia: se evaluará la actividad antitumoral de la combinación en términos de:
    -Supervivencia libre de progresión definida como el momento desde la fecha de registro hasta la fecha de progresión documentada por RECIST v.1.1 o fallecimiento (independientemente de la causa del fallecimiento). Si el paciente recibe terapia antitumoral posterior o se pierde el seguimiento antes de la EP, se censurará la SLP en la fecha de la última evaluación tumoral antes de la fecha del siguiente tratamiento antitumoral.
    -La duración de respuesta (DR) se calculará desde la fecha de la primera documentación de respuesta según RECIST v.1.1 (respuesta completa o parcial, aquello que ocurra primero) hasta la fecha de la EP o fallecimiento documentado. Se utilizarán para DR las reglas de censura definidas anteriormente para la SLP.
    -Beneficio clínico definido como el porcentaje de pacientes evaluables con respuesta completa, respuesta parcial o enfermedad estable que dure ≥3 meses, según lo definido por RECIST v1.1.
    -Supervivencia global (SG): calculada desde la fecha de registro hasta la fecha de fallecimiento o último contacto (en este caso, la supervivencia se censurará en esa fecha).
    -La supervivencia a medio y largo plazo (SG en los meses 12, 18 y 24) será la estimación de Kaplan-Meier de la probabilidad de estar vivo en estos momentos.
    •Farmacocinética: se evaluarán los parámetros PK en plasma mediante métodos estándares no compartimentales (se puede realizar el modelo compartimental si procede).
    •Farmacogenética: se analizarán los factores que pueden ayudar a explicar la variabilidad individual en los parámetros principales de PK, la presencia o ausencia de mutaciones de la línea germinal o polimorfismos que pueden estar implicados en el metabolismo o el transporte de PM01183 en el ADN leucocitario extraído.
    •Farmacogenómica: para determinar los marcadores de respuesta predictivos/de pronóstico o resistencia a PM01183 y atezolizumab, se evaluarán las muestras tumorales disponibles en la basal en todos los pacientes. Además, se obtendrán y evaluarán las muestras de sangre (día 1 de cada ciclo y fin de tratamiento) y la muestra tumoral durante el tratamiento de la biopsia (de la 4ª a la 6ª semana después del comienzo del tratamiento) en pacientes que den su consentimiento para el subestudio de PGx
    E.5.2.1Timepoint(s) of evaluation of this end point
    see Protocol
    ver Protocolo
    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 Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    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 No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    maximum tolerated dose
    maxima dosis tolerada
    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
    diseño clásico 3+3
    classical 3+3 design
    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.8.3 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 concerned5
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    tratm continue until:Disease progres as per RECIST1.1.clinically stable patients w/ suspected pseudoprogression&Investigator’s perceived clinical benefit might continue treatm despite RECIST-defined progression•Unacceptable toxicity•Intercurrent illness of sufficient magnitude to preclude fulfillment of appropriate re-treatment criteria&/or safety contin of study•Patient refusal&/or non-compliance w/study requirements•Treatm delay>15d due toxicity&/or DLT(except clear benefit&Sponsor’s approval)
    tratm continúa hasta:•Progresión enfermedad según RECIST1.1.Pacientes clínic estables con sospecha pseudoprogresión y beneficio clínico del investigador pueden continuar tratamiento a pesar del RECIST•Toxicidad inaceptable•Enfermedad intercurrente magnitud suficiente que impide cumplimiento de criterios de nuevo tratamiento apropiado/continuación de seguridad•Paciente rechaza/incumple requisitos de estudio•Retraso tratm>15d por toxicidad/TLD(excep beneficio clínico claro,aprobación Promotor)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months30
    E.8.9.1In the Member State concerned days
    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: 25
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 25
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 25
    F.4.2.2In the whole clinical trial 25
    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)
    Standard of Care
    Practica clínica Habitual
    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 Decision2019-11-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-10-08
    P. End of Trial
    P.End of Trial StatusOngoing
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