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    Summary
    EudraCT Number:2021-001029-32
    Sponsor's Protocol Code Number:PBI-200-101
    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:2021-07-14
    Trial results View 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 number2021-001029-32
    A.3Full title of the trial
    A Phase 1/2 Study of PBI-200 in Subjects with NTRK-Fusion-Positive Advanced or Metastatic Solid Tumors
    Estudio de fase I/II de PBI‐200 en sujetos con tumores sólidos avanzados o metastásicos positivos para fusiones de NTRK
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 1/2 Study of PBI-200 in Subjects with NTRK-Fusion-Positive Advanced or Metastatic Solid Tumors
    Estudio de fase I/II de PBI‐200 en sujetos con tumores sólidos avanzados o metastásicos positivos para fusiones de NTRK
    A.4.1Sponsor's protocol code numberPBI-200-101
    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 SponsorPyramid Biosciences
    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 supportPyramid Biosciences
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPyramid Biosciences
    B.5.2Functional name of contact pointClinical Trial Information Desk
    B.5.3 Address:
    B.5.3.1Street Address330 Bear Hill Road, Suite 302
    B.5.3.2Town/ cityWaltham, MA
    B.5.3.3Post code02451
    B.5.3.4CountryUnited States
    B.5.6E-mailclinicaltrials@pyramidbio.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 namePBI-200
    D.3.2Product code PBI-200
    D.3.4Pharmaceutical form Capsule, soft
    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 INN(R)-5-(2-(2,5-difluorophenyl) pyrrolidin-1-yl)-3-(4-(trifluoromethyl)-1H-pyrazol-1-yl) pyrazolo[1,5-a] pyrimidine
    D.3.9.2Current sponsor codePBI-200
    D.3.9.3Other descriptive namePBI-4050
    D.3.9.4EV Substance CodeSUB179215
    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.3.1Product namePBI-200
    D.3.2Product code PBI-200
    D.3.4Pharmaceutical form Capsule, soft
    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 INN(R)-5-(2-(2,5-difluorophenyl) pyrrolidin-1-yl)-3-(4-(trifluoromethyl)-1H-pyrazol-1-yl) pyrazolo[1,5-a] pyrimidine
    D.3.9.2Current sponsor codePBI-200
    D.3.9.3Other descriptive namePBI-4050
    D.3.9.4EV Substance CodeSUB179215
    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
    One of the following solid tumors which has progressed on or following at least one systemic therapy regimen administered for advanced or metastatic disease or for which no approved therapy exists:
    • NTRK-fusion-positive, locally advanced (i.e., not amenable to surgical resection) or metastatic solid tumor
    • NTRK-gene amplified, locally advanced or metastatic solid tumor (Phase 1 only)
    • EWSR1-WT1-positive DSRCTs (Phase 1 only)
    Uno de los siguientes tumores sólidos que ha progresado durante o después de al menos una pauta de tratamiento sistémico administrada para enfermedad avanzada o metastásica o para la que no existe tratamiento aprobado:
    • Tumor sólido positivo para fusiones de NTRK metastásico o localmente avanzado (es decir,no susceptible de resección quirúrgica)
    • Tumor sólido amplificado por el gen NTRK localmente avanzado o metastásico (solo fase I)
    • TDCPR positivo para fusiones de EWSR1-WT1 (solo fase I)
    E.1.1.1Medical condition in easily understood language
    Subjects with NTRK-Fusion-Positive Advanced or Metastatic Solid Tumors
    Sujetos con tumores sólidos avanzados o metastásicos positivos para la fusión con NTRK
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level SOC
    E.1.2Classification code 10029104
    E.1.2Term Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    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 1:
    • To determine the safety and tolerability, maximum tolerated dose (MTD), and dose limiting toxicities (DLTs) of PBI-200 in subjects with NTRK-fusion-positive or NTRK-amplified advanced or metastatic refractory solid tumors or refractory EWSR1-WT1-fusion-positive desmoplastic small round cell tumors (DSRCTs).
    • To establish the Recommended Phase 2 Dose (RP2D) of PBI-200
    Phase 2:
    • To evaluate the antitumor activity of PBI‑200 in subjects with NTRK-fusion-positive advanced or metastatic refractory solid tumors as follows:
    Cohort A: Non-Brain Primary Tumors
    • ORR based on RECIST v1.1 by Independent Radiology Review
    Cohort B: Primary Brain Tumors
    • ORR based on RANO criteria by Independent Radiology Review
    Fase I:
    Objetivos principales:
    • Determinar la seguridad y tolerabilidad, la dosis máxima tolerada (DMT) y las toxicidades limitantes de la dosis (TLD) de PBI-200 en sujetos con tumores sólidos avanzados o metastásicos resistentes positivos para fusiones de NTRK o amplificados por NTRK o tumores desmoplásicos de células pequeñas y redondas (TDCPR) positivos para fusiones de EWSR1-WT1 resistentes.
    • Establecer la dosis recomendada para la fase II (DRF2) de PBI-200
    Fase II:
    • Evaluar la actividad antitumoral de PBI-200 en sujetos con tumores sólidos resistentes metastásicos o avanzados positivos para fusiones de NTRK de la siguiente manera:
    Cohorte A: tumores primarios no cerebrales
    • TRO basada en los criterios RECIST v1.1 según la revisión radiológica independiente
    Cohorte B: tumores cerebrales primarios
    • TRO basada en los criterios RANO según la revisión radiológica independiente
    E.2.2Secondary objectives of the trial
    Phase 1:
    • Evaluate the pharmacokinetics (PK) of PBI-200
    • Evaluate the antitumor activity of PBI-200 as follows:
    Subjects with Non-Brain Primary Tumors
    • Objective response rate (ORR), duration or response (DoR), and progression-free survival (PFS) based on RECIST version 1.1 by Investigator Assessment and by Independent Radiology Review (IRR).
    • Intracranial ORR (IORR), intracranial DoR (IDoR), and intracranial PFS (IPFS) based on Response Assessment in Neuro-oncology – Brain Metastases (RANO-BM) by Investigator Assessment and by Independent Radiology Review for subjects with measurable brain metastasis by RANO-BM during Screening
    Subjects with Primary Brain Tumors
    • ORR, DoR, and PFS based on Response Assessment in Neuro-oncology (RANO) criteria by Investigator Assessment and by IRR

    Phase 2
    • To evaluate antitumor activity based on RECIST v1.1, RANO and/or RANO-BM
    • To confirm the safety and tolerability
    • To further evaluate the PK
    Fase 1
    • Evaluar la farmacocinética (PK) de PBI-200
    • Evalúe la actividad antitumoral de PBI-200 del siguiente modo:
    Sujetos con tumores primarios no cerebrales
    • Tasa de respuesta objetiva (ORR), duración o respuesta (DoR) y supervivencia libre de progresión (PFS) según RECIST versión 1.1 de Investigator Assessment y Indep Rad Review (IRR).
    • ORR intracran (IORR), DoR intracran (IDoR) y SLP intracran (IPFS) basado en la Evaluación de la respuesta en neuro-oncología-Metástasis cerebrales (RANO-BM) por la Evaluación del investigador y por la Revisión radiológica independiente para sujetos con metástasis cerebral medible por RANO-BM durante el cribado
    Sujetos con tumores cerebrales primarios
    • ORR, DoR y PFS basados ​​en los criterios de Response Assessment in Neuro-oncology (RANO) por Inv Assessment y por IRR
    Fase 2
    • Evaluar la actividad antitumoral en base a RECIST v1.1, RANO y / o RANO-BM
    • Para confirmar la seguridad y tolerabilidad
    • Para evaluar más a fondo la PK
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subject has one of the following solid tumors which has progressed on or following at least one systemic therapy regimen administered for advanced or metastatic disease or for which
    no approved therapy exists:
    • NTRK-fusion-positive, locally advanced (i.e., not amenable to surgical resection) or metastatic solid tumor
    • NTRK-gene amplified, locally advanced or metastatic solid tumor (Phase 1 only)
    • EWSR1-WT1-positive DSRCTs (Phase 1 only)
    Note: Subjects with any grade of malignant glioma previously treated with systemic therapy are eligible. Subject’s prior treatment should include all approved regimens that have demonstrated a
    survival advantage for the subject’s disease, stage, and line of therapy.
    2. Phase 1
    • Subjects with NTRK-fusion-positive solid tumors other than primary brain tumors (non-brain primary tumors) must have previously received treatment with a TRK
    inhibitor, unless the subject does not have access to TRK-inhibitor therapy (e.g., no TRK inhibitor is marketed and available to the subject in the subject’s country) or the subject
    has declined treatment with available marketed TRK inhibitors.
    • Subjects with NTRK-gene-amplified solid tumors, primary brain tumors or EWSR1-WT1- positive DSRCTs may have received prior treatment with a TRK inhibitor but this is not
    required.
    3. Phase 2
    • Has measurable disease by RECIST v1.1 for subjects with non-brain primary tumors or RANO criteria for subjects with primary brain tumors.
    • Subjects with non-brain primary tumors must have previously received treatment with a TRK inhibitor and must have a documented on-target resistance mutation(s) (e.g., solvent
    front, gatekeeper or xDFG mutation) as the mechanism of resistance to their prior
    TRK-inhibitor treatment based on a tumor biopsy obtained following their most recent systemic therapy. Archival tissue from a prior biopsy taken after the subject completed
    TRK-inhibitor treatment but prior to additional systemic therapy may be used to meet this eligibility criterion with Medical Monitor approval.
    • Subjects with primary brain tumors may have received prior treatment with a TRK inhibitor but this is not required. For these subjects who have previously been treated
    with a TRK inhibitor, a tumor biopsy any time following TRK-inhibitor treatment is encouraged, and if analyzed for resistance mechanisms, must demonstrate an on-target
    resistance mutation (e.g. solvent front, gatekeeper or xDFG mutation) as the mechanism of resistance to their prior TRK-inhibitor treatment. However, biopsies of brain tumors
    are not required for eligibility.
    • Note: Subjects with NTRK-gene amplified tumors or EWSR1-WT1-positive DSRCTs are not eligible in Phase 2.
    4. Subjects with brain tumors and brain metastasis must be neurologically stable. Subjects with ongoing neurologic signs, symptoms, or a history of seizures due to their intracranial tumor or
    on antiseizure medication must be approved for enrollment by the Medical Monitor.
    5. Age ≥ 18 years at the time of signing the informed consent form (ICF)
    6. Has provided written informed consent
    7. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 or 1. Subjects with PS = 2 may be approved by the Medical Monitor.
    8. Acceptable liver, renal, hematologic, and coagulation function
    • Bilirubin ≤ 1.5x ULN
    • AST, ALT ≤ 3.0x ULN
    • Serum creatinine ≤ 1.5x ULN and/or an estimated creatinine clearance of ≥ 45 ml/min based on the Cockcroft-Gault formula
    • Absolute neutrophil count ≥ 1000/mm3
    • Platelet count ≥ 75,000/mm3
    • Hemoglobin ≥ 8 g/dL
    • International normalized ratio (INR) ≤ 1.5 ULN and activated partial thromboplastin time (aPTT) ≤ 1.5 ULN. Study subjects on therapeutic doses of anticoagulation medication must have INR and/or aPTT ≤ the upper limit of the therapeutic range for intended use
    9. Ability to swallow capsules and no gastrointestinal issues that may impact absorption of oral medication
    10. Women of child-bearing potential must agree to use highly effective contraceptive methods and avoid egg donation during the study treatment and for 4 months after the last dose of
    PBI-200. A woman is considered to be of child-bearing potential unless she:
    • has had a hysterectomy, bilateral tubal occlusion, or bilateral oophorectomy;
    • is age ≥ 60 years and is amenorrhoeic; or
    • is age < 60 years and has been amenorrhoeic for ≥ 12 months
    11. For women of child-bearing potential: A negative serum pregnancy test during Screening and a negative pregnancy test (either serum or urine) predose on Day -2 (the first day of PBI-200
    treatment)
    12. Men of reproductive potential agree to use highly effective contraceptive methods and avoid sperm donation during the study treatment and for 4 months after the last dose of PBI-200. A
    man is considered to be of child-producing potential unless he has had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy.
    1. El sujeto tiene uno de los siguientes tumores sólidos que ha progresado durante o después de al menos una pauta de tratamiento sistémico administrada para enfermedad avanzada o metastásica o para la que no existe tratamiento aprobado:
    • Tumor sólido positivo para fusiones de NTRK metastásico o localmente avanzado (es decir, no susceptible de resección quirúrgica)
    • Tumor sólido amplificado por el gen NTRK localmente avanzado o metastásico (solo fase I)
    • TDCPR positivo para fusiones de EWSR1-WT1 (solo fase I)
    Nota: los sujetos con cualquier grado de glioma maligno tratado previamente con tratamiento sistémico son aptos.
    El tratamiento previo del sujeto debe incluir todas las pautas aprobadas que hayan demostrado una ventaja en cuanto a supervivencia para la enfermedad, el estadio y la línea de tratamiento del sujeto.
    2. Fase I
    • Los sujetos con tumores sólidos positivos para fusiones de NTRK que no sean tumores cerebrales primarios (tumores primarios no cerebrales) deben haber recibido previamente tratamiento con un inhibidor de TRK, a menos que el sujeto no tenga acceso al tratamiento con un inhibidor de TRK (p. ej., no se comercializa ningún inhibidor de TRK ni está disponible para el sujeto en el país del sujeto) o el sujeto haya rechazado el tratamiento con los inhibidores de TRK comercializados disponibles.
    • Los pacientes con tumores sólidos amplificados por genes NTRK, tumores cerebrales primarios o TDCPR positivos para fusiones de EWSR1-WT1 pueden haber recibido tratamiento previo con un inhibidor de TRK, pero esto no es un requisito.
    3. Fase II
    • Tiene enfermedad medible según los criterios RECIST v1.1 para sujetos con tumores primarios no cerebrales o los criterios RANO para sujetos con tumores cerebrales primarios.
    • Los sujetos con tumores primarios no cerebrales deben haber recibido previamente tratamiento con un inhibidor de TRK y deben tener alguna mutación de resistencia documentada en el objetivo (p. ej., mutación del frente del solvente, del guardián o de xDFG) como mecanismo de resistencia a su tratamiento previo con un inhibidor de TRK basado en una biopsia tumoral obtenida después de su tratamiento sistémico más reciente. El tejido de archivo de una biopsia anterior tomada después de que el sujeto completara el tratamiento con el inhibidor de TRK, pero antes del tratamiento sistémico adicional, se puede utilizar para cumplir este criterio de idoneidad con la aprobación del supervisor médico.
    • Los pacientes con tumores cerebrales primarios pueden haber recibido tratamiento previo con un inhibidor de TRK, pero esto no es un requisito. Para estos sujetos que han sido tratados previamente con un inhibidor de TRK, se recomienda una biopsia tumoral en cualquier momento después del tratamiento con inhibidor de TRK, y si se analiza para detectar mecanismos de resistencia, debe demostrar una mutación de resistencia en el objetivo (p. ej., mutación del frente del disolvente, del guardián o de xDFG) como el mecanismo de resistencia a su tratamiento previo con inhibidores de TRK. Sin embargo, no se requieren biopsias de tumores cerebrales para la idoneidad.
    • Nota: los sujetos con tumores amplificados por genes NTRK o con TDCPR positivos para fusiones de EWSR1-WT1 no son aptos en la fase II.
    4. Los pacientes con tumores cerebrales y metástasis cerebrales deben encontrarse neurológicamente estables.
    5. Edad ≥18 años en el momento de firmar el formulario de consentimiento informado (FCI)
    6. Ha dado el consentimiento informado por escrito
    7. Puntuación del estado general (EG) de 0 o 1 según la Escala del grupo de oncología cooperativo del este (ECOG). Los sujetos con EG = 2 pueden ser aprobados por el supervisor médico.
    8. Función hepática, renal, hematológica y de coagulación aceptable
    • Bilirrubina ≤1,5 veces el LSN
    • ALT, AST ≤3,0 veces el LSN
    • Creatinina sérica ≤1,5 veces el LSN y/o aclaramiento de creatinina estimado de ≥45 ml/min según la fórmula de Cockcroft-Gault
    • Recuento absoluto de neutrófilos ≥1000/mm 3
    • Recuento de plaquetas ≥75 000/mm 3
    • Hemoglobina ≥8 g/dl
    • Índice internacional normalizado (INR) ≤1,5 veces el LSN o tiempo de tromboplastina parcial activada (TTPa) ≤1,5 veces el LSN. Los sujetos del estudio que reciban dosis terapéuticas de medicación anticoagulante deben tener un INR y/o un TTPa ≤ al límite superior del rango terapéutico para el uso previsto
    9. Capacidad para tragar cápsulas y sin problemas gastrointestinales que puedan afectar a la absorción de la medicación por vía oral
    10. Las mujeres en edad fértil deben aceptar el uso de métodos anticonceptivos altamente eficaces y evitar la donación de óvulos durante el tratamiento del estudio y durante 4 meses después de la última dosis de PBI-200.

    Por favor consultar protocolo para los dos últimos criterios de inclusión debido a la falta de carácteres
    E.4Principal exclusion criteria
    1. Cytotoxic chemotherapy, biologic agent, investigational agent, or radiation therapy ≤ 3 weeks
    prior to the first dose of PBI-200 (6 weeks for nitrosoureas). The interval may be reduced to
    2 weeks for bone-only radiation therapy or investigational agents not expected to be
    associated with AEs after 2 weeks of last administration, with Medical Monitor approval.
    a. Subjects with either primary brain tumors or brain metastasis must have completed brain
    radiation therapy 12 weeks prior to the brain MRI obtained within 4 weeks of the first
    dose of PBI-200. The Medical Monitor may approve an interval of less than 12 weeks if
    there is reasonable certainty of radiographic disease progression (e.g., new disease
    outside the radiation therapy field following completion of the radiation therapy) or
    histopathologic documentation of unequivocal disease progression
    2. Small-molecule kinase inhibitors or hormonal agents ≤ 14 days and within 5 half-lives prior
    to the first dose of PBI-200
    3. For subjects enrolled in Phase 2: Treatment with more than one prior TRK inhibitor.
    Note: Subjects enrolled in the Phase 1 part of the study may have received more than one
    TRK inhibitor.
    4. Clinically significant AEs that have not returned to baseline or ≤ Grade 1 based on NCI
    CTCAE v5.0 unless approved by the Medical Monitor
    5. Subjects with leptomeningeal disease (primary or metastatic) unless approved by the Medical
    Monitor
    6. Major surgery ≤ 6 weeks or minor surgery ≤ 14 days prior to the first dose of PBI-200
    7. Clinically significant intercurrent disease including but not limited to:
    • New York Heart Association Class III or IV heart failure
    • Myocardial infarction or stroke ≤ 26 weeks prior to the first dose of PBI-200
    • Unstable angina within ≤ 13 weeks prior to the first dose of PBI-200 unless the
    underlying disease has been corrected by procedural intervention e.g., stent, bypass
    • Severe aortic stenosis
    • Uncontrolled arrhythmia. Medical Monitor approval of subjects with an arrhythmia is
    required
    • Congenital long QT syndrome. Medical Monitor approval is required
    • QTc > 470 milliseconds by Fredericia criteria (QTcF) based on the average of 3 ECGs
    taken approximately 1 minute apart and all within 10 minutes of each other. The subject
    should be reclining for 5 minutes prior to ECGs. Local readings may be used for this
    inclusion criterion.
    • Clinically significant active infection requiring systemic antibiotic, antiviral or antifungal
    medication. Subjects must be medically stable, afebrile, and not taking antimicrobial
    treatment for ≥ 3 days prior to the first dose of PBI-200
    8. Subjects taking sensitive substrates of CYP2B6, CYP2C8, CYP2C9 and CYP3A unless the
    subject can safely discontinue these medications or change to comparable medications that
    are not sensitive substrates of these CYPs
    9. Subjects that are taking strong CYP3A inhibitors or inducers unless the subject can safely
    discontinue these medications or change to comparable medications that are not strong
    inhibitors or inducers of CYP3A at least 5 half-lives or 7 days prior to the first dose of
    PBI-200
    10. Human immunodeficiency virus (HIV) infection
    11. Active hepatitis B or C infection
    12. Has a history of another malignancy, unless the subject has been treated with curative intent
    for this malignancy. Medical Monitor approval for enrollment is required for subjects with a
    history of another malignancy. Study subjects with early-stage prostate cancer on active
    surveillance may be enrolled with Medical Monitor approval.
    13. Women who are pregnant or breastfeeding
    14. Unwillingness or inability to comply with procedures required in this protocol
    15. Currently receiving any other anticancer or investigational agent
    1. Quimioterapia citotóxica, fármaco biológico, fármaco en investigación o radioterapia ≤3 semanas antes de la primera dosis de PBI-200 (6 semanas para nitrosoureas). El intervalo puede reducirse a 2 semanas para la radioterapia únicamente ósea o los fármacos en investigación que no se espera que estén asociados con AA después de 2 semanas tras la última administración, con la aprobación del supervisor médico.
    a. Los sujetos con tumores cerebrales primarios o metástasis cerebrales deben haber completado la radioterapia cerebral 12 semanas antes de la RM cerebral obtenida en las 4 semanas anteriores a la primera dosis de PBI-200. El supervisor médico puede aprobar un intervalo de menos de 12 semanas si existe una certeza razonable de la progresión radiográfica de la enfermedad (p. ej., nueva enfermedad fuera del campo de la radioterapia tras la finalización de la radioterapia) o documentación histopatológica de progresión de la enfermedad inequívoca
    2. Inhibidores de la cinasa de molécula pequeña o fármacos hormonales ≤14 días y en el plazo de 5 semividas antes de la primera dosis de PBI-200
    3. Para sujetos inscritos en la fase II: tratamiento con más de un inhibidor de TRK previo. Nota: los sujetos inscritos en la parte de fase I del estudio pueden haber recibido más de un inhibidor de TRK.
    4. AA clínicamente significativos que no hayan vuelto al valor inicial o un grado ≤1 según los CTCAE del NCI v5.0 a menos que lo apruebe el supervisor médico
    5. Sujetos con enfermedad leptomeníngea (primaria o metastásica) a menos que lo apruebe el supervisor médico
    6. Cirugía mayor ≤6 semanas o cirugía menor ≤14 días antes de la primera dosis de PBI-200
    7. Enfermedad intercurrente clínicamente significativa, incluidas, entre otras:
    • Insuficiencia cardíaca de clase III o IV según la Asociación de Cardiología de Nueva York
    • Infarto de miocardio o accidente cerebrovascular ≤26 semanas antes de la primera dosis de PBI-200
    • Angina inestable en las ≤13 semanas anteriores a la primera dosis de PBI-200, a menos que la enfermedad subyacente se haya corregido mediante intervención quirúrgica, p. ej., stent [endoprótesis], derivación
    • Estenosis aórtica grave
    • Arritmia no controlada. Es necesaria la aprobación del supervisor médico de los sujetos con arritmia
    • Síndrome de QT largo congénito. Es necesaria la aprobación del supervisor médico
    • QTc >470 milisegundos según los criterios de Fredericia (QTcF) basados en el promedio de 3 ECG realizados con aproximadamente 1 minuto de diferencia y todos dentro de un máximo de 10 minutos entre cada uno. El sujeto debe estar tumbado durante 5 minutos antes de los ECG. Para este criterio de inclusión se pueden utilizar lecturas locales.
    • Infección activa clínicamente significativa que requiere medicación antibiótica, antivírica o antimicótica sistémica. Los sujetos deben estar médicamente estables, sin fiebre y no recibir tratamiento antimicrobiano durante ≥3 días antes de la primera dosis de PBI-200
    8. Sujetos que toman sustratos sensibles de CYP2B6, CYP2C8, CYP2C9 y CYP3A, a menos que el sujeto pueda interrumpir de forma segura estos medicamentos o cambiar a medicamentos comparables que no sean sustratos sensibles de estos CYP
    9. Sujetos que estén tomando inhibidores o inductores potentes del CYP3A, a menos que el sujeto pueda interrumpir de forma segura estos medicamentos o cambiar a medicamentos comparables que no sean inhibidores o inductores potentes del CYP3A al menos 5 semividas o 7 días antes de la primera dosis de PBI-200
    10. Infección por el virus de la inmunodeficiencia humana (VIH)
    11. Infección activa por hepatitis B o C
    12. Tiene antecedentes de otra neoplasia maligna, a menos que el sujeto haya sido tratado con intención curativa para esta neoplasia maligna. Es necesaria la aprobación del supervisor médico para la inscripción de sujetos con antecedentes de otra neoplasia maligna. Los sujetos del estudio con cáncer de próstata en estadio inicial en vigilancia activa podrán inscribirse con la aprobación del supervisor médico.
    13. Mujeres que están embarazadas o en período de lactancia
    14. Falta de disposición o incapacidad de cumplir con los procedimientos requeridos en el presente protocolo
    15. Estar recibiendo actualmente cualquier otro antineoplásico o fármaco en investigación
    E.5 End points
    E.5.1Primary end point(s)
    • Safety as assessed by the incidence of adverse events (AEs) and changes in physical
    examinations, vital signs, clinical laboratory assessments, Eastern Cooperative
    Oncology Group (ECOG) performance status, and electrocardiogram (ECG)
    parameters.
    • Seguridad según la evaluación de la incidencia de eventos adversos (EA) y cambios en los parámetros del exámen del estado físico, signos vitales, evaluaciones de laboratorio clínico, estado funcional del Eastern Cooperative Oncology Group (ECOG) y electrocardiograma (ECG).
    E.5.1.1Timepoint(s) of evaluation of this end point
    This endpoint is to be measured throughout, until the end of the study
    Este criterio de valoración se medirá en todo momento, hasta el final del estudio.
    E.5.2Secondary end point(s)
    Phase 1 Dose-Escalation
    • Plasma PK of PBI-200 as assessed via:
    − Area under the plasma drug concentration-time curve from 0 to 48 hours
    (AUC0-48h) after one dose and 0 to 24 hours (AUC0-24h) after 28 doses.
    − Maximum concentration (Cmax)
    − Time to maximum concentration (Tmax)
    − Half-life (T1/2)
    − Apparent steady state volume of distribution (Vss/F)
    − Apparent clearance (CL/F)
    • Preliminary antitumor activity for subjects with non-brain primary tumors (ORR,
    DoR, PFS) based on RECIST v1.1 by Investigator assessment and Independent
    Radiology Review. Intracranial antitumor activity (IORR, IDoR, and IPFS) based on
    RANO-BM by Investigator assessment and Independent Radiology Review.
    • Preliminary antitumor activity for subjects with primary brain tumors based on
    RANO criteria by Investigator assessment and Independent Radiology Review as
    assessed via ORR, DoR, and PFS

    Phase 2 Cohort Expansion
    Primary Endpoints
    Cohort A: Non-Brain Primary Tumors
    • Antitumor (ORR) activity based on RECIST v1.1 by Independent Radiology Review
    • Antitumor activity (DoR, PFS) based on RECIST v1.1 by Independent Radiology
    Review
    • Intracranial antitumor activity (IORR, IDoR, and IPFS) based on RANO-BM by Independent Radiology
    Review
    • Antitumor activity (ORR, DoR, PFS) based on RECIST v1.1 by Investigator
    assessment. Intracranial antitumor activity (IORR, IDoR, and IPFS) based on RANO-BM
    by Investigator assessment

    Cohort B: Primary Brain Tumors
    • Antitumor activity (ORR) based on RANO criteria by Independent Radiology Review
    Secondary Endpoints
    • Antitumor activity:
    • Antitumor activity (DoR, PFS) based on RANO criteria by Independent Radiology Review
    • Antitumor activity (ORR, DoR, and PFS) based on RANO criteria by Investigator
    assessment
    • Safety as assessed by the incidence of treatment-emergent AEs (TEAEs) and changes in
    physical examinations, vital signs, clinical laboratory assessments, ECOG performance
    status, and ECG parameters.
    • Plasma PK of PBI-200 as assessed via:
    − AUC0-48h after single dose and AUC0-24h after 28 doses
    − Cmax
    − Tmax
    − T1/2
    − Vss/F
    − CL/F
    Escalada de dosis de fase 1
    • PK plasmática de PBI-200 evaluada mediante:
    - Área bajo la curva de concentración plasmática de fármaco-tiempo de 0 a 48 horas
    (AUC0-48h) después de una dosis y de 0 a 24 horas (AUC0-24h) después de 28 dosis.
    - Concentración máxima (Cmax)
    - Tiempo hasta la concentración máxima (Tmax)
    - Vida media (T1 / 2)
    - Volumen de distribución aparente en estado estacionario (Vss / F)
    - Aclaramiento aparente (CL / F)
    • Antitumoral preliminar
    E.5.2.1Timepoint(s) of evaluation of this end point
    Plasma PK of PBI-200 will be evaluated through Cycle 2 Day 2 for each subject. This equates to day 30.
    La PK plasmática de PBI-200 se evaluará durante el Día 2 del Ciclo 2 para cada sujeto. Esto equivale al día 30.
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 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 EEA25
    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
    Canada
    Korea, Republic of
    United States
    Belgium
    France
    Germany
    Italy
    Spain
    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
    Last visit last subject (LSLV)
    Ultima visita del ultimo sujeto (LSLV)
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    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: 74
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 37
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 37
    F.4.2.2In the whole clinical trial 74
    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)
    All study subjects will return to the study site 28 to 35 days after their last dose of PBI-200 for an
    end-of-treatment (EOT) evaluation. Study subjects who discontinue treatment for reasons other than
    disease progression will continue to be followed until progression or initiation of new systemic
    anti-cancer therapy. Additional follow-up will occur for ongoing PBI-200-related SAEs and clinically
    significant AEs until resolution or stabilization.
    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 Decision2021-11-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-10-18
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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