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    Summary
    EudraCT Number:2019-000998-23
    Sponsor's Protocol Code Number:CL1-64315-003
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-07-26
    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 number2019-000998-23
    A.3Full title of the trial
    A Phase I/II, open label, non-randomized study to evaluate safety, tolerability, pharmacokinetics and clinical activity of S64315 in patients with locally advanced or metastatic breast cancer in combination with various standard treatments including hormonal and cytotoxic agents
    Estudio de Fase I/II, abierto, no aleatorizado, para evaluar la seguridad, tolerancia, farmacocinética y actividad clínica de S64315 en pacientes con cáncer de mama localmente avanzado o metastásico, en combinación con varios tratamientos estándar incluyendo terapia hormonal y agentes citotóxicos
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study that tested S64315 plus different standard treatments in patients with breast cancer
    Estudio de Fase I/II de S64315 en combinación con varios tratamientos estándar incluyendo terapia hormonal y agentes citotóxicos en cáncer de mama (CM) localmente avanzado o metastásico
    A.4.1Sponsor's protocol code numberCL1-64315-003
    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 SponsorInstitut de Recherches Internationales Servier
    B.1.3.4CountryFrance
    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 supportLaboratorios Servier S.L. (Promotor Local)
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLaboratorios Servier S.L.
    B.5.2Functional name of contact pointIlaria Fasciani
    B.5.3 Address:
    B.5.3.1Street AddressAvenida de los madroños 33
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28043
    B.5.3.4CountrySpain
    B.5.4Telephone number+34660554054
    B.5.5Fax number+34913003249
    B.5.6E-maililaria.fasciani@servier.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 nameS64315
    D.3.2Product code S64315 (also referred as MIK665)
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNS64315
    D.3.9.2Current sponsor codeS64315
    D.3.9.3Other descriptive nameMIK665
    D.3.9.4EV Substance CodeSUB184625
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number61.75
    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.2.1.1.1Trade name Halaven
    D.2.1.1.2Name of the Marketing Authorisation holderEisai GmBH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form 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 INNEribulin
    D.3.9.1CAS number 441045-17-6
    D.3.9.3Other descriptive nameERIBULIN MESYLATE
    D.3.9.4EV Substance CodeSUB31126
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.44
    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 Falsodex
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca AB
    D.2.1.2Country which granted the Marketing AuthorisationRomania
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNFulvestrant
    D.3.9.1CAS number 129453-61-8
    D.3.9.3Other descriptive nameFULVESTRANT
    D.3.9.4EV Substance CodeSUB13933MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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.2.1.1.1Trade name Paclitaxel 6mg/mL
    D.2.1.1.2Name of the Marketing Authorisation holderAmneal Deutschland GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPACLITAXEL
    D.3.9.1CAS number 33069-62-4
    D.3.9.4EV Substance CodeSUB09583MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6
    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
    Locally advanced or metastatic breast cancer.
    Cáncer de mama metastásico o localmente avanzado
    E.1.1.1Medical condition in easily understood language
    Breast cancer that has come back and spread to the tissues and lymph nodes around the chest, neck and under the breastbone, or that has spread to other parts of the body beyond the original tumor
    Cáncer de mama que ha progresado y se ha propagado a los tejidos y ganglios linfáticos alrededor del tórax, el cuello y debajo del esternón, o que se ha diseminado a otras partes del cuerpo
    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 LLT
    E.1.2Classification code 10072740
    E.1.2Term Locally advanced breast cancer
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10027475
    E.1.2Term Metastatic breast cancer
    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
    Phase I objective:
    -To determine the safety profile (including Dose Limiting Toxicities, Maximum Tolerated Doses), tolerability and the Recommended Doses for Expansion (RDEs) of S64315 in combination with various standard treatments including hormonal and cytotoxic agents according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0

    Phase II objective:
    ­-To evaluate the Objective Response Rate (ORR) of S64315 in combination with various standard treatments including hormonal and cytotoxic agents
    Objetivo de la fase I:
    - Determinar el perfil de seguridad , incluyendo Toxicidad Limitante de Dosis (DLTs), Maxima Dosis Tolerada (MTDs), tolerabilidad y las dosis recomendadas para la Expansión (RDEs) de S64315 en combinación con varios tratamientos estándar incluyendo el hormonal y agentes citotóxicos según National Cancer Institute Common Terminology Criteria for Adverse Events (NCI_CTCAE) v5.0

    Objetivo de la fase II:
    - Evaluar la Tasa de Respuesta Objetiva (ORR) de S64315 en combinación con varios tratamientos estándar incluidos agentes hormonales y citotóxicos
    E.2.2Secondary objectives of the trial
    Phase I objectives:
    -To determine the pharmacokinetics (PK) profile in plasma of S64315 in combination with various standard treatments including hormonal and cytotoxic agents
    -To investigate any preliminary antitumor activity of these combinations

    Phase II objectives
    -To assess the anti-tumour activity according to the Response Evaluation Criteria In Solid Tumours version 1.1 (RECIST v1.1, 2009) in terms of:
    Response duration (RD)
    Overall survival (OS)
    Progression Free Survival (PFS)
    Best Overall Response (BOR)
    Disease Control Rate (DCR)
    -To assess the safety and tolerability of S64315 in combination with various standard treatments including hormonal and cytotoxic agents, at RDEs, according to NCI-CTCAE v5.0
    -To assess the PK profile in plasma of S64315 in combination with various standard treatments including hormonal and cytotoxic agents
    Objetivos de la fase I:
    - Determinar el perfil farmacocinético (PK) en plasma de S64315 en combinación con tratamientos estándar incluyendo el hormonal y agentes citotóxicos
    - Investigar cualquier actividad preliminar antitumoral de estas combinaciones

    Objetivos de la fase II:
    - Evaluar la actividad antitumoral según RECIST version 1.1, 2009 en términos de:
     Duración de la respuesta (RD)
     Supervivencia global (OS)
     Supervivencia libre de Progresión (PFS)
     Mejor respuesta global (BOR)
     Tasa de control de enfermedad (DCR)
    - Valorar la seguridad y tolerancia de S64315 en combinación con varios tratamientos estándar incluyendo tratamientos hormonales y citotóxicos a la Dosis Recomendada para la Expansión (DRE), según NCI-CTCAE v5.0
    - Valorar el perfil farmacocinético de S64315 en plasma en combinación con varios tratamientos estándar incluyendo tratamientos hormonales y agentes citotóxicos
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    In Arm 1: S64315 + paclitaxel
    -Histologically confirmed locally advanced or metastatic TNBC or HR+/Her2- (HR+ (Estrogen or Progesterone) > 10% and Her2- (score 0 or 1 by immunochemistry), FISH BC (Fluorescence In Situ Hybridization) negative if IHC (immuno-histochemistry) score 2):
    TNBC: no more than 2 prior chemotherapeutic regimens in the locally advanced or metastatic setting
    HR+/Her2-: no more than 2 prior chemotherapeutic regimens and no more than 1 prior PI3K inhibitor (PIKi) in the locally advanced or metastatic setting

    In Arm 2: S64315 + eribulin
    -Histologically confirmed locally advanced or metastatic TNBC or HR+/Her2- BC (HR+ (Estrogen or Progesterone) > 10% and Her2- (score 0 or 1 by immunochemistry), FISH (Fluorescence In Situ Hybridization) negative if IHC (immuno-histochemistry) score 2):
    TNBC: no more than 2 prior chemotherapeutic regimens in the locally advanced or metastatic setting
    HR+/Her2-: no more than 2 prior chemotherapeutic regimens and no more than 1 prior PI3Ki in the locally advanced or metastatic setting
    -No prior exposure to eribulin in the adjuvant, neoadjuvant or metastatic setting

    In Arm 3: S64315 + fulvestrant
    -Histologically confirmed locally advanced or metastatic HR+/Her2- BC: (HR+ (Estrogen or Progesterone) > 10% and Her2- (score 0 or 1 by mmunochemistry), FISH (Fluorescence In Situ Hybridization) negative if IHC (immuno-histochemistry) score 2)
    No more than two prior lines of hormonal therapy in the locally advanced or metastatic setting
    Prior treatment with CDK4/6 inhibitor (CDK4/6i) is permitted
    Prior treatment with PI3K inhibitor (PI3Ki) is permitted
    Patients for whom endocrine therapy (e.g., fulvestrant) is recommended and treatment with cytotoxic chemotherapy is not indicated at the time of entry into the study, as per national or local treatment guidelines
    -Post-menopausal women

    For all patients:
    -Patient must have at least one measurable lesion, as defined by revised RECIST v1.1, 2009
    -Estimated life expectancy ≥ 12 weeks
    -Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
    -Adequate haematological function based on the last assessment performed within 7 days prior to the first IMP administration.
    -Adequate renal function based on the last assessment performed within 7 days prior to the first IMP administration.
    -Adequate hepatic function based on the last assessment performed within 7 days prior to the first IMP administration.
    -Serum CK/CPK ≤ 2.5 ULN
    Brazo 1: S64315 + paclitaxel
    - TNBC metastásico o localmente avanzado histológicamente confirmado o HR+/Her2- (HR+ (Estrógeno o Progesterona) > 10% y Her2- (0 o 1 por inmunohistoquímica), cáncer de mama FISH (Fluorescence In Situ Hybridization) negativo si la puntuación IHC (immuno-histoquímica) es 2:
    * TNBC: no más de 2 regímenes de quimioterapia previos en enfermedad localmente avanzada o metastásica
    * HR+/Her2-: no más de 2 regímentes de quimioterapia previos y no más de 1 inhibidor PI3K (PIKi) previo en la enfermedad localmente avanzada o metastásica

    Brazo 2: S64315 + eribulina
    - TNBC metastásico o localmente avanzado histológicamente confirmado o HR+/Her2- (HR+ (Estrógeno o Progesterona) > 10% y Her2- (0 o 1 por inmunohistoquímica), cáncer de mama FISH (Fluorescence In Situ Hybridization) negativo si la puntuación IHC (immuno-histoquímica) es 2:
    * TNBC: no más de 2 regímenes de quimioterapia previos en enfermedad localmente avanzada o metastásica
    * HR+/Her2-: no más de 2 regímentes de quimioterapia previos y no más de 1 inhibidor PI3K (PIKi) previo en la enfermedad localmente avanzada o metastásica
    - No exposición previa a eribulina en el tratamiento adyuvante, neoadyuvante o metastásico

    Brazo 3: S64315 + fulvestrant
    - TNBC o HR+/Her2- (HR+ (Estrógeno o Progesterona) > 10% y Her2- (0 o 1 por inmunohistoquímica), cáncer de mama FISH (Fluorescence In Situ Hybridization) negativo si la puntuación IHC (immuno-histoquímica) es 2:
    * No más de dos líneas previas de tratamiento hormonal en la enfermedad localmente avanzada o metastásica
    * Se permite tratamiento previo con CDK4/6 inhibidor (CDK4/6i)
    * Se permite tratamiento previo con inhibidor de PI3K (PI3Ki)
    * Pacientes para los que se recomienda la terapia endocrina (ej. Fulvestrant) y la quimioterapia no está indicada en el momento de entrar en el estudio, según las guías nacionales o locales
    - Mujeres post-menopáusicas

    Para todos los pacientes:
    - La paciente debe tener al menos una lesión medible, definida según la versión revisada RECIST v1.1, 2009 o lesiones óseas líticas o mezcla de lesiones líticas y blásticas que puedan evaluarse mediante TC o RM
    - Esperanza de vida estimada ≥ 12 semanas
    - Status ECOG ≤ 1
    - Función hematológica adecuada basada en la última valoración hecha dentro de los 7 días anteriores a la primera administración de IMP
    - Función renal adecuada, basada en la última valoración llevada a cabo dentro de los 7 días previos a la primera administración de IMP
    - Función hepática adecuada, basada en la última valoración llevada a cabo dentro de los 7 días previos a la primera administración de IMP
    - CK/CPK sérica ≤ 2.5 x ULN
    E.4Principal exclusion criteria
    -Only for Arm 1 and 2: Pregnant and lactating women
    -Patients who have not recovered from toxicity of previous anticancer therapy, including grade ≥ 2 non-haematologic toxicity, according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 5.00), prior to the first IMP administration Certain toxicities will not be considered in this category (e.g. alopecia)
    -Severe or uncontrolled active acute or chronic infection
    -Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, active viral or other hepatitis or cirrhosis
    -Medical history of acute or chronic pancreatitis
    -Unresolved diarrhoea ≥ CTCAE Grade 2 or presence of medical condition associated with chronic diarrhoea (such as irritable bowel syndrome, inflammatory bowel disease)
    -Clinically significant cardiac dysfunction (including NYHA Class ≥ II heart failure, left ventricular ejection fraction (LVEF) < 50% as assessed by echocardiography or Multi Gated Acquisition Scan (MUGA))
    -Uncontrolled arterial hypertension (systolic blood pressure > 150 mmHg or diastolic blood pressure > 95 mmHg despite treatment)
    -Acute coronary syndrome including unstable angina pectoris (anginal symptoms at rest), new onset angina, acute myocardial infarction, coronary artery bypass graft (CABG) within 3 months prior to starting study treatment
    -Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia, atrial fibrillation), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block)
    -Congenital or substance-induced long QT defined as QTc interval > 450 ms for males and > 470 ms for females according to Frederica’s formula
    -Troponin (I or T) > ULN
    -Patients with coagulopathy that will increase the risk of bleeding complications according to investigator’s judgment (e.g. disseminated intravascular coagulation)
    -Known hypersensitivity to paclitaxel /eribulin /fulvestrant or S65315 including excipients of the liposomal vehicle, eggs or soybean
    -Only for Arm 1 and Arm 2: Evidence of peripheral neuropathy ≥ CTCAE grade 2
    -Major surgery (involving a risk to the life of the patient) within 4 weeks prior to the first dose of IMP, or patients who have not recovered from side effects of the surgery
    -Any radiotherapy within 2 weeks before the first dose of IMP (except for palliative radiotherapy at localised lesions)
    - Solo para el Brazo 1 y Brazo 2: Mujeres potencialmente gestantes
    - Pacientes que no se hayan recuperado de toxicidades de terapias anticancerosas previas, incluyendo toxicidad no hematológica grado ≥ 2, según el National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 5.00), antes de la primera administración del IMP. Ciertas toxicidades no serán consideradas en esta categoría (ej. alopecia)
    - Infección aguda grave o no controlada o infección crónica
    - Portadores conocidos de anticuerpos HIV
    - Historia de enfermedad hepática conocida clínicamente significativa consistente con Child-Pugh Class B o C hepatitis activa viral o de otro tipo o cirrosis
    - Historia médica de pancreatitis aguda o crónica
    - Diarrea no resuelta ≥ grado 2 CTCAE o presencia de una patología asociada a diarrea crónica (como síndrome de colon irritable, enfermedad inflamatoria intestinal)
    - Pacientes con metástasis cerebral o leptomeníngea (exceptuando pacientes con metástasis cerebrales que hubieran permanecido estables después de la radioterapia y sin esteroides durante > 2 meses)
    - Disfunción cardiaca clínicamente significativa (incluyendo insuficiencia cardiaca NYHA Class ≥ II, fracción de eyección de ventrículo izquierdo (FEVI) < 50% evaluada mediante ecocardiografía o mediante angiografía radioisotópica en reposo (MUGA)
    - Hipertensión arterial no controlada (presión arterial sistólica > 150 mmHg o presión arterial diastólica > 95 mmHg a pesar de tratamiento)
    - Síndrome coronario agudo incluyendo la angina pectoris inestable (síntomas de angina en reposo), angina de inicio reciente, infarto agudo de miocardio, bypass con injerto coronario (CABG) dentro de los 3 meses previos al comienzo del tratamiento del estudio
    - Arritmias clínicamente significativas (ej. taquicardia ventricular, fibrilación auricular), bloqueo completo de rama izquierda, bloqueo AV de alto grado (ej. bloqueo bifascicular, bloqueo AV Mobitz II o bloqueo AV de tercer grado)
    - Intervalo QT alargado congénito o inducido por sustancias, definido como un QTc > 450 ms para hombres y > 470 ms para mujeres según la fórmula de Fridericia
    - Troponina (I o T) > límite superior de la normalidad (ULN)
    - Pacientes con coagulopatía que aumente el riesgo de complicaciones de sangrado a juicio del investigador (ej. coagulación intravascular diseminada)
    - Hipersensibilidad conocida a paclitaxel / eribulina / fulvestrant o S64315 incluidos los excipientes del vehículo liposomal, a huevo o a soja
    - Solo para el brazo 3: paciente con historia de acontecimientos tromboembólicos en los 3 meses previos a la primera dosis de IMP
    - Solo para brazo 1 y brazo 2: Evidencia de neuropatía periférica ≥ grado 2 CTCAE
    - Cirugía mayor (que implique un riesgo para la vida del paciente) en las 4 semanas previas a la primera dosis de IMP, o pacientes que no se hayan recuperado de los efectos de la cirugía
    - Cualquier radioterapia en las 2 semanas previas a la primera dosis de IMP (excepto radioterapia paliativa en lesiones localizadas)
    E.5 End points
    E.5.1Primary end point(s)
    Phase 1:
    -Incidence of DLTs during the first cycle of treatment with S64315 combined with various standard treatments including hormonal and cytotoxic agents
    -Incidence and severity of AEs and SAEs will be evaluated according:
    Laboratory tests: haematology with differential, blood biochemistry, thyroid function, coagulation and urinary analysis
    Vital signs and performance status
    ECG parameters to be centrally read, cardiac function assessment
    LVEF assessed by echocardiography or MUGA scan
    -Dose interruptions, reductions and dose intensity

    Phase 2:
    -ORR which is the proportion of patients with confirmed Complete Response (CR) or a confirmed Partial Response (PR), as best overall response according to RECIST v1.1. and based on the Investigator-assessed radiological assessment
    Fase I:
    -Incidencia de la Toxicidad Limitante de Dosis (DLT) durante el primer ciclo de tratamiento con S64315 combinado con varios tratamientos estándar que incluyen agentes hormonales y citotóxicos
    -La incidencia y severidad de AEs ​​y SAEs serán evaluadas de acuerdo a:
    * Pruebas de laboratorio: hematología con diferencial, bioquímica sanguínea, función tiroidea, coagulación y urianálisis.
    * Signos vitales y status ECOG
    * Parámetros de ECG para lectura central, evaluación de la función cardíaca
    * FEVI evaluada mediante ecocardiografía o MUGA
    - Interrupciones, reducciones e intensidad de dosis

    Fase II:
    Tasa de Respuesta Objetiva (ORR), que es la proporción de pacientes con respuesta completa (CR) confirmada o respuesta parcial (PR) confirmada, como mejor respuesta global según RECIST v1.1 y basado en la evaluación radiológica evaluada por el investigador
    E.5.1.1Timepoint(s) of evaluation of this end point
    Unless precised, all timepoints are at pre-dose.
    DLT assessment: C1Dn (not at predose)
    Haematology: all visits in C1 and C2 for all arms then, CnD1, CnD8 and CnD15 (arm1) ; CnD1 and CnD8 (arm 2) ; CnD1, CnD8, CnD15 and CnD22 (arm 3)
    Blood biochemistry: all visits
    Thyroid function: CnD1
    Blood coagulation: CnD1
    Urinary analysis: CnD1
    Vital signs: all visits
    Performance status: CnD1
    ECG parameters: at pre-dose, end of infusion, 1h, 2h, 6h, 24h after end of S64315 infusion for the two firsts visits. At pre-dose and end of S64315 infusion for others. Arm1: C1D2, C1D9, C1D16, C1D23, CnD2. Arm 2: C1D2, C1D9, C1D16, CnD2. Arm 3: C1D2, C1D8, C1D15, C1D22, CnD1.
    Echocardiography or MUGA scan: C2D1 then CnD1 (arm 3) / C2D2 then CnD2 (arm 1 + 2)
    AE: all visits (not at pre-dose)
    Salvo si se precisa, los tiempos son pre-dosis
    Eval. DLT: C1Dn (no pre-dosis)
    Hematología: todas las visitas C1 y C2 para todos los brazos, CnD1, CnD8 y CnD15 (brazo1); CnD1 y CnD8 (brazo 2); CnD1, CnD8, CnD15 y CnD22 (brazo 3)
    Bioquímica: todas las visitas
    Función tiroidea: CnD1
    Coagulación: CnD1
    urianálisis: CnD1
    Signos vitales: todas las visitas
    ECOG: CnD1
    Parámetros ECG: pre-dosis, fin de infusión, 1h, 2h, 6h, 24h tras finalizar infusión de S64315 para las dos primeras visitas. Pre-dosis y fin de infusión de S64315 para el resto. Brazo 1: C1D2, C1D9, C1D16, C1D23, CnD2. Brazo 2: C1D2, C1D9, C1D16, CnD2. Brazo 3: C1D2, C1D8, C1D15, C1D22, CnD1.
    Ecocardiografía o exploración MUGA: C2D1, luego CnD1 (brazo 3) / C2D2 luego CnD2 (brazo 1 + 2)
    AE: todas las visitas (no pre-dosis)
    E.5.2Secondary end point(s)
    Phase 1:
    -PK parameters of S64315 administered in combination with various standard treatments including hormonal and cytotoxic agents in plasma
    -Tumor response assessed by RECIST v1.1 (ORR, BOR, DCR)

    Phase 2:
    -RD is derived for those patients with objective PR or CR and is defined from the time measurement criteria are first met for CR/PR (whichever is first recorded) until the date of progression or death (whatever the reason of death), whichever occurs first
    -OS is defined as the time from the study enrolment to death from any cause (the follow-up period will be 12 months)
    -PFS is defined as the time from the study enrolment date until the date of the investigator-assessed radiological disease progression according to RECIST v1.1 or death due to any cause
    -BOR is defined as the best response recorded from the start of the study treatment until the disease progression/recurrence
    -DCR is defined as the percentage of patients who achieve best response:
    Complete response (disappearance of all target lesions),
    Partial response (≥30% decrease in the sum of the longest diameter of target lesions)
    Or stable disease ≥24 weeks based on RECIST v.1.1
    -Safety and tolerability of S64315 in combination with various standard treatments including hormonal and cytotoxic agents assessed by:
    Incidence and severity of AEs and SAEs
    Laboratory tests (haematology, haemolysis biochemistry, urinary analysis and pregnancy test)
    Vital signs and body weight
    Physical examination and performance status
    ECG parameters
    Dose interruptions, dose reductions and dose intensity
    -PK parameters of S64315 in combination with various standard treatments including hormonal and cytotoxic agents
    Fase 1:
    - parámetros farmacocinéticos de S64315 administrado en combinación con varios tratamientos estándar que incluyen agentes hormonales y citotóxicos en plasma
    - Evaluación de la respuesta tumoral por RECIST v1.1 (ORR, BOR, DCR)

    Fase 2:
    - RD se deriva para aquellos pacientes con RP objetiva o CR y se define desde el momento en que los criterios de medición se cumplen por primera vez para CR / PR (lo que se registre primero) hasta la fecha de progresión o muerte (cualquiera sea la razón de la muerte), lo que ocurra primero
    - OS se define como el tiempo desde la inclusión en el estudio hasta la muerte por cualquier causa (el período de seguimiento será de 12 meses)
    - PFS se define como el tiempo desde la fecha de inclusión en el estudio hasta la fecha de la progresión de la enfermedad radiológica evaluada por el investigador según RECIST v1.1 o muerte por cualquier causa
    - BOR se define como la mejor respuesta registrada desde el inicio del tratamiento del estudio hasta la progresión / recurrencia de la enfermedad
    - DCR se define como el porcentaje de pacientes que logran la mejor respuesta:
    * Respuesta completa (desaparición de todas las lesiones diana),
    * Respuesta parcial (≥30% de disminución en la suma del diámetro más largo de las lesiones diana)
    * O enfermedad estable ≥24 semanas según RECIST v.1.1
    -Seguridad y tolerabilidad de S64315 en combinación con varios tratamientos estándar que incluyen agentes hormonales y citotóxicos evaluados por:
    * Incidencia y severidad de AEs y SAEs
    * Pruebas de laboratorio (hematología, bioquímica, análisis urinario y prueba de embarazo)
    * Signos vitales y peso corporal
    * Examen físico y ECOG
    * Parámetros de ECG
    * Interrupciones, reducciones e intensidad de dosis
    - parámetros farmacocinéticos de S64315 administrado en combinación con varios tratamientos estándar que incluyen agentes hormonales y citotóxicos en plasma
    E.5.2.1Timepoint(s) of evaluation of this end point
    Blood samples for PK: Arm 1 and arm 2: C1D1, C1D2, C1D3, C1D8, C1D9 and C1D10. Arm 3: C1D1, C1D2, C1D3, C1D8, C1D15.
    Tumor measurement by RECIST v1.1: at the end of every two cycles
    Muestras de sangre para analísis farmacocinéticos (PK): Brazo 1 y 2: C1D1, C1D2, C1D3, C1D8, C1D9 and C1D10. Brazo 3: C1D1, C1D2, C1D3, C1D8, C1D15.
    Medición del tumor por RECIST v1.1: al final de cada dos ciclos
    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 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
    Dose escalation study
    Estudio de escalada de dosis
    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 Information not present in EudraCT
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Fase I de escalada de dosis (3 brazos paralelos) seguido de Fase II de expansión de dosis (4 brazos)
    Dose escalation phase 1 with 3 parallel arms followed by dose expansion phase 2 with 4 parallel arms
    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 trial3
    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 Yes
    E.8.5.1Number of sites anticipated in the EEA12
    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
    Australia
    France
    Hungary
    Italy
    Spain
    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
    LVLS
    Ultima visita del último paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    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 years5
    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: 174
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 116
    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 state18
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 220
    F.4.2.2In the whole clinical trial 290
    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)
    After the discontinuation of the study treatment, the participant will receive a treatment and/or have access to other appropriate care by her/his doctor, which will be at the investigator's discretion.
    Después de la discontinuación del tratamiento del estudio, el participante recibirá un tratamiento y / o tendrá acceso a otro tipo de atención adecuada por parte de su médico, que será a criterio del investigador.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-09-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-07-30
    P. End of Trial
    P.End of Trial StatusOngoing
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