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    Summary
    EudraCT Number:2019-002261-35
    Sponsor's Protocol Code Number:MedOPP300
    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:2020-02-28
    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 number2019-002261-35
    A.3Full title of the trial
    “Phase I/II, Multicenter, Open-label, Clinical and Pharmacokinetic Study of Lurbinectedin (PM01183) in Combination with Pembrolizumab in Patients with Relapsed Small Cell Lung Cancer (the LUPER study).”
    Estudio fase I/II, multicéntrico, abierto, para evaluar la seguridad, eficacia y farmacocinética de lurbinectedina (PM01183) en combinación con pembrolizumab en pacientes con cáncer de pulmón de células pequeñas recidivante (estudio LUPER)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of Lurbinectedin (PM01183) in Combination with Pembrolizumab in Patients with Relapsed Small Cell Lung Cancer
    Estudio de Lurbinectedina en combinación con Pembrolizumab en pacientes con cáncer de pulmón microcítico recidivante.
    A.3.2Name or abbreviated title of the trial where available
    Lurbinectedin (PM01183) Combined with Pembrolizumab in Small Cell Lung Cancer.
    Lurbinectedina (PM01183) combinada con Pembrolizumab en cáncer de pulmón de células pequeñas
    A.4.1Sponsor's protocol code numberMedOPP300
    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 SponsorDr.Antonio Calles Blanco
    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 supportPharma Mar S.A
    B.4.2CountrySpain
    B.4.1Name of organisation providing supportMerck Sharp & Dohme de España S.A
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedica Scientia Innovation Research (MedSIR)
    B.5.2Functional name of contact pointOperations Unit
    B.5.3 Address:
    B.5.3.1Street AddressTorre Glòries. Avda. Diagonal 211, planta 27
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08018
    B.5.3.4CountrySpain
    B.5.4Telephone number34932214135
    B.5.6E-mailmarta.malo@medsir.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 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 namePembrolizumab
    D.3.2Product code MK-3475
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPembrolizumab
    D.3.9.1CAS number 1374853-91-4
    D.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/19/2143
    D.3 Description of the IMP
    D.3.1Product nameLurbinectedin
    D.3.2Product code PM01183
    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 INNLURBINECTEDIN
    D.3.9.1CAS number 497871-47-3
    D.3.9.4EV Substance CodeSUB190540
    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.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name KEYTRUDA (pembrolizumab, MK3475)
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePembrolizumab
    D.3.2Product code MK-3475
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPembrolizumab
    D.3.9.1CAS number 1374853-91-4
    D.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    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
    Small Cell Lung Cancer
    Cáncer de pulmón microcítico
    E.1.1.1Medical condition in easily understood language
    Small Cell Lung Cancer
    Cáncer de pulmón microcítico
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10041067
    E.1.2Term Small cell lung cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase I stage:
    (1) Objective: To determine the MTD and the recommended phase II dose (RD) of PM01183 in combination with pembrolizumab in patients with relapsed SCLC.

    Phase II stage:
    (1) Objective: To assess the efficacy of PM01183 in combination with pembrolizumab in terms of ORR, according to RECIST 1.1, in patients with relapsed SCLC.
    Fase I:
    (1) Objetivo: determinar la DMT y la dosis recomendada para la fase II (DR) de PM01183 en combinación con pembrolizumab en pacientes con CPCP recidivante.

    Fase II:
    (1) Objetivo: evaluar la eficacia de PM01183 en combinación con pembrolizumab en cuanto a TGR, según RECIST 1.1 en pacientes con CPCP recidivante.
    E.2.2Secondary objectives of the trial
    Phase I stage
    (1)to obtain preliminary information on the clinical antitumor activity of this combination in patients with relapsed SCLC
    (2)to determine the MTD and the RD of PM01183 in combination with pembrolizumab with mandatory primary prophylaxis with G-CSF in patients with relapsed SCLC (if DLTs of this combination are exclusively related to neutropenia)
    Phase II stage
    (1)to further characterize the antitumor activity of this combination as per RECIST 1.1 in terms of: ORR or stable disease (SD) ≥3 months);DOR;PFS;OS
    Both stages
    (1)To characterize the safety profile and feasibility of PM01183 in combination with pembrolizumab in patients with relapsed SCLC
    (2)To characterize the plasma pharmacokinetics (PK) of PM01183 in this combination and to detect major drug-drug PK interactions
    (3)to perform a PGt analysis
    (4)to perform a PGx analysis in tumor samples of patients exposed to PM01183 and pembrolizumab in order to assess potential markers of response and/or resistance
    Fase I
    1)obtener información preliminar sobre la actividad antitumoral clínica de esta combinación en pacientes con CPCP recidivante
    2)determinar la DMT y la DR de PM01183 en combinación con pembrolizumab con profilaxis primaria obligatoria con G-CSF en pacientes con CPCP recidivante (si las TLD de esta combinación están exclusivamente relacionadas con neutropenia)
    Fase II
    1)continuar caracterizando la actividad antitumoral de esta combinación según RECIST 1.1 en cuanto a:TGR o enfermedad estable que dure más de 3 meses;DR;SLP;SG.
    Ambas fases:
    1)caracterizar perfil de seguridad y viabilidad de PM01183 en combinación con pembrolizumab en pacientes con CPCP recidivante
    2)caracterizar la PK en plasma de PM01183 en esta combinación y detectar las interacciones fármaco-fármaco importantes de PK
    3)realizar un análisis PGt
    4)realizar un análisis PGx en muestras tumorales de pacientes expuestos a PM01183 y pembrolizumab para evaluar marcadores potenciales de respuesta o resistencia
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Participants are eligible to be included in the study only if all of the following criteria apply:
    1. Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of SCLC whose disease has progressed
    after first-line chemotherapy-based regimen will be enrolled in this study.
    2. At least 4 weeks since the last anticancer therapy.
    3. Male participants: a male participant must agree to use a contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 120 days after the
    last dose of study treatment and refrain from donating sperm during this period.
    4. Female participants: a female participant is eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies:
    a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the
    treatment period and for at least 90 days after the last dose of study treatment.
    5. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
    6. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE)
    tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.
    Note: If submitting unstained cut slides, newly cut slides should be submitted to the testing laboratory within 14 days from the date slides are cut.
    7. Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1.
    Evaluation of ECOG PS is to be performed within 7 days prior to the date of allocation/randomization.
    8. Have adequate organ function as defined in the following table (Table 1)*see protocol pages 28 & 29. Specimens must be collected within 10 days prior to the start of study treatment.
    9. Recovery to NCI-CTCAE grade ≤1 or to baseline from any AE derived from previous treatment (excluding alopecia and/or cutaneous toxicity and/or peripheral sensory neuropathy and/or asthenia, all grade ≤2 and/or correctable electrolyte abnormality with supplementation).
    10. Patients included in the expansion cohort at the RD (phase I stage) and all patients included in the phase II stage must have:
    a) Measurable disease according to RECIST 1.1; and
    b) Documented disease progression during or immediately after last therapy according to any of the aforementioned criteria.
    Los participantes únicamente son elegibles para ser incluidos en este estudio si cumplen todos los criterios siguientes:
    1. Se incluirá en este estudio a participantes de ambos sexos mayores de 18 años de edad el día de la firma del consentimiento informado con un diagnóstico histológicamente confirmado de CPCP y cuya enfermedad haya progresado después de una pauta basada en quimioterapia de primera línea.
    2. Deben haber transcurrido al menos 4 semanas desde la última terapia contra el cáncer.
    3. Hombres participantes: los hombres que participen deberán aceptar utilizar un anticonceptivo como se detalla en el anexo 3 de este protocolo durante el período de tratamiento y durante al menos 120 días después de la última dosis del tratamiento del estudio, y abstenerse de donar esperma durante este período.
    4. Mujeres participantes: las mujeres serán elegibles para participar si no están embarazadas (véase el Anexo 3), ni en período de lactancia, y si se cumple al menos una de las condiciones siguientes:
    a.) No se trata de una mujer en edad fértil (MEF) tal y como se define en anexo 3 O b.) Se trata de una MEF que acepte aplicar las medidas anticonceptivas de anexo 3 durante el período de tratamiento y durante al menos los 90 días posteriores a la última dosis del tratamiento del estudio.
    5. El participante (o su representante legal, si corresponde) da su consentimiento informado por escrito para el ensayo.
    6. Haber proporcionado una muestra de tejido tumoral archivada o una biopsia de una lesión tumoral con aguja gruesa o excisional recién obtenida y que no haya sido irradiada previamente. Se prefieren los bloques de tejido fijados en formalina y embebidos en parafina (FFPE) a las láminas. Se prefieren las biopsias recién obtenidas al tejido archivado.
    Nota: si se presentan láminas cortadas sin teñir, las láminas recién cortadas deberán enviarse al laboratorio de análisis en un plazo de 14 días a partir de la fecha en que se corten las láminas.
    7. Presentar un estado funcional (PS) del Grupo Cooperativo Oncológico del Este (ECOG) de 0 a 1. La evaluación de PS del ECOG debe realizarse durante los 7 días anteriores a la fecha de asignación/aleatorización.
    8. Presentar una función orgánica adecuada según se define en la tabla siguiente (Tabla 1)* Consultar Resumen Protocolo, páginas 15 y 16. Las muestras deben recogerse durante los 10 días anteriores al inicio del tratamiento del estudio
    9. Recuperación a grado CTCAE del NCI ≤1 o al valor basal de cualquier AA derivado de un tratamiento previo (excluyendo alopecia o toxicidad cutánea o neuropatía sensorial periférica o astenia, todos ellos de grado ≤2 o anomalía electrolítica corregible con suplementación).
    10. Los pacientes incluidos en la cohorte de expansión en la DR (fase I) y todos los pacientes incluidos en la fase II deben tener:
    a) Enfermedad medible según los criterios RECIST 1.1. y
    b) progresión documentada de la enfermedad durante o inmediatamente después del último tratamiento de acuerdo con cualquiera de los criterios antes mencionados.
    E.4Principal exclusion criteria
    1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation.
    2. Has had prior treatment with or exposure to: PM01183, Radioimmunoconjugates, T-cell or other cell-based or biologic therapies, Experimental anti-tumor vaccines; therapies that target any T-cell co-stimulation or checkpoint pathways, such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti CTLA-4 antibody, including ipilimumab; or other medicines specifically targeting Tcells.
    3. Has received prior radiotherapy within 2 weeks of start of study treatment.
    4. Has had radiotherapy (RT) in more than 35% of the bone marrow.
    5. Has a history of previous bone marrow and/or stem cell transplantation and allogenic transplant.
    6. Has an impending need for RT (e.g., painful bone metastasis and/or risk of spinal cord compression).
    7. Has received a live vaccine within 30 days prior to the first dose of study drug.
    8. Has any of the following concomitant diseases/conditions:
    a)History or presence of unstable angina, myocardial infarction, congestive heart failure, or clinically significant valvular heart disease within last year.
    b)Symptomatic arrhythmia or any uncontrolled arrhythmia requiring ongoing treatment.
    c)History of idiopathic, pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis or evidence of active pneumonitis on screening chest CT-scan. History of radiation pneumonitis in radiation field (fibrosis) is permitted, as long as it is asymptomatic and no steroids are needed.
    d)Known history of active neurologic paraneoplastic syndrome.
    e)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).
    f)Limitation of the patient’s ability to comply with the treatment or follow-up protocol.
    g)Any other major illness that, in the Investigator’s judgment, will substantially increase the risk associated with the patient’s participation in this study.
    9. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
    10. Has active autoimmune disease that has required systemic treatment in the past 2 years
    11. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
    12. Has an active infection requiring systemic therapy.
    13. Has a known history of Human Immunodeficiency Virus (HIV).
    14. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA is detected) infection.
    15. Has a known history of active tuberculosis (Mycobacterium tuberculosis).
    16. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator.
    17. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
    18. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.
    1. Una MEF con una prueba de embarazo positiva en orina durante las 72 horas anteriores a la asignación
    2. Haber recibido tratamiento previo con o exposición a: PM01183; Radioinmunoconjugados;Tratamiento con células T u otros tratamientos celulares o biológicos;Vacunas antitumorales experimentales; tratamientos dirigidos a las vías de coestimulación de células T o de puntos de control inmunitario, como anticuerpos antiPD-1, anti-PD-L1, anti-PD-L2, anti-CD137 o anti-CTLA-4, incluyendo ipilimumab;
    u otros medicamentos dirigidos específicamente a las células T.
    3. Haber recibido radioterapia previa durante las 2 semanas anteriores al inicio del tratamiento del estudio
    4. Haber recibido radioterapia en más del 35 % de la médula ósea.
    5. Tener antecedentes de trasplante de médula ósea o células madre y trasplante alogénico.
    6. Tener necesidad inminente de RT (p. ej., metástasis ósea dolorosa o riesgo de compresión de la médula espinal).
    7. Haber recibido una vacuna viva durante los 30 días anteriores a la primera dosis del fármaco del estudio.
    8. Tener alguna de las siguientes enfermedades o condiciones concomitantes:
    a) Antecedentes o presencia de angina inestable, infarto de miocardio, insuficiencia cardíaca congestiva o cardiopatía valvular clínicamente significativa durante el último año.
    b) Arritmia sintomática o cualquier arritmia no controlada que requiera tratamiento continuo.
    c) Antecedentes de fibrosis pulmonar idiopática, neumonía organizativa, neumonitis inducida por fármacos, neumonitis idiopática o evidencia de neumonitis activa según la TC de tórax en la selección. Se permiten antecedentes de neumonitis por radiación en el campo de radiación (fibrosis), siempre y cuando sea asintomática y no se necesiten esteroides.
    d) Antecedentes de síndrome paraneoplásico neurológico activo.
    e) 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).
    f) Limitación de la capacidad del paciente de cumplir con el protocolo de tratamiento o seguimiento.
    g) Cualquier otra enfermedad mayor que, según el criterio del investigador, aumentará considerablemente el riesgo de la participación del paciente en este estudio
    9. Presentar un diagnóstico de inmunodeficiencia o estar recibiendo tratamiento crónico con esteroides sistémicos (en dosis superiores a 10 mg diarios de equivalente de prednisona) o cualquier otra forma de tratamiento inmunosupresor durante los 7 días anteriores a la
    primera dosis del fármaco del estudio
    10. Enfermedad autoinmune activa que haya requerido tratamiento sistémico durante los dos años anteriores
    11. Tener antecedentes de neumonitis (no infecciosa) que haya requerido esteroides o padecer neumonitis actualmente.
    12. Tener una infección activa que requiera tratamiento sistémico.
    13. Tener antecedentes del virus de la inmunodeficiencia humana (VIH).
    14. Tener antecedentes de infección activa por el virus de la hepatitis B (definido como antígeno de superficie de la hepatitis B [HBsAg] reactivo) o infección activa por el virus de la hepatitis C (definido como ARN del VHC). Nota: no se requiere ninguna prueba de hepatitis B y hepatitis C a menos que así lo exija la autoridad sanitaria local.
    15. Tener antecedentes de tuberculosis activa (Mycobacterium tuberculosis).
    16. Tener antecedentes o evidencia actual de cualquier condición, tratamiento o anomalía de laboratorio que pudiera confundir los resultados del estudio, interferir en la participación del sujeto durante todo el estudio, o que el investigador a cargo del tratamiento considere
    que al sujeto no le conviene participar
    17. Tener trastornos psiquiátricos o trastornos por abuso s que pudieran interferir en el cumplimiento de los requisitos del ensayo.
    18. Estar embarazada o en periodo de lactancia, o prever concebir o engendrar hijos durante el periodo previsto del estudio, desde la visita de selección hasta 120 días después de la última dosis del tratamiento del ensayo.
    E.5 End points
    E.5.1Primary end point(s)
    Phase I Stage
    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 develop a DLT in Cycle 1.
    •The RD will be the highest dose level explored at which less than one third of evaluable patients develop a DLT during Cycle 1.
    If the DLTs of the PM01183 and pembrolizumab 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 Stage
    The primary objective of this stage is to assess the antitumor activity of PM01183 combined with pembrolizumab in terms of ORR, defined as the percentage of evaluable patients with a confirmed response, either complete (CR) or partial (PR).
    The ORR will be assessed using the RECIST 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 computed tomography [CT]-scan, magnetic resonance imaging [MRI]).
    Radiological tumor assessment will be performed at baseline, and every 2 cycles from the onset of the study treatment until evidence of PD. If an objective response is observed, according to the RECIST 1.1, it must be confirmed by the same method at least 4 weeks after the date of the first documentation of response.
    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 MDT y DR:
    • La Maxima dosis Tolerada (MDT) será el nivel de dosis más bajo explorado durante la escalada de la dosis en el que uno de tres pacientes evaluables desarrollan una Toxicidad limitante de dosis (TLD) en el ciclo 1.
    • La Dosis recomendada (DR) será el nivel de dosis más alto explorado en el que uno de tres pacientes evaluables desarrollan una Toxicidad limitante de dosis (TLD) en el ciclo 1.
    Si las TLDs de la combinación PM01183 y pembrolizumab sin profilaxis con G-CSF están relacionadas exclusivamente con la neutropenia, la MDT y la DR también se determinarán con la profilaxis primaria con G-CSF.

    Toxicidades limitantes de la dosis:
    Las TLDs se definen como cualquier evento adverso y anomalías de laboratorio relacionadas con el tratamiento en estudio durante el primer ciclo de tratamiento y el cumplimiento de al menos uno de los criterios descritos a continuación:

    . Neutropenia Grado 4 (recuento absoluto de neutrofilos (RAN) <0.5 x 109/L) de más de 3 dias.

    . Neutropenia Grado 3 - RAN 0.5-1.0 x 109/L) de más de 7 dias.

    . Neutropenia febril o cualquier duración de sepsis neutropénica

    . Trombocitopenia de Grado 4 (plaquetas <25 x 109/L) o Grado 3 con cualquier episodio de sangrado mayor que requiera una tranfusión de plaquetas.

    . Aumento de alanina aminotransferasa (ALT) y/o Aspartato Aminotransferasa (AST) de Grado 4 y/o aumento en Grado 3 con duración de más de 14 días

    . Aumento de grado 2 o mayor de ALT o AST y con un incremento de bilirubina total de ≥2.0 x Limite superior Normal y con una Fosfatasa Alcalina normal.

    . Cualquier otro EA no hematológico de grado 3 o 4 que sea sospechoso de estar relacionado con los fármaco(s) del estudio excepto nauseas /vómitos (a no ser que el paciente esté recibiendo un régimen antiemético óptimo), reacciones de hipersensibilidad, extravasaciones, astenia grado 3 con duración de menos de una semana, y anomalías bioquímicas aisladas clínicamente no relevantes (eg. Aumento aislado de la GGT.) En cualquier caso, la relevancia clínica debe ser discutida entre los miembros del Comité de Dirección Científica, tal y como se define en la sección 8.4 del protocolo, y también con Pharma Mar y MSD.





    Fase II

    El objetivo principal de esta etapa es evaluar la actividad antitumoral de PM01183 combinada con pembrolizumab en términos de tasa global de respuesta (TGR o ORR), definida como el porcentaje de pacientes evaluables con una respuesta confirmada, ya sea completa (RC) o parcial (RP).

    La TGR o ORR se evaluará utilizando el RECIST 1.1 en un conjunto de lesiones medibles identificadas al inicio del estudio como lesiones objetivo o como lesiones no objetivo (si las hay), y se seguirá hasta la progresión de la enfermedad (PE) mediante un método apropiado (p. Ej., Tomografía computarizada helicoidal [TC]) exploración, resonancia magnética [MR]).

    La evaluación radiológica del tumor se realizará al inicio del estudio y cada 2 ciclos desde el inicio del tratamiento del estudio hasta la evidencia de PE. Si se observa una respuesta objetiva, de acuerdo con RECIST 1.1, debe confirmarse por el mismo método al menos 4 semanas después de la fecha de la primera documentación de respuesta.

    La fecha de respuesta, la fecha de PE radiológica o clínica y la fecha de fallecimiento se registrarán y documentarán, según corresponda.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase 1 stage: Until MTD and RD have been defined

    Phase 2 stage:Time from randomization to disease progression
    Periodo Fase 1: Hasta que DMT y DR se hayan definido.

    Periodo Fase 2:Desde la randomización hasta progresión de la enfermedad.
    E.5.2Secondary end point(s)
    Both Stages:Safety: patients will be evaluable for safety if they have received at least one partial infusion of PM01183. AEs will be graded according to the NCI-CTCAE v.5. Additionally, treatment compliance, in particular dose reduction requirements, skipped doses and/or cycle delays due to AEs, will be described.
    • Efficacy: preliminary antitumor activity in the phase I stage, will be evaluated according to the RECIST 1.1 (and the iRECIST 1.1, whenever applicable) at least 6 weeks after treatment initiation in all patients with measurable disease.
    During expansion at the RD in the phase II stage, antitumor activity will also be evaluated according to the RECIST 1.1 (and the iRECIST 1.1, whenever applicable) as described
    above.
    In both stages, a patient evaluable for efficacy should have received at least one complete cycle (including observation period) and must have had at least one tumor assessment as per
    RECIST 1.1, except if non-evaluability is due to treatment failure such as treatment-related AEs, death or early unequivocal PD outside the central nervous system (CNS).
    • Pharmacokinetics: PK parameters will be evaluated in plasma by standard noncompartmental methods (compartmental modeling may be performed if appropriate).
    • Pharmacogenetics: a blood sample will be collected at any time during the trial (but preferably just before treatment start in Cycle 1 along with the first PK sample) to analyze
    germline DNA for the presence or absence of mutations or polymorphisms in genes relevant for the metabolism and/or transport of PM01183 that may help explain individual variability
    in main PK parameters.
    • Pharmacogenomics: this exploratory analysis will be performed if there is evidence of clinical benefit in the cohort of patients with available samples for PGx analysis. The mutational status of factors involved in DNA repair mechanisms, or related to the
    mechanism of action of PM01183 or pembrolizumab, will be evaluated from available prior paraffin-embedded tumor tissue samples obtained at diagnosis or relapse. mRNA and/or
    protein expression levels of these factors might be also analyzed, if relevant. Potentially whole exome sequencing will also be analyzed. Their correlation with the clinical response and outcome after treatment will be assessed.
    En ambas etapas:
    Seguridad:Los pacientes serán evaluados por seguridad si han recibido al menos una infusión parcial de PM01183. Los EAs se calificarán de acuerdo con el NCI-CTCAE v.5. Adicionalmente, el cumplimiento del tratamiento y, en particular requisitos de reducción de dosis, dosis omitidas y / o retrasos del ciclo debido a EAs , será descrito.
    Eficacia:La actividad antitumoral preliminar en la fase I se evaluará de acuerdo con el RECIST 1.1 (y el iRECIST 1.1, cuando corresponda) al menos 6 semanas después del inicio del tratamiento en todos los pacientes con enfermedad medible.
    Durante la expansión en la dosis recomendada (DR) en la etapa de fase II, también se evaluará la actividad antitumoral de acuerdo con el RECIST 1.1 (y el iRECIST 1.1, cuando corresponda) tal y como se describe más arriba.

    En ambas etapas, un paciente evaluable para eficacia debe haber recibido al menos un ciclo completo (incluyendo el período observacional) y debe haber tenido al menos una evaluación tumoral según RECIST 1.1, excepto si la falta de evaluabilidad se debe al fracaso del tratamiento, como los relacionados con el tratamiento EAs, muerte o una temprana inequívoca PE fuera del sistema nervioso central (SNC).
    Farmacocinética:los parámetros de Farmacocinética (PK) se evaluarán en plasma mediante métodos estándar no compartimentados (se puede realizar un modelado compartimentado si es apropiado).
    Farmacogenética: se recogerá una muestra de sangre en cualquier momento durante el ensayo (aunque es preferible justo antes del inicio del tratamiento en el Ciclo 1 junto con la primera muestra de PK) para analizar ADN de línea germinal para la presencia o ausencia de mutaciones o polimorfismos en genes relevantes para el metabolismo y / o transporte de PM01183 que puede ayudar a explicar la variabilidad individual en los principales parámetros PK.
    Farmacogenómica: este análisis exploratorio se realizará si hay evidencia de beneficio clínico en la cohorte de pacientes con muestras disponibles para análisis de Farmacogenómica (PGx). El status mutacional de los factores involucrados en los mecanismos de reparación del ADN, o relacionados con el mecanismo de acción de PM01183 o pembrolizumab, se evaluará a partir de la disponibilidad de previas muestras de tejido tumoral incluidas en parafina obtenidas en el momento del diagnóstico o recaída. ARNm y / o los niveles de expresión de proteínas de estos factores también podrían analizarse, si es relevante. Potencialmente se analizará también la secuenciación completa del exoma. Su correlación con la respuesta clínica y resultado después del tratamiento será evaluado.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Time from randomization to disease progression
    Desde la randomización hasta progresión de la enfermedad
    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 No
    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 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
    To find MTD and RD
    Encontrar la MDT y la DR
    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.8.3 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 concerned3
    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
    LPLV at the end of the follow-up period. Unless premature termination of the study, end-of- study date will occur at one of the 2 following time points (whichever happens last):
    • The following visit after last dose of pembrolizumab is administered to the last patient in the study.
    • 12 months after the last patient has been enrolled (received 1st dose of treatment) in the study.
    Se define como la última visita del último paciente (LPLV) al final del periodo de seguimiento. A menos que se finalice prematuramente el estudio, la fecha de fin del mismo será una de las siguientes (aquello que ocurra en último lugar):
    •La visita posterior a la administración de la última dosis de pembrolizumab al último paciente del estudio.
    •12 meses después de que se haya incluido al último paciente (y que este haya recibido la primera dosis de tratamiento) en el estudio
    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 months
    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: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 22
    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 state42
    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
    Práctica 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 Decision2020-03-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-02-18
    P. End of Trial
    P.End of Trial StatusOngoing
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