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    Summary
    EudraCT Number:2018-000469-35
    Sponsor's Protocol Code Number:CL03-ORY-1001SCLC
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-08-02
    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 number2018-000469-35
    A.3Full title of the trial
    A pilot study to assess the safety, tolerability, dose finding and efficacy ORY-1001 in combination with platinum-etoposide chemotherapy in patients with relapsed, extensive-stage disease small cell lung cancer
    Estudio piloto para evaluar la seguridad, tolerabilidad, búsqueda de dosis y eficacia de ORY-1001 en combinación con Platino-Etopósido en pacientes con cáncer de pulmón de células pequeñas extendido y recidivante.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to assess the safety, tolerability, dose finding and efficacy ORY-1001 in combination with platinum-etoposide chemotherapy in patients with relapsed, extensive-stage disease small cell lung cancer
    Estudio para evaluar la seguridad, tolerabilidad, búsqueda de dosis y eficacia de ORY-1001 en combinación con Platino-Etopósido en pacientes con cáncer de pulmón de células pequeñas extendido y recidivante.
    A.3.2Name or abbreviated title of the trial where available
    CLEPSIDRA
    CLEPSIDRA
    A.4.1Sponsor's protocol code numberCL03-ORY-1001SCLC
    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 SponsorOryzon Genomics S. A.
    B.1.3.4CountrySpain
    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 supportOryzon Genomics S. A.
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationOryzon Genomics S. A.
    B.5.2Functional name of contact pointRoger Bullock
    B.5.3 Address:
    B.5.3.1Street AddressSant Ferran 74
    B.5.3.2Town/ cityCornellà de Llobregat
    B.5.3.3Post code08940
    B.5.3.4CountrySpain
    B.5.4Telephone number+34 93 515 13 13
    B.5.5Fax number+34 93 377 40 28
    B.5.6E-mailrbullock@oryzon.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 nameORY-1001.2HCl
    D.3.2Product code PEI 13-106
    D.3.4Pharmaceutical form Powder for oral solution
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNORY-1001
    D.3.9.1CAS number 1431303-72-8
    D.3.9.3Other descriptive nameORY-1001
    D.3.9.4EV Substance CodeSUB124833
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4.19
    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: 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.2.1.1.2Name of the Marketing Authorisation holderEtopósido
    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 nameEtoposide
    D.3.2Product code Etoposide
    D.3.4Pharmaceutical form Concentrate for solution for injection
    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 INNETOPOSIDE
    D.3.9.1CAS number 33419-42-0
    D.3.9.3Other descriptive nameETOPOSIDE
    D.3.9.4EV Substance CodeSUB07337MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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.2.1.1.2Name of the Marketing Authorisation holderCarboplatino
    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 nameCarboplatin
    D.3.2Product code Carboplatin
    D.3.4Pharmaceutical form Concentrate for solution for injection
    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 INNCARBOPLATIN
    D.3.9.1CAS number 41575-94-4
    D.3.9.3Other descriptive nameCARBOPLATIN
    D.3.9.4EV Substance CodeSUB06614MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration numberAUC 5-6
    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: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.2Name of the Marketing Authorisation holderCisplatino
    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 nameCisplatin
    D.3.2Product code Cisplatin
    D.3.4Pharmaceutical form Concentrate for solution for injection
    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 INNCISPLATIN
    D.3.9.1CAS number 15663-27-1
    D.3.9.3Other descriptive nameCISPLATIN
    D.3.9.4EV Substance CodeSUB07483MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number75
    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
    Relapsed, extended-stage disease small cell lung cancer (ED SCLC).
    Cáncer de pulmón de célula pequeña con enfermedad extendida (CPCP) y recidivante.
    E.1.1.1Medical condition in easily understood language
    Relapsed, extended-stage disease small cell lung cancer.
    Cáncer de pulmón de célula pequeña con enfermedad extendida y recidivante.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10041071
    E.1.2Term Small cell lung cancer stage unspecified
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the maximum tolerated dose (MTD), schedule and recommended Phase II dose (RP2D) of ORY-1001 in combination with platinum-etoposide based chemotherapy (EP) in patients with relapsed, extensive-stage disease small cell lung cancer (ED SCLC). This will include characterization of ORY-1001 dose-limiting toxicities (DLTs) and overall safety profile in this population.
    Determinar la dosis máxima tolerada (DMT), establecer una dosis recomendada de fase II (DRF2) de ORY-1001 en combinación con quimioterapia basada en platino-etopósido (PE) en pacientes con cáncer de pulmón de célula pequeña con enfermedad extendida (CPCP-EE) y recidivante. Esto incluirá la caracterización de las toxicidades limitantes de la dosis (TLD) de ORY-1001 y el perfil de seguridad general en esta población.
    E.2.2Secondary objectives of the trial
    -Tumor response according to RECIST v1.1
    -Duration of Response: the time from the first response (PR or CR) to disease progression or death from any cause, whichever occurs first
    -Time to progression: the time from first study treatment to disease progression
    -Time to response: the time from first study treatment to either a CR or PR
    -Objective Response: partial response plus complete response, confirmed by repeat assessments ≥ 4 weeks after initial documentation
    -Progression-Free Survival: the time from first study treatment to the first occurrence of disease progression or death, whichever occurs first
    -Overall Survival: the time from first study treatment, the length of time the patient is alive
    -To monitor ORY-1001 exposure and accumulation at steady state
    -To monitor ORY-1001 pharmacodynamics in terms of LSD1 target engagement (PD/TE) in peripheral blood mononuclear cells
    -Respuesta tumoral según RECIST v1.1
    -Duración de la respuesta: tiempo desde la 1ª respuesta (RP o RC) hasta la progresión de la enfermedad o la muerte por cualquier causa, lo que ocurra primero
    -Tiempo hasta la progresión: tiempo desde el 1er tto del estudio hasta la progresión de la enfermedad
    -Tiempo hasta la respuesta: tiempo transcurrido desde el 1er tto de estudio hasta una RC o RP
    -Respuesta objetiva: RP más RC, confirmada por evaluaciones repetidas ≥ 4 semanas después de la documentación inicial
    -Supervivencia libre de progresión: el tiempo desde el 1er tto del estudio hasta la 1ª aparición de la progresión de la enfermedad o la muerte, lo que ocurra primero
    -Supervivencia global: el tiempo desde el 1er tto del estudio, el tiempo que el paciente está vivo
    -Observar la exposición y acumulación de ORY-1001 en estado estacionario
    -Observar la farmacodinámica de ORY-1001 en relación con la interacción con la diana LSD1 (FD/ID) en las cel mononucleares de sangre periférica
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age ≥ 18 years.
    2. Patients who present a relapse ≥ 3 months and are candidate to re-challenge with platinum-based chemotherapy (TFI>90 days).
    3. Patient must have histologically- or cytologically-confirmed diagnosis of SCLC. Archival primary tumor tissue (formalin-fixed paraffin-embedded (FFPE) tissue is acceptable) should be provided to analyse predictive biomarkers.
    4. Positive results to ORY-1001 candidate predictive biomarkers confirmed by central laboratory through primary archival tumor tissue analysis.
    5. Patients with ECOG Performance Status 0-2.
    6. Patients with life expectancy of at least 12 weeks.
    7. Patients with measurable lesions according to RECIST criteria 1.1.
    8. Patients with an adequate bone marrow reserve: absolute neutrophil (segmented and bands) count (ANC) ≥1500 cells/μL, platelet count ≥100,000 cells/μL and hemoglobin ≥9 g/dL.
    9. Patients with preserved hepatic function: bilirubin ≤1.5 X ULN; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 X ULN.
    10. Patients with preserved renal function: serum creatinine <2.0mg/dL or calculated creatinine clearance >60mL/min.
    11. Patient must be able to swallow and retain orally administered study treatment.
    12. For women of childbearing potential: Agreement to remain abstinent (refrain from heterosexual intercourse) or use one highly effective (less than 1% failure rate) method of contraception during the treatment period and for at least 28 days after the last dose of ORY-1001.
    • A woman is considered to be of childbearing potential if she is post-menarcheal, has not reached a post-menopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).
    • Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, established proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intra-uterine devices, and copper intra-uterine devices.
    • The reliability of sexual abstinence should be evaluated in relation to the duration of clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception.
    For men: Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below:
    • With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for at least 4 months after the last dose of ORY-1001 to avoid exposing the embryo. Men must refrain from donating sperm during this same period.
    • The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence and withdrawal are not acceptable methods of contraception.
    13. Patients with ability to understand the requirements of the study, provide written informed consent and authorization of use and disclosure of protected health information, and agree to abide by the study restrictions and to return for the required assessments.
    1. Edad ≥18 años.
    2. Pacientes que presentan una recaída ≥3 meses y son candidatos para reiniciar la quimioterapia basada en platino (intervalo sin tratamiento [IST] >90 días).
    3. El paciente debe tener un diagnóstico histológica o citológicamente confirmado de CPCP. Se debe proporcionar tejido tumoral primario de archivo (se acepta tejido incluido en parafina, fijado con formol [FFPE]) para analizar los biomarcadores predictivos.
    4. Resultados positivos para posibles biomarcadores predictivos de ORY-1001 confirmados por el laboratorio central a través del análisis del tejido tumoral primario de archivo.
    5. Pacientes con estado funcional del ECOG de 0-2.
    6. Pacientes con una esperanza de vida de al menos 12 semanas.
    7. Pacientes con lesiones medibles según los criterios RECIST 1.1.
    8. Pacientes con una reserva de médula ósea suficiente: recuento absoluto de neutrófilos (RAN) (segmentados y cayados) ≥1500 células/μl, recuento plaquetario ≥100 000 células/μl y hemoglobina ≥9 g/dl.
    9. Pacientes con función hepática conservada: bilirrubina ≤1,5 x LSN; alanina aminotransferasa (ALT) y aspartato aminotransferasa (AST) ≤3,0 x LSN.
    10. Pacientes con función renal conservada: creatinina sérica <2,0 mg/dl o aclaramiento de creatinina calculado >60 ml/min.
    11. El paciente debe poder tragar y retener el tratamiento del estudio administrado por vía oral.
    12. En mujeres con capacidad de concebir: estar de acuerdo en practicar la abstinencia (abstenerse de mantener relaciones heterosexuales) o usar un método anticonceptivo muy eficaz (tasa de fallo menor al 1%) durante el período de tratamiento y al menos durante 28 días después de la última dosis de ORY-1001.
    • Se considera que una mujer es capaz de concebir si es posmenárquica, no ha alcanzado un estado posmenopáusico (≥12 meses continuos de amenorrea sin una causa identificada que no sea la menopausia) y no se ha sometido a esterilización quirúrgica (extirpación de ovarios o útero).
    • Los ejemplos de métodos anticonceptivos con una tasa de fallo <1% por año incluyen ligadura de trompas bilateral, esterilización masculina, uso adecuado establecido de anticonceptivos hormonales que inhiben la ovulación, dispositivos intrauterinos liberadores de hormonas y dispositivos intrauterinos de cobre.
    • La fiabilidad de la abstinencia sexual debe evaluarse en relación con la duración del ensayo clínico y el estilo de vida preferido y habitual de la paciente. La abstinencia periódica (por ejemplo, los métodos del calendario, ovulación, sintotérmicos o de posovulación) y la marcha atrás no se aceptan como métodos anticonceptivos.
    En hombres: estar de acuerdo en practicar la abstinencia (abstenerse de mantener relaciones heterosexuales) o usar métodos anticonceptivos, y estar de acuerdo en abstenerse de donar esperma, como se define a continuación:
    • Con parejas femeninas con capacidad de procrear o parejas femeninas embarazadas, los hombres deben practicar la abstinencia o usar un preservativo más un método anticonceptivo adicional que combinados tengan una tasa de fallo <1% al año durante el período de tratamiento y al menos durante 4 meses después del última dosis de ORY-1001 para evitar la exposición del embrión. Los hombres deben abstenerse de donar esperma durante este mismo período.
    • La fiabilidad de la abstinencia sexual debe evaluarse en relación con la duración del ensayo clínico y el estilo de vida preferido y habitual del paciente. La abstinencia periódica y la marcha atrás no se aceptan como métodos anticonceptivos.
    13. Los pacientes con capacidad para entender los requisitos del estudio proporcionan un consentimiento informado por escrito y la autorización para usar y divulgar información médica protegida, y aceptan cumplir las restricciones del estudio y regresar para las evaluaciones requeridas.
    E.4Principal exclusion criteria
    1. Patients with symptomatic and/or unstable pre-existing brain metastases; has known active central nervous system (CNS) metastases. Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment.
    2. Patients with other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception of basal cell carcinoma or cervical cancer in situ.
    3. Patients who currently participate or have participated in a study of an investigational agent or are using an investigational device within 28 days of the first dose of treatment.
    4. Patients who have had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
    5. Patiens who have undergone major surgery, he/she must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
    6. Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study including:
    • Unstable angina, symptomatic or otherwise uncontrolled arrhythmia (does not include stable, lone atrial fibrillation), QTcF > 480 ms based on the average of 3 screening electrocardiograms (ECGs), uncontrolled hypertension, symptomatic congestive heart failure (NYHA II, III, IV), myocardial infarction ≤ 6 months prior to first study treatment,serious uncontrolled cardiac arrhythmia, cerebrovascular accidents ≤ 6 months before study treatment start.
    • Any active (acute or chronic) or uncontrolled infection/disorders that impair the ability to evaluate the patient or for the patient to complete the study.
    • Non-malignant medical illnesses that are uncontrolled or whose control may be
    • Jeopardized by this study treatment, such as, severe diabetes mellitus that is not controlled with medical management.
    7. Patients with evidence of interstitial lung disease, or history of (non-infectious) pneumonitis that required steroids, or current pneumonitis.
    8. Patients with evidence of electrolyte imbalance, such as hypokalemia, hyperkalemia, hypocalcemia, hypercalcemia, hypomagnesemia, and hypermagnesemia of Grade > 1, as per NCI CTCAE, version 5.0. Treatment for correction of above electrolyte imbalances is permitted during screening to meet eligibility.
    9. Patients who refuse to potentially receive blood products and/or have a hypersensitivity to blood products.
    10. A physical exam or laboratory finding that contraindicates the use of investigational therapy or otherwise places the patient at excessively high risk for treatment, as determined by the Investigator.
    11. Patients with known bone marrow disorders which may interfere with bone marrow recovery (i.e., tumor involvement, fibrosis), or patients with delayed recovery from prior chemoradiotherapy (i.e., after radiation to the pelvis).
    12. Patients with known coagulopathy, platelet disorder or history of non-drug-induced thrombocytopenia.
    13. Patients with known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
    14. Patients with known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
    15. Patients with known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
    16. Patients with known history of active TB (Bacillus Tuberculosis).
    17. Patients with hypersensitivity to ORY-1001, EP, or to any of its excipients.
    18. Patients medicated with, or the expected need for treatment with, anti-depressants reported to have KDM1A/LSD1 inhibitory activity (such as tranylcypromine or phenelzine) within 28 days of treatment start.
    19. Use of strong CYP3A4 inducers while on study medication. CYP3A4 inducers must be discontinued 14 days prior to study drug administration.
    20. Patients with history of clinically significant bleeding, specifically any history of intracranial hemorrhage / hemorrhagic cardiovascular accident (CVA), or patients with gastrointestinal bleeding within the 12 months prior to study entry.
    21. Patients receiving therapeutic anti-coagulation or anti-platelet (anti-aggregant) therapies, except for therapeutic enoxaparin or low dose aspirin. Use of subcutaneous heparin prophylaxis, including low molecular weight heparin is also permitted.
    22. Any medical condition which, in the opinion of the Investigator, places the patient at unacceptable risk for toxicities if entered into the clinical study.
    1. Pacientes con metástasis cerebrales preexistentes sintomáticas y/o inestables; se sabe que tienen metástasis activas del SNC. Los pacientes con metástasis cerebrales tratados con anterioridad pueden participar siempre que sean estables (sin evidencia de progresión en estudios de imagen al menos durante 4 semanas antes de la 1ª dosis del tto del ensayo y cuando cualquier síntoma neurológico haya vuelto al nivel inicial), no tengan evidencia de metástasis cerebrales nuevas o en crecimiento, y no estén usando esteroides al menos durante 7 días antes del tto del ensayo
    2. Pacientes con otras neoplasias malignas concomitantes o diagnosticadas en los últimos 5 años, salvo el carcinoma de células basales o el cáncer de cuello uterino in situ
    3. Pacientes que actualmente participan o han participado en un estudio de un producto en investigación o están usando un dispositivo en investigación durante los 28 días anteriores a la 1ªdosis de tto.
    4. Pacientes que hayan recibido quimioterapia previa, terapia dirigida de moléculas pequeñas o radioterapia durante las 2 semanas previas al día 1 del estudio o que no se hayan recuperado de los acontecimientos adversos debidos a un fármaco administrado previamente
    5. Pacientes que se hayan sometido a una cirugía mayor; deben haberse recuperado adecuadamente de la toxicidad o de las complicaciones de la intervención antes de comenzar el tto
    6. Pacientes que tienen enfermedades graves o no controladas u otras enfermedades que puedan afectar a su participación en el estudio, lo que incluye:
    • Angina inestable, arritmia sintomática o no controlada (no incluye fibrilación auricular estable y aislada), QTcF >480 ms en según el promedio de 3 electrocardiogramas en la selección, hipertensión no controlada, insuficiencia cardíaca congestiva sintomática, infarto de miocardio ≤6 meses antes del primer tto del estudio, arritmia cardíaca no controlada grave, accidentes cerebrovasculares ≤6 meses antes del inicio del tto del estudio
    • Cualquier infección/trastorno activo o no controlado que afecte a la capacidad de evaluar al paciente o de que el paciente complete el estudio
    • Enfermedades no malignas que no están controladas o cuyo control pueda ser puesto en peligro por el tto de este estudio, como la diabetes mellitus grave que no esté controlada con tto médico
    7. Pacientes con evidencia de enfermedad pulmonar intersticial o antecedentes de neumonitis (no infecciosa) que requirió esteroides o neumonitis actual
    8. Pacientes con evidencia de desequilibrio electrolítico, como hipocalemia, hipercalemia, hipocalcemia, hipercalcemia, hipomagnesemia e hipermagnesemia de grado >1, según los CTCAE del NCI, v5.0. El tto para la corrección de los desequilibrios electrolíticos anteriores está permitido durante la selección para reunir los requisitos de idoneidad
    9. Pacientes que rechazan la posibilidad de recibir hemoderivados y/o tienen una hipersensibilidad a los productos sanguíneos
    10. Exploración física o resultado analítico que contraindique el uso del tto en invest o ponga al paciente en un riesgo excesivamente alto para el tto, según lo determine el investigador
    11. Pacientes con trastornos conocidos de la médula ósea que puedan interferir en la recuperación de la médula ósea o pacientes con un retraso en la recuperación de la quimiorradioterapia previa
    12. Pacientes con coagulopatía conocida, trastorno plaquetario o antecedentes de trombocitopenia no inducida por fármacos
    13. Pacientes con trastornos psiquiátricos o de abuso de sustancias conocidos que puedan interferir en la cooperación con los requisitos del ensayo
    14. Pacientes con antecedentes conocidos del VIH (anticuerpos del VIH 1/2)
    15. Pacientes con hepatitis B o hepatitis C activa conocida
    16. Pacientes con antecedentes conocidos de TB activa
    17. Pacientes con hipersensibilidad a ORY-1001, PE o a cualquiera de sus excipientes
    18. Pacientes medicados o que se prevé que van a necesitar tto con antidepresivos que tengan actividad inhibidora de KDM1A/LSD1 durante los 28 días posteriores al inicio del tto
    19. Uso de inductores potentes de CYP3A4 mientras se toma la medicación en estudio. Los inductores de CYP3A4 deben interrumpirse 14 días antes de la administración del fármaco del estudio
    20. Pacientes con antecedentes de hemorragia clínicamente significativa, específicamente antecedentes de hemorragia intracraneal/accidente cardiovascular hemorrágico o pacientes con hemorragia gastrointestinal durante los 12 meses previos a incorporarse al estudio
    21. Pacientes que reciben ttos anticoagulantes o antiplaquetarios (antiagregantes), excepto la enoxaparina terapéutica o la aspirina en dosis baja. También se permite el uso de profilaxis con heparina subcutánea, incluida la heparina de bajo peso molecular
    22. Cualquier enfermedad que, en opinión del investigador, ponga al paciente en riesgo inaceptable de toxicidad si se incorpora al estudio clínico
    E.5 End points
    E.5.1Primary end point(s)
    To asses safety, tolerability and dose finding of combo therapy
    Evaluar la seguridad, la tolerabilidad y la búsqueda de dosis del tratamiento combinado
    E.5.1.1Timepoint(s) of evaluation of this end point
    For a maximum of 4-6 cycles according to investigator criteria, or until disease progression/treatment failure, or unacceptable toxicity or study discontinuation, whichever occurs the first.
    Durante un máximo de 4-6 ciclos de acuerdo con los criterios del investigador, hasta la progresión de la enfermedad/fallo del tratamiento, la toxicidad sea inaceptable o la interrupción del estudio, lo que ocurra primero.
    E.5.2Secondary end point(s)
    1. Tumor response according to RECIST version 1.1
    2. Duration of Response (DOR) of combo therapy
    3. Time to progression (TTP) of combo therapy
    4. Time to response (TTR) of combo therapy
    5. Objective Response (OR ) of combo therapy
    6. Progression-Free Survival (PFS) of combo therapy
    7. Overall Survival (OS) of combo therapy
    8. To monitor ORY-1001 exposure and accumulation at steady state (PK)
    9. To monitor ORY-1001 pharmacodynamics in terms of LSD1 target engagement (PD/TE) in peripheral blood mononuclear cells (PBMCs)
    1. Respuesta tumoral según RECIST, versión 1.1.
    2. Duración de la respuesta (DR) del tratamiento combinado.
    3. Tiempo hasta la progresión (THP) del tratamiento combinado.
    4. Tiempo hasta la respuesta (THR) del tratamiento combinado.
    5. Respuesta objetiva (RO) del tratamiento combinado.
    6. Supervivencia libre de progresión (SLP) del tratamiento combinado.
    7. Supervivencia global (SG) del tratamiento combinado.
    8. Observar la exposición y la acumulación de ORY-1001 en estado estacionario (FC).
    9. Observar la farmacodinámica de ORY-1001 en relación con la interacción con la diana LSD1 (FD/ID) en las células mononucleares de sangre periférica (CMSP).
    E.5.2.1Timepoint(s) of evaluation of this end point
    For a maximum of 4-6 cycles according to investigator criteria, or until disease progression/treatment failure, or unacceptable toxicity or study discontinuation, whichever occurs the first.
    Durante un máximo de 4-6 ciclos de acuerdo con los criterios del investigador, hasta la progresión de la enfermedad/fallo del tratamiento, la toxicidad sea inaceptable o la interrupción del estudio, lo que ocurra primero.
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled 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 concerned4
    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
    LVLP
    LPLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned 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: 18
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 15
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state33
    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)
    According medical practice
    Acorde a 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 Decision2018-10-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-09-19
    P. End of Trial
    P.End of Trial StatusOngoing
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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