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    Summary
    EudraCT Number:2016-005039-34
    Sponsor's Protocol Code Number:ASTX660-01
    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 number2016-005039-34
    A.3Full title of the trial
    Phase 1-2 Study of the Safety, Pharmacokinetics, and Preliminary Activity of ASTX660 in Subjects with Advanced Solid Tumors and Lymphomas
    Estudio en fase I-II de la seguridad, farmacocinética y actividad preliminar de ASTX660 en sujetos con tumores sólidos avanzados y linfomas
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of the safety, activity, and effect on the body of ASTX660 in people with advanced cancers.
    Estudio de la seguridad, actividad y efecto en el cuerpo de ASTX660 en personas con cáncer avanzado
    A.4.1Sponsor's protocol code numberASTX660-01
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02503423
    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 SponsorAstex Pharmaceuticals, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAstex Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstex Pharmaceuticals, Inc
    B.5.2Functional name of contact pointASTX660-01 Clinical Team
    B.5.3 Address:
    B.5.3.1Street Address4420 Rosewood Drive, Suite 200
    B.5.3.2Town/ cityPleasanton, CA
    B.5.3.3Post code94588
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1925 5602913
    B.5.5Fax number+1925 551 3226
    B.5.6E-mailASTX660-01MM@astx.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.3.2Product code ASTX660
    D.3.4Pharmaceutical form Capsule
    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 INNASTX660
    D.3.9.1CAS number 1799328-87-2
    D.3.9.2Current sponsor codeASTX660
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number180
    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 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.3.2Product code ASTX660
    D.3.4Pharmaceutical form Capsule
    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 INNASTX660
    D.3.9.1CAS number 1799328-87-2
    D.3.9.2Current sponsor codeASTX660
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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 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.3.2Product code ASTX660
    D.3.4Pharmaceutical form Capsule
    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 INNASTX660
    D.3.9.1CAS number 1799328-87-2
    D.3.9.2Current sponsor codeASTX660
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number90
    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
    Advanced Solid Tumors and Lymphomas that are metastatic or unresectable: cohort 1:Recurrent/metastatic head and neck squamous cell carcinoma; cohort 2:Relapsed or refractory diffuse large B-cell lymphoma; cohort 3:Progressive, refractory or relapsed peripheral T-cell lymphoma; cohort 4:Relapsed or refractory cutaneous T-cell lymphoma; cohort 5: Other tumor types that may have sensitivity to ASTX660: cohort 6: Cervical carcinoma not responsive or relapsed after standard therapy
    Tumores sólidos avanzados y linfomas metastásicos o no resecables;Cohortes: 1: Carcinoma epidermoide de cabeza y cuello recidivante/metastásico; 2: Linfoma difuso de células B grandes recidivante o resistente; 3: Linfoma de linfocitos T periféricos progresivo, resistente o recidivante; 4: Linfoma de linfocitos T cutáneos recidivante o resistente ; 5: Otros tumores con sensibilidad frente a ASTX660; 6: Carcinoma cervicouterino que no responde o recidivante tras tratamiento de referencia
    E.1.1.1Medical condition in easily understood language
    multiple tumour types (solid and liquid)
    Múltiples tipos de tumor (sólido y líquido)
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10012818
    E.1.2Term Diffuse large B-cell lymphoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 22.0
    E.1.2Level PT
    E.1.2Classification code 10011677
    E.1.2Term Cutaneous T-cell lymphoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10067821
    E.1.2Term Head and neck cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10008229
    E.1.2Term Cervical cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10034623
    E.1.2Term Peripheral T-cell lymphoma unspecified
    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 1: To assess safety, and to identify the maximum tolerated dose (MTD), the recommended Phase 2 dose (RP2D), and the recommended dosing regimen of ASTX660(Completed).
    • Phase 2: To assess preliminary efficacy, as determined by response rate in certain tumor types.
    • Fase I: Evaluar la seguridad e identificar la dosis máxima tolerada (DMT), la dosis recomendada para la fase II (DRF2) y la pauta posológica recomendada de ASTX660.
    • Fase II: Evaluar la eficacia preliminar, determinada mediante la tasa de respuesta en ciertos tipos de tumores.
    E.2.2Secondary objectives of the trial
    • To determine the pharmacokinetic (PK) parameters of orally administered ASTX660 in humans.
    • To evaluate other efficacy parameters, such as duration of response and progression-free survival.
    • To evaluate relevant pharmacodynamic (PD) targets and potential biomarkers of ASTX660 activity.
    • Determinar los parámetros de farmacocinética (FC) de ASTX660 administrado por vía oral en seres humanos.
    • Evaluar otros parámetros de eficacia, tales como la duración de la respuesta (DR) y la supervivencia sin progresión (SSP).
    • Evaluar objetivos de farmacodinámica (FD) relevantes y posibles biomarcadores de la actividad de ASTX660.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects must fulfill all of the following inclusion criteria.
    1. Able to understand and comply with the protocol and study procedures, understand the risks involved in the study, and provide written informed consent before any study-specific procedure is performed.
    2. Men and women 18 years of age or older.
    3. Subjects with histologically or cytologically confirmed advanced solid tumors or lymphoma that is metastatic or unresectable, and for whom standard life-prolonging measures are not available.
    a) For Phase 2 Cohort 3, subjects must have histologically confirmed PTCL (local pathology report) as defined by 2016 World Health Organization (WHO) classification. The following subtypes are eligible for the study: adult T-cell lymphoma/leukemia, extranodal natural killer (NK)/T-cell lymphoma nasal type, enteropathy-associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, hepatosplenic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, peripheral T-cell lymphoma not otherwise specified, angioimmunoblastic T-cell lymphoma, follicular T-cell lymphoma, nodal peripheral T-cell with T-follicular helper (THF) phenotype, and anaplastic large-cell lymphoma.
    4. For Phase 2 Cohorts 3 and 4, patients must have evidence of documented progressive disease and must have received at least two prior systemic therapies [Phase 2 Cohort 3 and 4].
    a) Subjects with CD30-positive lymphoma must have received, be ineligible for, or intolerant to brentuximab vedotin.
    b) Subjects with mycosis fungoides or Sezary syndrome must have received, be ineligible, or intolerant to mogamulizumab.
    5. In the Phase 2 portion of the protocol only, subjects must have measurable disease according to response criteria appropriate to their type of cancer (as explained in Section 9.1).
    a) For Phase 2 Cohort 3 (PTCL), measurable disease by contrast-enhanced diagnostic CT (at least 1 nodal lesion ≥1.5 cm or extranodal lesions >1.0 cm) is required.
    6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
    7. Acceptable organ function, as evidenced by the following laboratory data:
    a. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.0 × upper limit of normal (ULN).
    b. Total serum bilirubin ≤1.5 × ULN.
    c. Absolute neutrophil count (ANC):
    o Phase 1 and 2 (except subjects with known lymphoma): ≥1500 cells/mm3.
    o Phase 2 subjects with known lymphoma: ≥1000 cells/mm3 (≥750 cells/mm3 for subjects with lymphoma in bone marrow) (Administration of myeloid growth factors within 14 days prior to study entry are not allowed).
    d. Platelet count:
    o Phase 1 and 2 (except subjects with known lymphoma): ≥100,000 cells/mm3.
    o Phase 2 subjects with known lymphoma: ≥50,000 cells/mm3 (≥25,000 cells/mm3 for subjects with lymphoma in bone marrow) (transfusion within 21 days prior to study entry are not allowed).
    e. Serum creatinine levels ≤1.5 × ULN, or calculated (by Cockcroft-Gault formula or other accepted formula) or measured creatinine clearance ≥50 mL/min.
    f. Amylase and lipase ≤ULN. [Applies to Phase 2].
    8. Women of child-bearing potential (according to recommendations of the Clinical Trial Facilitation Group [CTFG]; see protocol for details) must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Women of child-bearing potential and men with female partners of child-bearing potential must agree to practice 2 highly effective contraceptive measures of birth control (as described in the protocol) and must agree not to become pregnant or father a child while receiving treatment with study drug and for at least 3 months after completing treatment.
    Los pacientes deben cumplir todos los criterios de inclusión siguientes.
    1. Ser capaz de entender y cumplir con los procedimientos del protocolo y del estudio, comprender los riesgos que implica el estudio y proporcionar el consentimiento informado por escrito antes de llevar a cabo ningún procedimiento específico del estudio.
    2. Hombres y mujeres de ≥18 años de edad.
    3. Sujetos con tumores sólidos avanzados histológica o citológicamente confirmados o linfoma irresecable o metastásico y para los que no haya medidas habituales para prolongar la vida.
    a) En la cohorte 3 de fase II, los pacientes deben tener LLTP confirmado histológicamente (informe de anatomopatología local) según la definición de la clasificación de la Organización Mundial de la Salud (OMS) de 2016. Los siguientes subtipos son aptos para el estudio: leucemia/linfoma de linfocitos T del adulto, linfoma de linfocitos citolíticos naturales (CN)/linfocitos T extragranglionar de tipo nasal, linfoma de linfocitos T asociado a la enteropatía, linfoma de linfocitos T intestinal epiteliotrópico monomórfico, linfoma de linfocitos T hepatoesplénico, linfoma de linfocitos T de tipo paniculitis subcutánea, linfoma de linfocitos T periférico sin especificar, linfoma de linfocitos T angioinmunoblástico, linfoma de linfocitos T folicular, linfocito T periférico ganglionar con fenotipo cooperador de linfocitos T (THF) y linfoma de células grandes anaplásico.
    4. En las cohortes 3 y 4 de fase II, los pacientes deben tener evidencias de enfermedad progresiva documentada y deben haber recibido al menos dos tratamientos sistémicos previos [cohortes 3 y 4 de fase II].
    a) Los sujetos con linfoma CD30-positivo deben haber recibido, no ser aptos, o ser intolerantes a brentuximab vedotina.
    b) Los sujetos con micosis fungoide o síndrome de Sezary deben haber recibido, no ser aptos, o ser intolerantes a mogamulizumab.
    5. En la parte de fase II del protocolo solo, los sujetos deben tener enfermedad medible de acuerdo con los criterios de respuesta adecuados para su tipo de cáncer (como se explica en la Sección 9.1).
    a) Para la cohorte 3 de la fase II (LLTP), se requiere la presencia de una enfermedad medible mediante TC diagnóstica potenciada con contraste (al menos una lesión nodal ≥1,5 cm o lesiones extranodales >1,0 cm).
    6. Estado funcional del Grupo Oncológico Cooperativo del Este (ECOG) de 0, 1 o 2.
    7. Función orgánica aceptable, como evidencian los siguientes datos de laboratorio:
    a) Aspartato-aminotransferasa (AST) o alanina-aminotransferasa (ALT) ≤2,0 × límite superior de la normalidad (LSN).
    b) Bilirrubina sérica total ≤1,5 × LSN.
    c) Recuento absoluto de neutrófilos (RAN):
    + Fase I y II (excepto los sujetos de la fase II con linfoma): ≥1500 células/mm3.
    + Sujetos de fase II con linfoma conocida: ≥1000 células/mm3 (≥750 células/mm3 para los pacientes con linfoma en la médula ósea) (no se permite la administración de factores de crecimiento mieloide en el plazo de los 14 días anteriores a la entrada en el estudio).
    d) Recuento de plaquetas:
    + Fase I y II (excepto los sujetos de la fase II con linfoma): ≥100 000 células/mm3.
    + Sujetos de fase II con linfoma conocida: ≥50 000 células/mm3 (≥25 000 células/mm3 para los pacientes con linfoma en la médula ósea) (no se permiten las transfusiones en un plazo de 21 días antes de la entrada en el estudio).
    e) Niveles de creatinina sérica ≤1,5 × LSN, o aclaramiento de creatinina calculado (mediante la fórmula de Cockcroft-Gault u otra fórmula aceptada) o medido ≥50 ml/min.
    f) Amilasa y lipasa ≤LSN [se aplica a la fase II].
    8. Las mujeres con capacidad de concebir (de acuerdo con las recomendaciones del Grupo de facilitación del ensayo clínico [Clinical Trial Facilitation Group, CTFG]; para más información, véase el protocolo) no deben estar embarazadas ni amamantando y deben presentar un resultado negativo en la prueba de embarazo en la selección. Las mujeres con capacidad de concebir y los hombres con parejas que tengan capacidad de concebir deben aceptar el uso de 2 métodos anticonceptivos altamente eficaces (tal como se describe en el protocolo) y deben aceptar no quedarse embarazadas o engendrar un hijo mientras estén recibiendo el tratamiento con el fármaco del estudio y durante un mínimo de 3 meses tras finalizar el tratamiento.
    E.4Principal exclusion criteria
    1. Hypersensitivity to ASTX660, excipients of the drug product, or other components of the study treatment regimen.
    2. Poor medical risk because of systemic diseases (eg, active uncontrolled infections) in addition to the qualifying disease under study.
    3. Life-threatening illness, significant organ system dysfunction, or other condition that, in the investigator’s opinion, could compromise subject safety or the integrity of the study outcomes, or interfere with the absorption or metabolism of ASTX660.
    4. History of, or at risk for, cardiac disease, as evidenced by 1 or more of the following conditions:
    a) Abnormal left ventricular ejection fraction (LVEF; <50%) on echocardiogram (ECHO) or multiplegated acquisition scan (MUGA). [Applies to both Phase 1 and Phase 2].
    b) Congestive cardiac failure of ≥ Grade 3 severity according to New York Heart Association (NYHA) functional classification defined as subjects with marked limitation of activity and who are comfortable only at rest.
    c) Unstable cardiac disease including unstable angina or hypertension as defined by the need for overnight hospital admission within the last 3 months (90 days).
    d) History or presence of complete left bundle branch block, third-degree heart block, cardiac pacemaker or clinically significant arrhythmia.
    e) Concurrent treatment with any medication that prolongs QT interval and may induce torsades de pointes, and which cannot be discontinued at least 2 weeks before treatment with ASTX660. [Applies to Phase 1 only.]
    f) Personal history of long QTc syndrome or ventricular arrhythmias including ventricular bigeminy.
    g) Screening 12-lead ECG with measurable QTc interval (according to either Fridericia's or Bazett’s correction) of ≥470 msec).
    h) Any other condition that, in the opinion of the investigator, could put
    the subject at increased cardiac risk.
    5. Known history of human immunodeficiency virus (HIV) infection, or seropositive results consistent with active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection.
    6. Grade 2 or greater neuropathy. [Applies to Phase 1 ]. Grade 3 or greater neuropathy [Applies to Phase 2].
    7. Known brain metastases, unless stable or previously treated.
    8. Known significant mental illness or other conditions such as active alcohol or other substance abuse that, in the opinion of the investigator, predisposes the subject to high risk of noncompliance with the protocol treatment or assessments.
    9. Prior anticancer treatments or therapies within the indicated time window prior to first dose of study treatment (ASTX660), as follows:
    a) Cytotoxic chemotherapy or radiotherapy within 3 weeks prior (6 weeks if nitrosoureas). Palliative radiotherapy to a single lesion within 2 weeks prior. Any encountered treatment-related toxicities (excepting alopecia) must be stabilized or resolved to Grade 1 or less [Phase 1] or Grade 2 or less [Phase 2].
    b) Skin directed treatments, including topicals and radiation within 2 weeks prior.
    c) Monoclonal antibodies within 4 weeks prior. Any encountered treatment-related toxicities must be stabilized or resolved to Grade 1 or less [Phase 1] or Grade 2 or less [Phase 2].
    d) At least 6 weeks must have elapsed since CAR-T infusion and subjects must have experienced disease progression, and not have residual circulating CAR-T cells in peripheral blood (based on local assessment). Any encountered treatment-related toxicities must have resolved to Grade ≤1.
    e) Investigational drugs (small molecules or biologics) within the longer of 2 weeks or 5 half-lives prior to study treatment. Any encountered treatment-related toxicities must be stabilized or resolved to Grade 1 or less [Phase 1] or Grade 2 or less [Phase 2].
    10. Concurrent second malignancy currently requiring active therapy, except breast or prostate cancer stable on or responding to endocrine therapy or superficial bladder cancer [Phase 2].
    11. Known central nervous system (CNS) lymphoma [Phase 2].
    12. Patients with a history of allogenic transplant must not have ≥Grade 3 graft-versus-host disease (GVHD) or any clinically significant GVHD requiring systemic immunosuppression [Phase 2].
    13. Systemic corticosteroids >20 mg prednisone equivalent (unless patient has been taking a continuous dose for >3 weeks prior to study entry and there is documented radiological progression) [Phase 2]. Stable dose of medium or low potency topical corticosteroids for at least 3 weeks prior to study entry are permitted [Phase 2].
    1. Hipersensibilidad a ASTX660, sus excipientes u otros componentes de la pauta posológica del tratamiento del estudio
    2. Riesgo médico bajo por enfermedades sistémicas (p. ej., infecciones activas no controladas) además de la enfermedad en estudio
    3. Enfermedad potencialmente mortal, disfunción del sistema orgánico significativa u otra afección que, según el investigador, podría comprometer la seguridad del paciente o la integridad de los resultados del estudio, o interferir en la absorción o el metabolismo de ASTX660
    4. Antecedentes o riesgo de enfermedad cardíaca, como se demuestra por 1 o más de lo siguiente:
    a) Fracción de eyección del ventrículo izquierdo (FEVI; <50 %) en el ecocardiograma (ECO) o la ventriculografía isotópica (MUGA). [Tanto para fase I como II]
    b) Insuficiencia cardíaca congestiva de grado ≥3 de intensidad de acuerdo con la clasificación funcional de la Nueva York Heart Association (NYHA), definida como los sujetos con una marcada limitación de la actividad y que están cómodos solo en reposo
    c) Enfermedad cardíaca inestable que incluye angina inestable o hipertensión definida por la necesidad de ingreso en el hospital durante los últimos 3 meses (90 días)
    d) Antecedentes o presencia de bloqueo completo de la rama izquierda del haz de His, bloqueo cardíaco de tercer grado, marcapasos cardíaco o arritmia clínicamente significativa
    e) Tratamiento simultáneo con cualquier medicamento que prolongue el intervalo QT y pueda inducir torsades de pointes y que no se pueda interrumpir al menos 2 semanas antes del tratamiento con ASTX660 [Solo para la fase I]
    f) Antecedentes personales de síndrome del intervalo QTc prolongado o arritmias ventriculares, incluido bigeminismo ventricular
    g) ECG de 12 derivaciones de la selección con intervalo QTc medible (según la corrección de Fridericia o de Bazett) ≥470 ms
    h) Cualquier otra afección que, según el investigador, podría poner al sujeto en mayor riesgo cardíaco
    5. Antecedentes conocidos de infección por el virus de la inmunodeficiencia humana (VIH), o resultados seropositivos consistentes con el virus de la hepatitis B (VHB) activo o el virus de la hepatitis C (VHC) activo
    6. Neuropatía de grado 2 o superior [para la fase I]. Neuropatía de grado 3 o superior [para la fase II]
    7. Metástasis cerebrales conocidas, a menos que sean estables o previamente tratadas
    8. Enfermedad mental importante conocida u otro tipo de trastornos, como alcoholismo o abuso de otras sustancias que, según el investigador, predispongan al sujeto a un riesgo elevado de incumplimiento con el tratamiento o las evaluaciones del protocolo
    9. Tratamientos o terapias contra el cáncer previos dentro del margen de tiempo indicado antes de la primera dosis del tratamiento del estudio (ASTX660), como sigue:
    a) Quimioterapia citotóxica o radioterapia en las 3 semanas previas (6 semanas en caso de nitrosoureas). Radioterapia paliativa para una única lesión en las 2 semanas previas. Cualquier toxicidad relacionada con el tratamiento observada (excepto la alopecia) debe estabilizarse o resolverse a grado 1 o menos [Fase I] o de grado 2 o menos [Fase II]
    b) Tratamientos dirigidos cutáneos, incluidos los de uso tópico y radioterapia en las 2 semanas anteriores
    c) Anticuerpos monoclonales en las 4 semanas previas. Cualquier toxicidad relacionada con el tratamiento observada debe estabilizarse o resolverse a grado 1 o menos [Fase I] o de grado 2 o menos [Fase II]
    d) Deberán haber transcurrido al menos 6 semanas desde la infusión de CAR-T y los pacientes deberán haber experimentado progresión de la enfermedad y no presentar células CAR-T residuales en circulación en sangre periférica (según la evaluación local). Cualquier toxicidad relacionada con el tratamiento deberá haberse resuelto a grado ≤1
    e) Fármacos en investigación (moléculas pequeñas o productos biológicos) en el plazo de 2 semanas o 5 semividas antes del tratamiento del estudio. Cualquier toxicidad relacionada con el tratamiento observada debe estabilizarse o resolverse a grado 1 o menos [Fase I] o de grado 2 o menos [Fase II]
    10. Segunda neoplasia maligna concomitante que precisa en la actualidad tratamiento activo, excepto cáncer de próstata o mama que se encuentra estable o en respuesta con la hormonoterapia o cáncer de vejiga superficial [Fase II]
    11. Linfoma del sistema nervioso central (SNC) conocido [Fase II]
    12. Los pacientes con antecedentes de trasplante alogénico no deben tener enfermedad de injerto contra huésped (EICH) de grado ≥3 o EICH clínicamente significativa que requiera inmunosupresión sistémica [Fase II]
    13. Corticoesteroides sistémicos >20 mg de equivalente de prednisona (excepto si el paciente ha estado recibiendo una dosis continua durante >3 semanas antes de la entrada en el estudio y haya progresión radiológica documentada) [Fase II]. Se permite una dosis estable de corticoesteroides tópicos de media o baja potencia durante al menos 3 semanas antes de la entrada [Fase II]
    E.5 End points
    E.5.1Primary end point(s)
    Primary Endpoint(s)
    Phase 1: Incidence of DLTs and other adverse events (AEs) to determine the MTD, RP2D, and recommended dosing regimen of ASTX660.
    Phase 2: Antitumor activity assessed by objective response rate (ORR) and disease control rate (DCR) as assessed by the Investigator using the following criteria:
    - Cohort 1, 5, and 6: RECIST 1.1 criteria
    - Cohort 2 and 3: 2014 Lugano Classification
    - Cohort 4: Global Response Score
    Criterio de valoración principal
    Fase I: Incidencia de TLD y otros acontecimientos adversos (AA) para determinar la DMT, DRF2 y pauta posológica recomendada de ASTX660.
    Fase II: Actividad antitumoral evaluada mediante la tasa de respuesta objetiva (TRO) y la tasa de control de la enfermedad (TCE) según la evaluación del investigador usando los siguientes criterios:
    + Cohortes 1, 5 y 6: criterios RECIST 1.1
    + Cohortes 2 y 3: clasificación de Lugano de 2014
    + Cohorte 4: puntuación de respuesta global
    E.5.1.1Timepoint(s) of evaluation of this end point
    Safety will be monitored at each study visit by recording of AEs, SAEs, DLTs, and concomitant medications; additional assessments that may be performed at selected visits include complete or symptom-directed physical examinations, recording of weight and height, vital signs, ECOG performance status, 12-lead ECGs, and clinical laboratory tests.
    Phase 1: echocardiogram (ECHO)/multiple-gated acquisition scans will be performed.
    Phase 2: Every 2 months for the first 6 months (6 cycles), and then every 3 months hereafter until clinical and/or radiographic disease progression, or death, or the subject withdraws consent
    En cada visita del estudio, la seguridad se vigilará mediante el registro de acontecimientos adversos (AA), acontecimientos adversos graves (AAG), TLD y medicamentos concomitantes. Las evaluaciones de seguridad adicionales en visitas seleccionadas incluyen exploraciones físicas basadas en los síntomas o completas, registro de la estatura y el peso, constantes vitales, estado funcional el ECOG, electrocardiogramas (ECG) de 12 derivaciones y análisis clínicos de laboratorio
    Fase I: pruebas de ecocardiograma (ECO) o ventriculografía isotópica (MUGA)
    Fase II: cada 2 meses durante los primeros 6 meses (6 ciclos) y, a continuación, cada 3 meses a partir de entonces hasta la progresión de la enfermedad radiográfica y/o clínica, la muerte, o la retirada del consentimiento del sujeto
    E.5.2Secondary end point(s)
    Secondary Endpoint(s)
    1. PK parameters of ASTX660, including area under the concentration-time curve (AUC), maximum concentration (Cmax), minimum concentration (Cmin), time to maximum concentration (Tmax), elimination half-life (t½), and other secondary PK parameters of ASTX660 if data permit; analysis of ASTX660 metabolites if applicable.
    2. Overall survival.
    3. Percentage degradation of cIAP1 protein in PBMCs from baseline, in response to ASTX660 treatment [applies to Phase 1 only].
    4. Antitumor activity (ORR, DOR, and PFS) based on independent review committee (IRC) assessment using 2014 Lugano Classification (Phase 2 Cohort 3 Expansion) and Global
    Response Score (Phase 2 Cohort 4 Expansion)
    5. Antitumor activity (ORR, DOR, and PFS) based on investigator assessment using the LYRIC criteria (Phase 2 Cohort 3 Expansion)
    6. Antitumor activity (ORR, DOR, and PFS) based on IRC assessment using the LYRIC criteria(Phase 2 Cohort 3 Expansion)
    Criterio(s) de valoración secundarios
    1. Parámetros de FC de ASTX660, incluidos el área bajo la curva de concentración-tiempo (AUC), la concentración máxima (Cmáx.), la concentración mínima (Cmín.), el tiempo hasta la concentración máxima (Tmáx.), la semivida de eliminación (t½) y otros parámetros FC secundarios de ASTX660 si los datos lo permiten; análisis de los metabolitos de ASTX660, si procede.
    2. Supervivencia global.
    3. Porcentaje de degradación de proteínas cIAP1 en células mononucleares de sangre periférica (CMSP) desde el inicio, en respuesta al tratamiento con ASTX660. [Se aplica solo a la fase I].
    4. Actividad antitumoral (TRO, DR y SSP) según la evaluación del comité de revisión independiente (CRI) usando la clasificación de Lugano de 2014 (expansión de la cohorte 3 de la fase II) y la puntuación de respuesta global (expansión de la cohorte 4 de la fase II)
    5. Actividad antitumoral (TRO, DR y SSP) según la evaluación del investigador usando los criterios LYRIC (expansión de la cohorte 3 de la fase II)
    6. Actividad antitumoral (TRO, DR y SSP) según la evaluación del CRI usando los criterios LYRIC (expansión de la cohorte 3 de la fase II)
    E.5.2.1Timepoint(s) of evaluation of this end point
    1.At specified study visits, blood samples for PK will be collected predose for assessment of ASTX660 concentration in plasma. In addition, serial samples will be collected predose and at several specified time points after dosing on C1D1, C1D7, C2D1, and C2D7. Additionally, in Phase 2 for Cohorts 3 [PTCL] and 4 [CTCL], blood will be collected for PK analysis in Cycle 1 only.
    2.Every 2 months for the first 6 months (6 cycles), and then every 3 months hereafter until clinical and/or radiographic disease progression, or death, or the subject withdraws consent
    3. Blood samples will be collected at screening and at prespecified times after dosing for the assessment of cIAP1 protein degredation in PBMCs (Phase 1: on several study days during Cycles 1 and 2).
    1. En visitas especificadas del estudio, las muestras de sangre se recogerán antes de la dosis para la evaluación de la concentración de ASTX660 en plasma. Además, se obtendrán muestras seriadas antes de la dosis y en varios momentos de evaluación especificados después de la dosis el D1C1, D7C1, D1C2 y D7C2. Además, en las cohortes 3 [LLTP] y 4 [LLTC] se recogerán muestras de sangre para el análisis de FC en el ciclo 1 solamente
    2. Cada 2 meses los primeros 6 meses (6 ciclos) y después cada 3 meses hasta la progresión de la enfermedad radiográfica y/o clínica, la muerte, o la retirada del consentimiento del sujeto
    3. Se recogerán muestras de sangre en la selección y en los momentos de evaluación especificados previamente para explorar la degradación de la proteína cIAP1 en las CMSP
    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) Yes
    E.7.1.1First administration to humans Yes
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA30
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Belgium
    France
    Hungary
    Italy
    Spain
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    6 months from last subject treatment visit
    6 meses tras la última visita de tratamiento del último sujeto
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months6
    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: 184
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 46
    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 state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 46
    F.4.2.2In the whole clinical trial 230
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    Ninguno
    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 Decision2020-05-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-03-31
    P. End of Trial
    P.End of Trial StatusOngoing
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