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    Summary
    EudraCT Number:2021-005724-38
    Sponsor's Protocol Code Number:TL-895-209
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2022-05-30
    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 number2021-005724-38
    A.3Full title of the trial
    An Open-Label, Multicenter, Phase 1b/2 Study of the Safety and Efficacy of TL-895 Combined with Ruxolitinib in Janus associated Kinase Inhibitor (JAKi) Treatment-Naïve Myelofibrosis (MF) Subjects and Subjects with MF who have a Suboptimal Response to Ruxolitinib
    Estudio de fase 1b/2, abierto y multicéntrico para evaluar la seguridad y la eficacia de TL-895 combinado con ruxolitinib en sujetos con mielofibrosis (MF) sin tratamiento previo con inhibidores de la cinasa Janus (iJAK) y sujetos con mielofibrosis y respuesta subóptima a ruxolitinib.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 1b/2 Study of TL-895 Combined with Ruxolitinib in JAKi Treatment-Naïve MF Subjects and Subjects with MF who have a Suboptimal Response to Ruxolitinib
    Estudio de fase 1b/2 de TL-895 combinado con ruxolitinib en sujetos con mielofibrosis sin tratamiento previo con iJAK y sujetos con mielofibrosis y respuesta subóptima a ruxolitinib
    A.4.1Sponsor's protocol code numberTL-895-209
    A.5.4Other Identifiers
    Name:INDNumber:150807
    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 SponsorTelios Pharma, 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 supportTelios Pharma, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTelios Pharma, Inc.
    B.5.2Functional name of contact pointVP, Regulatory Affairs
    B.5.3 Address:
    B.5.3.1Street Address275 Shoreline Drive, Suite 235
    B.5.3.2Town/ cityRedwood City
    B.5.3.3Post codeCA 94065
    B.5.3.4CountryUnited States
    B.5.6E-mailpryan@teliospharma.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 TL-895
    D.3.4Pharmaceutical form Film-coated tablet
    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 INNTL-895
    D.3.9.1CAS number 1415823-49-2
    D.3.9.2Current sponsor codeTL-895
    D.3.9.3Other descriptive nameM7583
    D.3.9.4EV Substance CodeSUB216480
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 TL-895
    D.3.4Pharmaceutical form Film-coated tablet
    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 INNTL-895
    D.3.9.1CAS number 1415823-49-2
    D.3.9.2Current sponsor codeTL-895
    D.3.9.3Other descriptive nameM7583
    D.3.9.4EV Substance CodeSUB216480
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 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 TL-895
    D.3.4Pharmaceutical form Film-coated tablet
    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 INNTL-895
    D.3.9.1CAS number 1415823-49-2
    D.3.9.2Current sponsor codeTL-895
    D.3.9.3Other descriptive nameM7583
    D.3.9.4EV Substance CodeSUB216480
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    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 Jakavi
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form
    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 INNRuxolitinib
    D.3.9.3Other descriptive nameRuxolitinib
    D.3.9.4EV Substance CodeSUB32273
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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
    Janus associated Kinase Inhibitor (JAKi) Treatment-Naïve Myelofibrosis (MF) Subjects and Subjects with MF who have a Suboptimal Response to Ruxolitinib
    Estudio de fase 1b/2 de TL-895 combinado con ruxolitinib en sujetos con mielofibrosis sin tratamiento previo con iJAK y sujetos con mielofibrosis y respuesta subóptima a ruxolitinib
    E.1.1.1Medical condition in easily understood language
    Myelofibrosis is an uncommon type of bone marrow cancer that disrupts the body's normal production of blood cells.
    La mielofibrosis es un tipo poco común de cáncer de médula ósea que interrumpe la producción normal de células sanguíneas en el cuerpo.
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10028537
    E.1.2Term Myelofibrosis
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase 1b: To determine the recommended Phase 2 dose (RP2D) of TL-895 in combination with ruxolitinib.

    Phase 2: To determine the spleen reduction volume (SVR) rate at Week 24.
    Fase 1b: Determinar la dosis recomendada para la fase 2 (DRF2) de TL-895 en combinación con ruxolitinib.

    Fase 2: Determinar la tasa de reducción del volumen esplénico (RVE) en la semana 24
    E.2.2Secondary objectives of the trial
    Phase 1b:

    To determine:
    the spleen volume reduction (SVR) rate at Week 24
    the improvement in Total Symptom Score (TSS) at Week 24
    spleen response
    the duration of spleen response (DoR-spleen)
    the rate of conversion from Red Blood Cell (RBC) transfusion dependent to independent
    the clinical response rate: complete response (CR) and partial response (PR)
    the overall survival (OS) rate
    progression-free survival (PFS)

    To characterize the pharmacokinetic (PK) profile of TL-895 and ruxolitinib
    To determine the safety and tolerability of TL 895

    Phase 2:
    To determine the improvement in TSS at Week 24
    To determine spleen response
    To determine the DoR-spleen
    To determine the rate of conversion from RBC transfusion dependent to independent
    To determine the clinical response rate: CR and PR
    To determine the OS rate
    To determine PFS
    To monitor the PK of TL 895 and ruxolitinib
    To determine the safety and tolerability of TL 895
    Fase 1b:
    Determinar: la tasa de reducción del volumen esplénico (RVE) en la semana 24; la mejora de la puntuación TSS (puntuación total de síntomas) en la semana 24; la respuesta esplénica; la duración de la respuesta esplénica (DR-bazo); la tasa de conversión de dependencia a independencia de transfusiones de eritrocitos; la tasa de respuesta clínica: respuesta completa (RC) y respuesta parcial (RP); la tasa de supervivencia global (SG); la supervivencia sin progresión (SSP); el perfil farmacocinético de TL-895 y ruxolitinib y determinar la seguridad y tolerabilidad de TL 895.

    Fase 2:
    Determinar: la mejora de la puntuación TSS en la semana 24; la respuesta esplénica; la DR-bazo; la tasa de conversión de dependencia a independencia de transfusiones de eritrocitos; la tasa de respuesta clínica: RC y RP; la tasa de SG; la SSP; Controlar la farmacocinética de TL 895 y ruxolitinib; la seguridad y tolerabilidad de TL 895.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Phase 1b and Phase 2 Cohort 2

    1. Treatment with ruxolitinib for ≥ 12 weeks prior to study entry, and on a stable dose of ruxolitinib in the 8 weeks prior to Sponsor approval of the enrollment form
    • A stable dose is defined as a ruxolitinib dose that has not required a treatment hold or dose adjustment
    • Subjects must be taking a stable dose of ruxolitinib of at least 5 mg BID or 10 mg QD

    Phase 1b and Phase 2 (both cohorts)
    2. Subjects ≥ 18 years of age and able to provide informed consent.
    3. Confirmed diagnosis of PMF, post-PV MF, or post-ET MF, as assessed by treating physician according to the World Health Organization (WHO) criteria
    4. High-risk, intermediate-2 risk, or intermediate-1 risk, defined by Dynamic International Prognostic System (DIPSS)
    5. Palpable spleen measuring ≥ 5 cm below the left lower coastal margin (LLCM) or spleen volume of ≥ 450 cm3 by MRI or CT scan assessment
    6. MF symptoms as defined by having at least 2 symptoms with a score of at least 1 each on the MFSAF v4.0
    7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
    8. Adequate hematological function within 7 days (Phase 1b) or 28 days (Phase 2) prior to first dose, independent of growth factor support for at least 7 days, with the exception of pegylated Granulocyte Colony-Stimulating Factor (G CSF) which requires at least 14 days, defined as:
    • Absolute neutrophil count (ANC) ≥ 1.0 × 109/L
    • Platelet count ≥ 50 × 109/L
    9. Adequate hepatic function within 7 days (Phase 1b) or 28 days (Phase 2) prior to first dose of study treatment defined as:
    • Total serum bilirubin ≤ 2.0 x upper limit of normal (ULN). Subjects with known Gilbert’s syndrome or disease-related hemolysis must have a total bilirubin ≤3.0 × ULN
    • Aspartate aminotransferase (AST) ≤ 2.5 × ULN, and alanine aminotransferase (ALT) ≤ 2.5 × ULN.
    10. Adequate renal function within 7 days (Phase 1b) or 28 days (Phase 2) defined as an estimated creatinine clearance ≥ 30 mL/min according to Cockcroft Gault.
    11. Female subjects of childbearing potential and their male partners, or male subjects who have female partners of childbearing potential, must both use a highly effective contraception method during the study. In addition, after the last dose of study drug, female subjects must continue to use contraception for 1 month and 1 week and male subjects must continue to use contraception for 3 months and 1 week. A woman is considered of childbearing potential (i.e., fertile, following menarche and until becoming postmenopausal) unless permanently sterile (refer to Appendix 2 of the protocol for additional details).

    Note: Marketed drugs administered concomitantly in this study may have different contraception requirements, including required duration of contraception use. The contraception requirements in the local prescribing guidelines must be followed for all concomitant drugs administered in this study.
    Fase 1b y cohorte 2 de la fase 2
    1. Tratamiento con ruxolitinib durante ≥12 semanas antes de la incorporación al estudio y recepción de una dosis estable de ruxolitinib durante las 8 semanas previas a la aprobación del formulario de inclusión por parte del promotor.
    • Una dosis estable se define como una dosis de ruxolitinib que no ha precisado interrupción del tratamiento ni ajuste de la dosis.
    • Los sujetos deberán estar tomando una dosis estable de ruxolitinib de al menos 5 mg dos veces al día o 10 mg una vez al día.

    Fase 1b y fase 2 (ambas cohortes)
    2. Sujetos mayores de 18 años con capacidad de otorgar su consentimiento informado.
    3. Diagnóstico confirmado de mielofibrosis primaria, mielofibrosis secundaria a policitemia vera o mielofibrosis secundaria a trombocitemia esencial, según la evaluación del médico responsable del tratamiento conforme a los criterios de la Organización Mundial de la Salud (OMS).
    4. Riesgo alto, riesgo intermedio-2 o riesgo intermedio-1, definido según la clasificación DIPSS (Sistema pronóstico internacional dinámico).
    5. Bazo palpable ≥5 cm por debajo del reborde costal inferior izquierdo (RCII) o volumen esplénico ≥450 cm3 según la RM o TC.
    6. Síntomas de mielofibrosis, definidos como la presencia de al menos dos síntomas con una puntuación mínima de 1 en cada uno en el MFSAF, versión 4.0.
    7. Estado funcional según la escala del Eastern Cooperative Oncology Group (ECOG) de 0 a 2.
    8. Función hematológica adecuada en los 7 (fase 1b) o 28 (fase 2) días previos a la primera dosis, independiente del apoyo con factores de crecimiento durante al menos 7 días, a excepción de factor estimulador de las colonias de granulocitos (G CSF) pegilado, con el que se exigen al menos 14 días, definida como:
    • Recuento absoluto de neutrófilos (RAN) ≥1,0 × 109/l.
    • Recuento de plaquetas ≥50 × 109/l.
    9. Función hepática adecuada en los 7 (fase 1b) o 28 (fase 2) días previos a la primera dosis del tratamiento del estudio, definida como:
    • Bilirrubina sérica total ≤2,0 veces el límite superior de la normalidad (LSN). Los sujetos con síndrome de Gilbert conocido o hemólisis relacionada con la enfermedad deberán tener una bilirrubina total ≤3,0 veces el LSN.
    • Aspartato aminotransferasa (AST) ≤2,5 veces el LSN y alanina aminotransferasa (ALT) ≤2,5 veces el LSN.
    10. Función renal adecuada en los 7 (fase 1b) o 28 (fase 2) días previos a la primera dosis del tratamiento del estudio, definida como un aclaramiento de creatinina estimado ≥30 ml/min según la fórmula de Cockcroft-Gault.
    11. Las mujeres con capacidad reproductiva y sus parejas, o los varones con parejas con capacidad reproductiva, deberán utilizar un método anticonceptivo muy eficaz durante el estudio. Además, después de la última dosis del fármaco del estudio, las mujeres deberán seguir utilizando un método anticonceptivo durante un mes y una semana y los varones, durante tres meses y una semana. Se considerará con capacidad reproductiva (es decir, fértil, desde la menarquia y hasta después de la menopausia) a todas las mujeres, a menos que hayan sido esterilizadas de forma permanente (consulte el Appendix 2 para obtener más detalles).
    Nota: Los medicamentos comercializados que se administren de forma concomitante en este estudio pueden tener requisitos de anticoncepción diferentes, incluida la duración exigida del uso de métodos anticonceptivos. Deberán seguirse los requisitos de anticoncepción recogidos en la ficha técnica local de todos los medicamentos concomitantes que se administren en este estudio.
    E.4Principal exclusion criteria
    Phase 2 Cohort 1

    1. Prior treatment with any JAKi

    Phase 1b and Phase 2 Cohort 2

    2. Documented disease progression while on ruxolitinib treatment, defined as any of the following:
    • ≥100% increase in palpable distance, below the LLCM from nadir for baseline splenomegaly of 5 to 10 cm while on ruxolitinib, or
    • ≥ 50% increase in palpable distance, below the LLCM from nadir, for baseline splenomegaly of >10 cm while on ruxolitinib, or
    • ≥25% increase from nadir in spleen volume by radiographic imaging while on ruxolitinib treatment, or
    • Regrowth after achieving complete response

    Phase 1b and Phase 2 (both cohorts)

    3. Prior splenectomy or splenic irradiation within 24 weeks prior to first dose of study treatment
    4. Prior treatment with a BTK or BMX inhibitor
    5. Chemotherapy, cytoreductive therapy, immune therapy, cytokine therapy or any investigational therapy within 28 days prior to first dose of study treatment. Subjects on hydroxyurea therapy may continue treatment until 1 day prior to the first dose of study drug.
    6. Active participation in other therapeutic clinical trials including supportive care trials
    7. Subjects with a history of bleeding diathesis; major hemorrhage or intracranial hemorrhage within 6 months prior to first dose of study treatment
    8. Major surgery or planned major surgery within 28 days prior to first dose of study treatment.
    9. History of major organ transplant
    10. Having history of difficulty swallowing, gastric or small bowel surgery with history of malabsorption or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the study treatment
    11. Uncontrolled intercurrent illness including, but not limited to clinically significant cardiac disease (New York Heart Association Class III or IV); symptomatic congestive heart failure; unstable angina pectoris; ventricular arrhythmia; history of myocardial infarction within 3 months
    12. Grade 2 or higher QTc prolongation (> 480 milliseconds [ms] per National Cancer Institute Common Terminology of Adverse Events [v 5.0])
    13. Clinically significant bacterial, mycobacterial, fungal, parasitic, or viral infection. Intravenous (IV) antibiotics within 2 weeks prior to first dose of study treatment.
    14. Subjects with active hepatitis B virus (HBV) or hepatitis C virus (HCV)
    15. Known infection with HIV
    16. Known hypersensitivity or contraindications to the study drugs or any of their excipients.
    17. History of another malignancy within the last 3 years, other than curatively treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, organ-confined or treated non-metastatic prostate cancer with normal prostate-specific antigen, in situ breast carcinoma after complete surgical resection or superficial transitional cell bladder carcinoma
    18. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment in this study provided the proton pump inhibitor is discontinued at least 3 days prior to first dose of study drug.
    19. Women who are pregnant or breastfeeding.
    20. Medical condition, serious intercurrent illness, psychiatric condition, or other circumstance (i.e., committed to an institution by judicial or administrative authority) that, in the Investigator's judgment, could jeopardize the subject's safety, or that could interfere with study objectives.
    Phase 1b
    21. Subjects receiving medications, herbal supplements, or food known to be strong inhibitors of CYP3A within 7 days prior to the first dose of study treatment.
    Cohorte 1 de la fase 2
    1. Tratamiento previo con cualquier iJAK.
    Fase 1b y cohorte 2 de la fase 2
    2. Progresión documentada de la enfermedad durante el tratamiento con ruxolitinib, definida como cualquiera de las circunstancias siguientes:
    • Aumento ≥100% de la distancia palpable por debajo del RCII con respecto al valor mínimo, en caso de esplenomegalia basal de 5 a 10 cm durante el tratamiento con ruxolitinib, o
    • Aumento ≥50% de la distancia palpable por debajo del MCI con respecto al valor mínimo, en caso de esplenomegalia basal >10 cm durante el tratamiento con ruxolitinib, o
    • Aumento del volumen esplénico ≥25% con respecto al valor mínimo en las imágenes radiológicas durante el tratamiento con ruxolitinib, o
    • Recrecimiento después de lograr una respuesta completa.
    Fase 1b y fase 2 (ambas cohortes)
    3. Esplenectomía o irradiación esplénica previas en las 24 semanas previas a la primera dosis del tratamiento del estudio.
    4. Tratamiento previo con un inhibidor de BTK o BMX.
    5. Quimioterapia, tratamiento citorreductor, inmunoterapia, tratamiento con citocinas o cualquier tratamiento en investigación en los 28 días previos a la primera dosis del tratamiento del estudio. Los sujetos en tratamiento con hidroxicarbamida podrán continuar con el tratamiento hasta un día antes de la primera dosis del fármaco del estudio.
    6. Participación activa en otros ensayos clínicos terapéuticos, incluidos ensayos sobre el tratamiento sintomático.
    7. Sujetos con antecedentes de diátesis hemorrágica, hemorragia importante o hemorragia intracraneal en los 6 meses previos a la primera dosis del tratamiento del estudio.
    8. Intervención de cirugía mayor practicada o programada en los 28 días previos a la primera dosis del tratamiento del estudio.
    9. Antecedentes de trasplante de un órgano importante.
    10. Antecedentes de dificultad para tragar y de cirugía gástrica o del intestino delgado con antecedentes de malabsorción u otras enfermedades o trastornos gastrointestinales crónicos que puedan dificultar el cumplimiento o la absorción del tratamiento del estudio.
    11. Enfermedad intercurrente no controlada, entre otras, cardiopatía clínicamente significativa (clase III o IV de la New York Heart Association), insuficiencia cardíaca congestiva sintomática, angina de pecho inestable, arritmia ventricular o antecedentes de infarto de miocardio en los tres meses previos.
    12. Prolongación del intervalo QTc de grado 2 o superior (>480 milisegundos [ms] según los Criterios terminológicos comunes para la clasificación de acontecimientos adversos del National Cancer Institute [versión 5.0]).
    13. Infección bacteriana, micobacteriana, micótica, parasitaria o vírica clínicamente significativa. Administración de antibióticos intravenosos (IV) en las dos semanas previas a la primera dosis del tratamiento del estudio.
    14. Sujetos con infección activa por el virus de la hepatitis B (VHB) o C (VHC).
    15. Infección conocida por el VIH.
    16. Hipersensibilidad o contraindicaciones conocidas a los fármacos del estudio o a cualquiera de sus excipientes.
    17. Antecedentes de otra neoplasia maligna en los tres últimos años, excepto carcinoma basocelular o espinocelular de piel tratado con intención curativa, carcinoma in situ de cuello uterino, cáncer de próstata no metastásico limitado al órgano o tratado con antígeno prostático específico normal, carcinoma de mama in situ después de una resección quirúrgica completa o carcinoma de vejiga de células de transición superficial.
    18. Necesidad de tratamiento con inhibidores de la bomba de protones (p. ej., omeprazol, esomeprazol, lansoprazol, dexlansoprazol, rabeprazol o pantoprazol). Los sujetos tratados con inhibidores de la bomba de protones que cambien a antagonistas de los receptores H2 o antiácidos podrán participar en este estudio siempre que el inhibidor de la bomba de protones se suspenda al menos tres días antes de la primera dosis del fármaco del estudio.
    19. Mujeres embarazadas o en período de lactancia.
    20. Proceso médico, enfermedad intercurrente grave, trastorno psiquiátrico u otra circunstancia (p. ej., internado en una institución por una autoridad judicial o administrativa) que, en opinión del investigador, pueda poner en peligro la seguridad del sujeto o interferir en los objetivos del estudio.
    Fase 1b
    21. Tratamiento con medicamentos, suplementos de herbolario o alimentos que sean inhibidores potentes conocidos de la enzima CYP3A en los siete días previos a la primera dosis del tratamiento del estudio
    E.5 End points
    E.5.1Primary end point(s)
    Phase 1b: Dose-limiting toxicities (DLTs) will be used to establish the maximum-tolerated dose (MTD) of TL-895 in combination with ruxolitinib. The safety review committee (SRC) will determine the RP2D based on safety and efficacy data of the combination of TL-895 and ruxolitinib.

    Phase 2: The proportion of subjects achieving SVR of ≥35% at Week 24 by MRI or CT scan (central review)
    Fase 1b: se utilizará la toxicidad limitante de la dosis (TLD) para establecer la dosis máxima tolerada (DMT) de TL-895 en combinación con ruxolitinib. El comité de revisión de la seguridad (CRS) determinará la DRF2 basándose en los datos de seguridad y eficacia de la combinación de TL-895 y ruxolitinib.

    Fase 2: proporción de sujetos que logren una reducción del volumen esplénico ≥35% en la semana 24 mediante RM o TC (evaluación centralizada).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase 1b: End of Phase

    Phase 2: Week 24
    Fase 1b: final de la fase

    Fase 2: semana 24
    E.5.2Secondary end point(s)
    Phase 1b:
    The proportion of subjects achieving ≥35% SVR at Week 24 by magnetic resonance imaging (MRI) or computed tomography (CT) scan (central review)
    The proportion of subjects achieving ≥50% reduction in TSS at Week 24 by Myelofibrosis Symptom Assessment Form (MFSAF) v4.0
    The proportion of subjects achieving ≥35% SVR at any time point from Baseline while on study, as assessed by MRI (or by CT scan for applicable subjects)
    Time from initial SVR of ≥ 35% by MRI/CT (central review) until the first occurrence of disease progression or death
    The proportion of RBC dependent subjects achieving RBC transfusion independence at Week 24
    The proportion of subjects with CR and PR at any time point, from Baseline while on study, defined according to International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and modified European LeukemiaNet (ELN) criteria
    OS is defined as the time from first dose to death from any cause
    PFS is the time from first dose date to:
    • Disease progression (≥25% increase in spleen volume)
    or
    • Leukemic transformation (bone marrow blasts ≥20% or peripheral blood blasts ≥20% associated with an absolute blast count of at least 1 x 10^9/L that lasts for at least 2 weeks)
    or
    • Death from any cause
    TL-895 and ruxolitinib PK parameters, including but not limited to:
    • Maximum observed concentration (Cmax)
    • Area under the plasma concentration-time curve (AUC)
    • Time of maximum plasma concentration (Tmax)
    Analyses of the safety endpoints will include the following measurements or assessments: physical examinations, laboratory tests, adverse events (AEs), serious AEs (SAEs), electrocardiograms (ECGs), and vital signs

    Phase 2:
    The proportion of subjects achieving ≥50% reduction in TSS at Week 24 by MFSAF v4.0
    The proportion of subjects achieving ≥35% SVR at any time point from Baseline while on study, as assessed by MRI (or by CT scan for applicable subjects)
    Time from initial SVR of ≥ 35% by MRI/CT (central review) until the first occurrence of disease progression or death
    The proportion of RBC dependent subjects achieving RBC transfusion independence at Week 24
    The proportion of subjects with CR and PR at any time point, from Baseline while on study, defined according to IWG-MRT and modified ELN criteria
    OS is defined as the time from first dose to death from any cause
    PFS is the time from first dose date to:
    • Disease progression (≥25% increase in spleen volume)
    or
    • Leukemic transformation (bone marrow blasts ≥20% or peripheral blood blasts ≥20% associated with an absolute blast count of at least 1 x 10^9/L that lasts for at least 2 weeks)
    or
    • Death from any cause
    TL-895 and ruxolitinib plasma concentrations monitored using sparse sampling.
    Analyses of the safety endpoints will include the following measurements or assessments: physical examinations, laboratory tests, AEs, SAEs, ECGs, and vital signs
    Fase 1b:
    Proporción de sujetos que logren una RVE ≥35% en la semana 24 mediante resonancia magnética (RM) o tomografía computarizada (TC) (evaluación centralizada).
    Proporción de sujetos que logren una reducción ≥50% de la puntuación TSS en la semana 24 según el Formulario de evaluación de los síntomas de mielofibrosis (MFSAF), versión 4.0.
    Proporción de sujetos que logren una RVE ≥35% en cualquier momento, con respecto al momento basal, durante el estudio, evaluada mediante RM (o TC en los sujetos pertinentes).
    Tiempo transcurrido entre una RVE inicial ≥35% mediante RM/TC (evaluación centralizada) y el primer episodio de progresión de la enfermedad o la muerte.
    Proporción de sujetos con dependencia de transfusiones de eritrocitos que logren la independencia de ellas en la semana 24.
    Proporción de sujetos con RC y RP en cualquier momento, con respecto al momento basal durante el estudio, definida conforme a los criterios del International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWGMRT) y los criterios de la European LeukemiaNet (ELN) modificados. La SG se define como el tiempo transcurrido entre la primera dosis y la muerte por cualquier causa. La SSP es el tiempo transcurrido entre la fecha de la primera dosis y:
    • Progresión de la enfermedad (aumento ≥25% del volumen esplénico)
    o
    • Transformación leucémica (≥20% de blastos en médula ósea o ≥20% de blastos en sangre periférica asociados a un recuento absoluto de blastos de al menos 1 x 109/l con una duración mínima de dos semanas)
    o
    • Muerte por cualquier causa
    Parámetros farmacocinéticos de TL-895 y ruxolitinib, entre
    otros:
    • Concentración máxima observada (Cmáx)
    • Área bajo la curva de concentración plasmática-tiempo (AUC)
    • Tiempo transcurrido hasta alcanzar la concentración plasmática máxima (Tmáx)
    Los análisis de los criterios de valoración de la seguridad incluirán las siguientes determinaciones o evaluaciones: exploraciones físicas, determinaciones analíticas, acontecimientos adversos (AA), AA graves (AAG), electrocardiogramas (ECG)
    y constantes vitales

    Fase 2:

    Proporción de sujetos que logren una reducción ≥50% de la puntuación TSS en la semana 24 según el MFSAF, versión 4.0.
    Proporción de sujetos que logren una RVE ≥35% en cualquier momento, con respecto al momento basal, durante el estudio, evaluada mediante RM (o TC en los sujetos pertinentes).
    Tiempo transcurrido entre una RVE inicial ≥35% mediante RM/TC (evaluación centralizada) y el primer episodio de progresión de la enfermedad o la muerte.
    Proporción de sujetos con dependencia de transfusiones de eritrocitos que logren la independencia de ellas en la semana 24.
    Proporción de sujetos con RC y RP en cualquier momento, con respecto al momento basal durante el estudio, definida conforme a los criterios del IWG-MRT y los criterios
    de ELN modificados
    La SG se define como el tiempo transcurrido entre la primera dosis y la muerte por cualquier causa. La SSP es el tiempo transcurrido entre la fecha de la primera dosis y:
    • Progresión de la enfermedad (aumento ≥25% del volumen esplénico)
    o
    • Transformación leucémica (≥20% de blastos en médula ósea o ≥20% de blastos en sangre periférica asociados a un recuento absoluto de blastos de al menos 1 x 109/l con una duración mínima de dos semanas)
    o
    • Muerte por cualquier causa
    Se controlarán las concentraciones plasmáticas de TL-895 y ruxolitinib mediante muestreo no intensivo.
    Los análisis de los criterios de valoración de la seguridad incluirán las siguientes determinaciones o evaluaciones: exploraciones físicas, determinaciones analíticas, AA, AAG, ECG y constantes vitales
    E.5.2.1Timepoint(s) of evaluation of this end point
    Phase 1b: End of Phase

    Phase 2: Week 24
    Fase 1b: final de la fase

    Fase 2: semana 24
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    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 No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Dose escalation
    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 No
    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 Yes
    E.8.5.1Number of sites anticipated in the EEA29
    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
    Brazil
    Israel
    United States
    France
    Poland
    Spain
    Germany
    Italy
    Hungary
    United Kingdom
    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
    LVLS
    Ultima visita, ultimo paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months1
    E.8.9.2In all countries concerned by the trial days1
    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: 52
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 70
    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)
    Subjects will be treated until disease progression, unacceptable toxicity, death or withdrawal of consent. For disease progression, unacceptable toxicity, or withdrawal of consent, subject would move on to standard care based on local practices.
    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 Decision2022-09-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-09-01
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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