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    Summary
    EudraCT Number:2021-003091-14
    Sponsor's Protocol Code Number:AB-106-G208
    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:2022-02-08
    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 number2021-003091-14
    A.3Full title of the trial
    A Single-Arm, Open-Label, Multicenter Phase 2 Study to Evaluate the Efficacy and Safety of Taletrectinib in Patients with Advanced or Metastatic ROS1 Positive NSCLC and Other Solid Tumors
    Estudio en fase II abierto, de un solo grupo y multicéntrico para evaluar la eficacia y la seguridad de taletrectinib en pacientes con CPNM ROS1 positivo avanzado o metastásico y otros tumores sólidos
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to assess the effect of Taletrectinib in patients with advanced ROS1 Positive non- small cell lung cancer and Other Solid Tumors
    Estudio para evaluar el efecto de Taletrectinib en pacientes con cáncer de pulmón no microcítico ROS1 positivo avanzado y otros tumores sólidos
    A.3.2Name or abbreviated title of the trial where available
    Taletrectinib in ROS1 Positive Lung Cancer Phase 2 Global Study (TRUST II)
    Taletrectinib en el estudio global de fase 2 de cáncer de pulmón positivo para ROS1 (TRUST II)
    A.4.1Sponsor's protocol code numberAB-106-G208
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04919811
    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 SponsorAnHeart Therapeutics 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 supportAnHeart Therapeutics Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAnHeart Therapeutics
    B.5.2Functional name of contact pointPublic Relations
    B.5.3 Address:
    B.5.3.1Street Address777 Third Ave, Suite 1704
    B.5.3.2Town/ cityNY
    B.5.3.3Post code10017
    B.5.3.4CountryUnited States
    B.5.4Telephone number349133030007547
    B.5.5Fax number516-364-1845
    B.5.6E-mailpr@anhearttherapeutics.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 nameTaletrectinib
    D.3.2Product code AB-106 / DS-6051b
    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 INNTaletrectinib
    D.3.9.2Current sponsor codeAB-106
    D.3.9.3Other descriptive nameDS-6051b
    D.3.9.4EV Substance CodeSUB218609
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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
    Non Small Cell Lung Cancer
    Cancer de pulmon de celulas no pequeñas
    E.1.1.1Medical condition in easily understood language
    Lung Cancer
    Cancer de Pulmon
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10029515
    E.1.2Term Non-small cell lung cancer recurrent
    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
    To evaluate the efficacy of taletrectinib by the objective response rate (ORR) in the patients with advanced or metastatic ROS1 positive NSCLC
    Evaluar la eficacia de talerectinib mediante la tasa de respuesta objetiva (ORR) en pacientes con NSCLC ROS1 positivo avanzado o metastásico
    E.2.2Secondary objectives of the trial
    Efficacy Objectives:
    1. To evaluate the efficacy by duration of response (DOR)
    2. To evaluate the efficacy by progression-free survival (PFS)
    3. To evaluate the efficacy by time to failure(TTF)
    4. To evaluate the efficacy by time to response(TTR)
    5. To evaluate the efficacy by overall survival(OS)
    6. To evaluate the efficacy endpoints (ORR,DOR and PFS) assessed by investigators
    7. To evaluate the intracranial efficacy of taletrectinib

    Safety Objective:
    • To evaluate the safety and tolerability of taletrectinib

    Pharmacokinetics (PK) Objective:
    • To evaluate pharmacokinetic profile of taletrectinib
    Objetivos de eficacia:
    1. Evaluar la eficacia según la duración de la remisión (DR)
    2. Evaluar la eficacia según la supervivencia sin progresión (SSP)
    3. Evaluar la eficacia según el tiempo transcurrido hasta el fracaso (THF)
    4. Evaluar la eficacia según el tiempo hasta la remisión (THR)
    5. Evaluar la eficacia según la supervivencia general (SG)
    6. Evaluar los criterios de valoración de la eficacia (TRO, DR y SSP) por los investigadores
    7. Evaluar la eficacia intracraneal del taletrectinib
    Objetivo de seguridad:
    • Evaluar la seguridad y la tolerabilidad del taletrectinib
    Objetivo farmacocinético (FC):
    • Evaluar el perfil farmacocinético de taletrectinib
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patient age ≥18 years (or ≥20 years as required by local regulations
    2. Histologically or cytologically confirmed diagnosis of locally advanced or metastatic NSCLC (cohorts 1-3) or other solid tumors (cohort 4).
    3. Evidence of ROS1 fusion in tumor tissue determined by a validated assay as performed in Clinical Laboratory Improvement Amendments (CLIA)-certified or locally equivalent diagnostic laboratories. The molecular assays (ie RT-PCR, NGS) are highly recommended.
    4. Sufficient tumor tissue is required for performing confirmatory ROS1 fusion testing at the designated central laboratories. For patients in cohort 1, an archival tumor tissue specimen should be available and collected prior to enrollment. If archival tumor tissue is unavailable, then a fresh biopsy must be performed. For patients in cohort 2, a fresh biopsy for tumor tissue is highly recommended before enrollment even if the archival tumor tissue is available. For patients in cohorts 3 and 4, either an archival tumor tissue or a fresh tumor tissue must be available before enrollment.
    5. Patients with central nervous system (CNS) involvement, including leptomeningeal carcinomatosis, which is either asymptomatic or previously treated and controlled, are allowed; the use of seizure prophylaxis is allowed as long as patients are taking non enzyme-inducing anti-epileptic drugs (non-EIAEDs). If corticosteroid treatment is required, it should be on stable or decreasing dose of ≤10 mg prednisone or equivalent. If patients have neurological symptoms or signs due to CNS metastasis, patients need to complete whole brain radiation or gamma knife irradiation treatment at least 14 days before enrollment and be clinically stable.
    6. The patient is either ROS1 TKI treatment naïve, or treated with prior ROS1 TKI(s):
    • Cohort 1: Systemic chemotherapy naïve or pretreated with one prior line of chemotherapy,
    but never treated with any ROS1 TKI;
    • Cohort 2: Prior treatment with one ROS1 TKI (crizotinib or entrectinib) and disease progression. The subject could be either chemotherapy naïve or has received one line of platinum and/or pemetrexed-based chemotherapy for the locally advanced or metastatic NSCLC.
    • Cohort 3: Prior treatment with ≤ 2 ROS1 TKIs and disease progression. The subject could be either chemotherapy naïve or has received ≤ 2 lines of platinum and/ or pemetrexed based chemotherapy for the locally advanced or metastatic NSCLC.
    • Cohort 4: Systemic chemotherapy naïve or pretreated with ≤ 2 prior lines of chemotherapy, but never treated with any ROS1 TKI. ROS1 positive solid tumor types other than NSCLC will be enrolled.
    7. At least one measurable disease per RECIST 1.1 assessed by investigators.
    8. Eastern Cooperative Oncology Group Performance Status: 0 or 1.
    9. Patient with a life expectancy ≥12 weeks based on the judgement of investigators.
    10. Patients with adequate organ function meeting the following criteria:
    a) Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT): ≤ 3.0 × upper limit of normal (ULN) (or ≤ 5.0 × ULN, for patients with concurrent liver metastases);
    b) Serum total bilirubin: ≤ 1.5 × ULN;
    c) Absolute neutrophil count: ≥1,500/μL;
    d) Platelet count: ≥100,000/μL;
    e) Hemoglobin: ≥ 9.0 g/dL;
    f) Serum creatinine ≤ 1.5 x ULN and estimated creatinine clearance (CLcr) ≥45 mL/min as
    calculated using the method standard for the institution (eg. Cockcroft - Gault Equation)
    11. Males and/or females who meet any of the following criteria
    a) For males (irrespective of surgical sterilization [vasectomy]): agree to use effective contraception methods during the study intervention period and for at least 90 days after the last dose of investigational drug or agree with complete abstinence;
    Females without menses for at least one year prior to screening or documented to be surgically sterilized. Women of childbearing potential (WOCBP) must agree to use two concurrent highly effective methods of contraception or agree with complete abstinence from sexual intercourse since the informed consent until 90 days after the last dose of investigational drug. Usage of hormonotherapy for contraception should be recorded as well. For detailed guidance on pregnancy and effective contraception, please refer to Appendix 4: Contraceptive and Barrier Guidance
    12. For all females of childbearing potential, a negative pregnancy test must be obtained within 7 days of initial administration. Female patients of non-childbearing potential must meet at least 1 of the following criteria
    Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed with a serum follicle-stimulating hormone (FSH) level confirming the postmenopausal state;
    Have undergone a documented hysterectomy and/or bilateral oophorectomy
    Have medically confirmed ovarian failure
    Full list in Protocol
    1.Edad≥18 años(o≥20años,segúnnorma.loc).2.Diagn.confirmado hist.o citológicamente de CPNM local~avanzado/metastásico(Chtes 1-3)otros tumores sólidos(Chte 4).3.Evidencia fusión ROS1 en tej.tumoral,determinada mediante un análisis validado realizado en lab.Diagn.con certificación según Enmiendas mejora de los lab. Clínicos(CLIA)o localmente equiv.Se recomiendan los anál. moleculares(RT-PCR, NGS).4.Requiere cantidad suficiente de tej. tumoral parapruebas confirmatorias de fusión de ROS1 en los lab. centrales designados después de la inscrip.Pac. Chte 1,debe haber una muestra de tej.tumoral de archivo disponible que se haya recogido antes de la inscripción.Si esta no estuviera disponible,se debe realizar una biopsia en fresco.Pac. Chte 2,se recomienda una biopsia en fresco de tej.tumoral antes de la inscripción,aun disponiendo del tej.Tumoral de archivo.Para los pac. Chtes 3 y 4, debe haber disponible tej.tumoral de archivo o reciente antes de la inscripción.5.Permite la inscrip.pac.con enfer. del SNC,como la carcinomatosis leptomeníngea,ya sea asintomática o ya se haya tratado y controlado previamente;se permite el uso de profilaxis contra la epilepsia siempre que los pac. tomen antiepilépticos no inductores enzimáticos(no AEIE).Si necesario el tto con Corticoester.,recibiendo una dosis estable o decreciente de ≤10 mg de prednisona o equivalente.Si los pac. tienen signos o síntomas neurológicos causados por metástasis en el SNC,tendrán que someterse a una radioterapia total del cerebro o a un tto de irradiación con bisturí de rayos γ al menos 14 días antes de la inscripción y encontrarse clínicamente estables.6.El paciente no ha recibido tto previo con ITC de ROS1 o ha recibido tto previo con uno o más ITC de ROS1:•Chte1: pac. no tratados previamente con quimio sistémica o pretratados con un tipo de quimio anterior, pero que nunca se han tratado con un ITC de ROS1.•Chte2:pac. tratados previamente con un ITC de ROS1 (crizotinib o entrectinib)y progresión de la enfermedad. El paciente puede no haber recibido tto previo con quimio o haber recibido un tipo de quimio basada en platino o pemetrexed para el CPNM localmente avanzado o metastásico.• Chte 3: pac. tratados previamente con ≤2 ITC de ROS1 y progresión de la enfermedad. Pac. puede no haber recibido tto previo con quimio o haber recibido ≤2tipos quimio basada en platino o pemetrexed para el CPNM localmente avanzado o metastásico.•Chte4: pac.no tratados previamente con quimio sistémica o pretratados con≤2 tipos de quimio anteriores, pero que nunca se han tratado con un ITC de ROS1. Se inscribirá a pac.con tipos de tum.sólidos ROS1 positivos distintos del CPNM.7.Al menos una enfermedad medible según los criterios RECIST 1.1 evaluada por el Invest.8.Estado gral según el Grupo Oncológico Cooperativo del Este: 0 o 1.9.Pac.con una esperanza de vida ≥12 semanas según el criterio del investigador.10.Pac. con una función orgánica adecuada que cumplan los criterios siguientes:a)Aspartato aminotransferasa (AST) y alanina aminotransferasa (ALT): ≤3,0×límite superior de la normalidad(LSN)(o ≤5,0× LSN, para pac. con metástasis hepáticas concurrentes)b) Bilirrubina sérica total: ≤1,5×LSNc) Cifra absoluta de neutrófilos: ≥1500/μld)Cifra de plaquetas: ≥100 000/μle)Hemoglobina: ≥9,0 g/dlf)Creatinina sérica ≤1,5×LSN y un aclaramiento de la creatinina(CLcr)≥45 ml/min calculado con el método estándar que use institución(fórmulaCockcroft-Gault).11.Varones o mujeres que cumplan criterios:a)varones (independ.de la esterilización quirúrgica:vasectomía):utilizar met. anticonc. eficaces durante intervención del estudio y durante al menos los 90 días posteriores a la última dosis del fármaco en investigación,o comprometerse a mantener abstinencia completa.b)Mujeres:no haber tenido la menstruación al menos durante el año anterior a la selec.o poder documentar que están esterilizadas quirúrgicamente.Mujeres edad fértil(MEF)uso de dos met. anticonceptivos altamente eficaces simultáneos o comprometerse a mantener abst.completa de relaciones sexuales desde la firma del consentimiento informado hasta los 90 días posteriores a la última dosis del fárm.investigación.Documentarse el uso de hormonas anticonceptivas.12.Todas las mujeres en edad fértil:debe obtenerse una prueba embarazo negativa en los 7 días anteriores al inicio del tto del estudio.Mujeres que no puedan quedarse embarazadas deben cumplir crit.:stado posmenopáusico,que se define de la siguiente manera:cese de lamenstruación habitual durante al menos 12 meses consecutivos sin otra causapatológica o fisiológica alternativa;el estado puede confirmarse midiendo el nivel de FSH en suero para confirmar el estado posmenopáusico.Haberse sometido a una histerectomía u ovariectomía bilateral documentadas.insuficiencia ovárica confirmada médicamente.Todas las demás mujeres(incluidas ligadura trompas)pueden quedarse embarazadas.
    E.4Principal exclusion criteria
    1. Treatment with other investigational agents or anticancer therapy within 2 weeks or 5 half-lives of the compound, whichever is longer) prior to study enrollment. In addition, no concurrent anticancer therapy is permitted.
    2. Previously treated with immuno-oncology (IO) including immune checkpoint inhibitors within 12 weeks before enrollment.
    3. Major surgery within 4 weeks prior to enrollment.
    4. Radiation therapy with a limited field for palliation within 1 week before study treatment.
    5. Adverse events due to prior therapy are unresolved to ≤ CTCAE Grade 1 except for AEs not constituting a safety risk to the patient in the judgment of investigators.
    6. Patients with spinal cord compression caused by tumor and/or cancerous meningitis.
    7. History or evidence of interstitial fibrosis, interstitial lung disease or TKI-induced pneumonitis. (Excluding clinically insignificant or asymptomatic post-radiation pneumonitis)
    8. Any gastrointestinal disorders that may affect absorption of oral medications.
    9. Active and clinically significant bacterial, fungal, or viral infection including hepatitis B virus (HBV), hepatitis C virus (HCV), or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), known human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS)-related illness.
    10. Clinically significant cardiovascular diseases within 3 months prior to the first dose of investigational drug: myocardial infarction, severe/unstable angina, coronary/peripheral endovascular treatment, heart failure or cerebrovascular disorder including transient ischemic attack.
    11. Ongoing cardiac dysrhythmias of ≥ CTCAE Grade 2, uncontrolled atrial fibrillation of any grade, or QT interval corrected for heart rate byFredericia’s formula (QTcF) >470 milliseconds, or symptomatic bradycardia <45 beats per minute.
    12. Pregnancy or lactation.
    13. Use of food or drugs that are known potent cytochrome P450 3A4/5 (CYP3A4/5) inhibitors, or inducers or P-glycoprotein inhibitors or inducers within 14 days prior to the first dose of study treatment and while on treatment.
    14. Administration of agents with potential QT interval prolonging effect within 14 days prior to first dose of study treatment and while on treatment.
    15. Patients with other severe medical or mental diseases in whom the risk is increased by the participation to the study or treatment with study treatment in the judgement of the Investigator.
    1. Haber recibido tratamiento con otros fármacos en investigación o tratamiento antineoplásico en las 2 semanas (o 5 semividas del compuesto, lo que sea más largo) anteriores a la inscripción en el estudio. Además, no se permiten tratamientos antineoplásicos simultáneos.
    2. Pacientes tratados previamente con inmunoncología (IO), incluidos los inhibidores del punto de control inmunitario, en las 12 semanas anteriores a la inscripción.
    3. Cirugía mayor en las 4 semanas anteriores a la inscripción.
    4. Radioterapia de campo limitado con fines paliativos 1 semana antes del tratamiento del estudio.
    5. Acontecimientos adversos debidos a un tratamiento previo no resueltos hasta un grado ≤1 según los criterios CTCAE, excepto los AA que no constituyan un riesgo de seguridad para el paciente según el criterio de los investigadores.
    6. Pacientes con compresión de la médula espinal causada por el tumor o meningitis carcinomatosa.
    7. Antecedentes o indicios de fibrosis intersticial, enfermedad pulmonar intersticial o neumonitis inducida por ITC (se excluye la neumonitis posterior a la radiación asintomática o no significativa clínicamente).
    8. Trastornos gastrointestinales que puedan afectar a la absorción de medicamentos por vía oral.
    9. Micosis, virosis o infecciones bacterianas activas y de trascendencia clínica, por ejemplo, el virus de la hepatitis B (VHB), el virus de la hepatitis C (VHC), coronavirus del síndrome respiratorio agudo grave de tipo 2 (SARS-CoV-2), infección conocida por el virus de la inmunodeficiencia humana (VIH) o enfermedad relacionada con el síndrome de inmunodeficiencia adquirida (SIDA).
    10. Enfermedades cardiovasculares de trascendencia clínica en los 3 meses anteriores a la primera dosis del fármaco en investigación: infarto de miocardio, angina grave o inestable, tratamiento endovascular coronario o periférico, insuficiencia cardíaca o trastorno cerebrovascular, incluido accidente isquémico transitorio.
    11. Disritmias cardíacas en curso de grado ≥2 según los criterios CTCAE, fibrilación auricular no controlada de cualquier grado o intervalo QT corregido para la frecuencia cardíaca según la fórmula de Fridericia (QTcF) >470 milisegundos o bradicardia sintomática <45 latidos por minuto.
    E.5 End points
    E.5.1Primary end point(s)
    Confirmed ORR according to RECIST 1.1 assessed by IRC for cohorts 1-2.
    ORR confirmado según RECIST 1.1 evaluado por IRC para las cohortes 1-2.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Throughout the entire study period.
    A lo largo de todo el período de estudio.
    E.5.2Secondary end point(s)
    Efficacy Endpoints:
    1. DOR according to RECIST 1.1 assessed by IRC (cohorts 1-2)
    2. PFS according to RECIST 1.1 assessed by IRC (cohorts 1-2)
    3. TTF according to RECIST 1.1 assessed by IRC(cohorts 1-2)
    4. TTR according to RECIST 1.1 assessed by IRC(cohorts 1-2)
    5. Overall Survival (cohorts 1-2)
    6. ORR, DOR and PFS according to RECIST 1.1 assessed by investigators (cohorts 1-2)
    7. Confirmed intracranial (IC)-ORR, IC-DOR, IC-PFS and time to intracranial progression(TTiP) according to RECIST 1.1 assessed by IRC (cohorts 1-2)
    Safety Endpoints:
    • Adverse events (AEs), laboratory abnormalities, vital signs, ECG and ophthalmologic data (cohorts 1-4)
    PK Endpoints:
    • PK parameters (Cmax, Tmax, AUC0-8 and AUCτ) of taletrectinib (free base form) on C1D1 and C1D15 for approximate 10 patients of each cohort with extensive PK sampling approach (cohorts 1-2)
    • PK concentrations of taletrectinib (free base form) for other patients via sparse PK sampling approach (cohorts 1-4)
    Criterios Valoracion Eficacia:
    1. DR según RECIST 1.1 evaluada por el CRI (cohortes 1-2)
    2. SSP según RECIST 1.1 evaluada por el CRI (cohortes 1-2)
    3. THF según RECIST 1.1 evaluado por el CRI (cohortes 1-2)
    4. THR según RECIST 1.1 evaluado por el CRI (cohortes 1-2)
    5. Supervivencia general (cohortes 1-2)
    6. TRO, DR y SSP evaluadas según RECIST 1.1 por los investigadores (cohortes 1-2)
    7. TRO intracraneal (IC) confirmada, DR-IC, SSP-IC y tiempo hasta la progresión intracraneal (THP-IC) según RECIST 1.1 evaluados por el CRI (cohortes 1-2)
    Criterios de valoración de la seguridad:
    • Acontecimientos adversos (AA), anomalías analíticas, constantes vitales, ECG y datos oftalmológicos (cohortes 1-4)
    Criterios de valoración de la FC:
    • Parámetros FC (Cmáx, Tmáx, ABC0-8 y ABCτ) del taletrectinib (forma de base libre) en el D1C1 y el D15C1 de unos 10 pacientes de
    cada cohorte mediante una estrategia de amplio muestreo FC (cohortes 1-2).
    Concentraciones FC de taletrectinib (forma de base libre) de otros pacientes mediante una estrategia de muestreo de FC disperso
    (cohortes 1-4)
    E.5.2.1Timepoint(s) of evaluation of this end point
    •Efficacy: Throughout the entire study period.
    •Safety: Adverse events (AEs) - Screening until Safety Follow up (30 days post last dose); laboratory abnormalities, vital signs, ECG - Screening until End of Treatment (EoT); and ophthalmologic data - Screening.
    •PK: C1D1, C1D8, C1D15, C2D1
    •Eficacia: Durante todo el periodo de estudio.
    •Seguridad: Eventos adversos (EA) - Detección hasta seguimiento de seguridad (30 días después de la última dosis); anomalías de laboratorio, signos vitales, ECG - Detección hasta el final del tratamiento (EoT); y datos oftalmológicos - Cribado.
    •PK: C1D1, C1D8, C1D15, C2D1
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    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 concerned29
    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
    Canada
    China
    France
    Italy
    Japan
    Korea, Republic of
    Poland
    Spain
    Ukraine
    United States
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    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 years1
    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: 71
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 48
    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 state14
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 48
    F.4.2.2In the whole clinical trial 119
    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)
    If the patient withdraws from the study before disease progression, a tumor evaluation should be performed every 12 weeks after the last dose, until disease progression or a new anti-cancer therapy is commenced. Follow up for survival will continue until death, withdrawal of informed consent, loss of follow-up and termination of the study by the sponsor, whichever occurs first.
    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 Decision2022-06-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-03-14
    P. End of Trial
    P.End of Trial StatusOngoing
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