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    Summary
    EudraCT Number:2018-004004-19
    Sponsor's Protocol Code Number:QBGJ398-301
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-07-05
    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 number2018-004004-19
    A.3Full title of the trial
    A Phase 3 Multicenter, Open-Label, Randomized, Controlled Study of Oral Infigratinib versus Gemcitabine with Cisplatin in Subjects with Advanced/Metastatic or Inoperable Cholangiocarcinoma with FGFR2 Gene Fusions/Translocations: The PROOF Trial
    Estudio de fase 3, multicéntrico, abierto, aleatorizado y controlado de infigratinib oral frente a gemcitabina con cisplatino en sujetos con colangiocarcinoma avanzado/metastásico o inoperable con fusiones/translocaciones del gen FGFR2: ENSAYO “PROOF”
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    NA
    NA
    A.3.2Name or abbreviated title of the trial where available
    The PROOF Trial
    A.4.1Sponsor's protocol code numberQBGJ398-301
    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 SponsorQED 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 supportQED Therapeutics, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPPD Global
    B.5.2Functional name of contact pointCasey Fabyanski
    B.5.3 Address:
    B.5.3.1Street Address980 Harvest Drive, Suite 210
    B.5.3.2Town/ cityBlue Bell
    B.5.3.3Post codePA 19422-1955
    B.5.3.4CountryUnited States
    B.5.4Telephone number900834223
    B.5.6E-mailRegistroEspanolDeEstudiosClinicos@druginfo.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 nameInfigratinib
    D.3.2Product code BGJ398
    D.3.4Pharmaceutical form Capsule, hard
    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 INNINFIGRATINIB
    D.3.9.1CAS number 872511-34-7
    D.3.9.2Current sponsor codeBGJ398
    D.3.9.4EV Substance CodeSUB186757
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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 nameInfigratinib
    D.3.2Product code BGJ398
    D.3.4Pharmaceutical form Capsule, hard
    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 INNINFIGRATINIB
    D.3.9.1CAS number 872511-34-7
    D.3.9.2Current sponsor codeBGJ398
    D.3.9.4EV Substance CodeSUB186757
    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 RoleComparator
    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 GEMCI-cell®
    D.2.1.1.2Name of the Marketing Authorisation holderStada Pharm
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameGEMCI-cell®
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous drip use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNGEMCITABINE
    D.3.9.1CAS number 95058-81-4
    D.3.9.4EV Substance CodeSUB07892MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1000
    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 RoleComparator
    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 GEMCI-cell®
    D.2.1.1.2Name of the Marketing Authorisation holderEG/Eurogenerics
    D.2.1.2Country which granted the Marketing AuthorisationBelgium
    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 nameGEMCI-cell®
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous drip use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNGEMCITABINE
    D.3.9.1CAS number 95058-81-4
    D.3.9.4EV Substance CodeSUB07483MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1000
    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: 5
    D.1.2 and D.1.3IMP RoleComparator
    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 Cisplatin TEVA®
    D.2.1.1.2Name of the Marketing Authorisation holderTEVA GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCisplatin
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous drip use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCISPLATIN
    D.3.9.2Current sponsor codeCisplatin TEVA® 50mg/50mL
    D.3.9.4EV Substance CodeSUB07483MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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
    Cholangiocarcinoma
    Colangiocarcinoma
    E.1.1.1Medical condition in easily understood language
    Biliary tract malignancy
    cáncer de vesícula biliar
    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 PT
    E.1.2Classification code 10008593
    E.1.2Term Cholangiocarcinoma
    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
    The primary objective is to determinate if treatment with infigratinib improves centrally assessed progression-free survival (PFS) compared to treatment with gemcitabine with cisplatin in subjects with advanced/metastatic or inoperable cholangiocarcinoma with fibroblast growth factor receptor 2 (FGFR2) gene fusions/ translocations.
    El objetivo principal es determinar si el tratamiento con infigratinib mejora la supervivencia sin progresión (SSP) evaluada de forma centralizada en comparación con el tratamiento con gemcitabina y cisplatino en sujetos con colangiocarcinoma avanzado/metastásico o inoperable con fusiones/translocaciones génicas del receptor 2 del factor de crecimiento de fibroblastos (FGFR2).
    E.2.2Secondary objectives of the trial
    • Evaluate the efficacy of treatment with infigratinib versus gemcitabine and cisplatin in terms of overall survival (OS) for subjects with advanced/metastatic or inoperable cholangiocarcinoma with FGFR2 gene fusions/translocation
    • Evaluate the efficacy of infigratinib treatment compared to gemcitabine and cisplatin in terms of investigator assessed PFS
    • Further evaluate the efficacy in subjects treated with infigratinib versus gemcitabine with cisplatin by ORR best overall response (BOR), duration of response and disease control rate determined centrally and by the investigator
    • Characterize the safety and tolerability of single agent infigratinib
    •Evaluar la eficacia del tratamiento con infigratinib en comparación con gemcitabina y cisplatino en términos de supervivencia global (SG) en sujetos con colangiocarcinoma avanzado/metastásico o inoperable con fusiones/translocaciones del gen FGFR2.
    •Evaluar la eficacia del tratamiento con infigratinib en comparación con gemcitabina y cisplatino en términos de SSP evaluada por el investigador.
    •Evaluar adicionalmente la eficacia en sujetos tratados con infigratinib frente a gemcitabina y cisplatino mediante la TRG, mejor respuesta global (MRG), duración de la respuesta y tasa de control de la enfermedad determinadas de forma centralizada y por el investigador.
    •Caracterizar la seguridad y la tolerabilidad de infigratinib en monoterapia.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Have histologically or cytologically confirmed non-resectable, recurrent, or metastatic cholangiocarcinoma. Subjects with gallbladder cancer or ampulla of Vater carcinoma are not eligible.
    2. Have written documentation of local or central laboratory determination of FGFR2 gene fusions/translocations. Note: Central confirmation is not required prior to enrollment in study.
    3. Have a representative tumor sample available for central FGFR2 fusion/translocation molecular testing. An archival tumor sample and associated pathology report may be submitted. However, if not available, a newly obtained tumor biopsy may be submitted instead.Note: If available FGFR2 fusion/translocation written documentation is from the central laboratory being used in the study, a tumor sample does not need to be submitted for central FGFR2 fusion/translocation molecular testing.
    4. Have full recovery from the following permitted prior treatments (as applicable) such that the subject is reasonably expected to tolerate study treatment (gemcitabine/cisplatin or infigratinib) according to the investigator’s assessment:
    a. A non-curative operation (ie., R2 resection [with macroscopic residual disease] or palliative bypass surgery only)
    b. Curative surgery with evidence of non-resectable disease relapse requiring systemic chemotherapy
    c. Adjuvant radiotherapy (with or without radio-sensitizing low-dose chemotherapy) for localized disease provided there has been clear evidence of disease progression before inclusion in this study
    d. Adjuvant chemotherapy, provided the treatment was completed > 6 months before trial entry
    e. Photodynamic treatment provided there is clear evidence of disease progression at the local site or at a new metastatic site.
    5. Are ≥ 18 years of age of either gender.
    6. Have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.
    7. Have a life expectancy > 3 months.
    8. Are able to read and/or understand the details of the study and provide written evidence of informed consent as approved by Institutional Review Board (IRB)/Independent Ethics Committee (IEC).
    9. Have recovered from AEs of previous systemic anti-cancer therapies to baseline or Grade 1, except for alopecia.
    10. Are able to swallow and retain oral medication.
    11. Are willing and able to comply with scheduled visits, treatment plan and laboratory tests.
    12. If a woman of childbearing potential (WOCBP), must have a negative pregnancy test within 7 days of the first dose of study drug. A woman is not of childbearing potential if she has undergone surgical sterilization (total hysterectomy, or bilateral tubal ligation or bilateral oophorectomy at least 6 weeks before taking study drug) or if she is postmenopausal and has had no menstrual bleeding of any kind including menstrual period, irregular bleeding, spotting, etc., for at least 12 months, with an appropriate clinical profile, and there is no other cause of amenorrhea (eg., hormonal therapy, prior chemotherapy).
    1.Tener un colangiocarcinoma no operable, recurrente o metastásico confirmado histológica o citológicamente. No podrán participar sujetos con cáncer de vesícula biliar o carcinoma de la ampolla de Vater.
    2.Documentación por escrito de la determinación en el laboratorio local o central de fusiones/translocaciones del gen FGFR2. Nota: No se requiere la confirmación central antes de la inclusión en el estudio.
    3.Disponer de una muestra tumoral representativa para análisis moleculares de fusión/translocación de FGFR2 en el laboratorio central. Podrá enviarse una muestra tumoral de archivo y el informe anatomopatológico correspondiente. Sin embargo, si no está disponible, podrá enviarse en su lugar una biopsia tumoral recién obtenida. Nota: Si la documentación por escrito de la fusión/translocación de FGFR2 disponible procede del laboratorio central utilizado en el estudio, no será necesario enviar una muestra tumoral para realizar el análisis molecular de fusión/translocación de FGFR2 en el laboratorio central.
    4.Recuperación completa de los siguientes tratamientos previos permitidos (según proceda), de modo que pueda esperarse razonablemente que el sujeto tolerará el tratamiento del estudio (gemcitabina/cisplatino o infigratinib) de acuerdo con el criterio del investigador:
    a.Una operación no curativa (es decir, resección R2 [con enfermedad residual macroscópica] o cirugía de derivación paliativa exclusivamente).
    b.Cirugía curativa con signos de recidiva irresecable de la enfermedad que precisa quimioterapia sistémica.
    c.Radioterapia adyuvante (con o sin quimioterapia radiosensibilizante en dosis bajas) para enfermedad localizada siempre que haya indicios claros de progresión de la enfermedad antes de la inclusión en este estudio.
    d.Quimioterapia adyuvante, siempre que el tratamiento se haya completado > 6 meses antes de la incorporación al ensayo.
    e.Tratamiento fotodinámico siempre que haya indicios claros de progresión de la enfermedad en el foco local o en un nuevo foco metastásico.
    5.Tener ≥ 18 años de edad en cualquiera de los sexos.
    6.Estado funcional del Eastern Cooperative Oncology Group (ECOG) ≤ 1.
    7.Tener una esperanza de vida > 3 meses.
    8.Ser capaz de leer y/o comprender los detalles del estudio y dar constancia por escrito del consentimiento informado aprobado por el comité de ética de investigación clínica (CEIC).
    9.Recuperación de AA de tratamientos antineoplásicos sistémicos previos hasta la situación basal o un grado 1, excepto alopecia.
    10.Ser capaz de tragar y de retener la medicación oral.
    11.Disposición y capacidad para cumplir las visitas programadas, el plan de tratamiento y las pruebas analíticas.
    12.Las mujeres en edad fértil (MEF) deben tener una prueba de embarazo negativa en los 7 días previos a la primera dosis del fármaco del estudio. Una mujer no está en edad fértil si se ha sometido a esterilización quirúrgica (histerectomía total, ligadura de trompas bilateral u ovariectomía bilateral al menos 6 semanas antes de empezar a recibir el fármaco del estudio) o si es posmenopáusica y no ha tenido ninguna hemorragia menstrual de ningún tipo, como menstruación, hemorragia irregular, manchado, etc., durante al menos 12 meses, con un perfil clínico adecuado, y no existe ninguna otra causa de amenorrea (p. ej., tratamiento hormonal, quimioterapia previa).
    E.4Principal exclusion criteria
    1. Have received treatment with any systemic anti-cancer therapy for unresectable, recurrent, or metastatic cholangiocarcinoma. Prior neoadjuvant or adjuvant therapy is permitted if completed > 6 months prior to first dose of study drug.
    2. Have history of a liver transplant.
    3. Have received prior or current treatment with a MEK or selective FGFR inhibitor.
    4. Have neurological symptoms related to underlying disease requiring increasing doses of corticosteroids. Note: Steroid use for management of central nervous system tumors is allowed but must be at a stable dose for at least 2 weeks preceding study entry.
    5. Have a history of another primary malignancy within 3 years except adequately treated in situ carcinoma of the cervix or non-melanoma carcinoma of the skin or any other curatively treated malignancy that is not expected to require treatment for recurrence during the course of the study.
    6. Have any other medical condition that would, in the investigator’s judgment, prevent the subject’s participation in the clinical study due to safety concerns or compliance with clinical study procedures.
    7. Have current evidence of corneal or retinal disorder/keratopathy including, but not limited to, bullous/band keratopathy, corneal abrasion, inflammation/ulceration, keratoconjunctivitis, confirmed by ophthalmic examination. Subjects with asymptomatic ophthalmic conditions assessed by the investigator to pose minimal risk for study participation may be enrolled in the study.
    8. Have a history and/or current evidence of extensive tissue calcification including, but not limited to, the soft tissue, kidneys, intestine, myocardium, vascular system and lung with the exception of calcified lymph nodes, minor pulmonary parenchymal calcifications, and asymptomatic coronary calcification.
    9. Have impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral infigratinib (eg., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection).
    10. Have current evidence of endocrine alterations of calcium/phosphate homeostasis, eg., parathyroid disorders, history of parathyroidectomy, tumor lysis, tumoral calcinosis etc.
    11. Are currently receiving treatment with agents that are known strong inducers or inhibitors of CYP3A4 and medications which increase serum phosphorus and/or calcium concentration. Subjects are not permitted to receive enzyme-inducing anti-epileptic drugs, including carbamazepine, phenytoin, phenobarbital, and primidone.
    12. Have consumed grapefruit, grapefruit juice, grapefruit hybrids, pomegranates, star fruits, pomelos, Seville oranges or products containing juice of these fruits within 7 days prior to first dose of study drug.
    13. Have used medications known to prolong the QT interval and/or are associated with a risk of Torsades de Pointes (TdP) 7 days prior to first dose of study drug.
    14. Have used amiodarone within 90 days prior to first dose of study drug.
    15. Are currently using therapeutic doses of warfarin sodium or any other coumadin-derivative anticoagulants or using direct thrombin inhibitors (e.g., argatroban) or Factor Xa inhibitors (e.g., rivaroxaban) that are primarily metabolized by CYP3A4.
    16. Have insufficient bone marrow function.
    17. Have insufficient hepatic and renal function.
    18. Have amylase or lipase >2.0 × ULN
    19. Have abnormal calcium-phosphate homeostasis:
    a. Inorganic phosphorus outside of local normal limits
    b. Total corrected serum calcium outside of local normal limits
    20. Have clinically significant cardiac disease.
    21. Have had a recent (≤ 3 months prior to first does of study drug) transient ischemic attack or stroke.
    22. CTCAE (v4.0 or later) Grade ≥ 2 hearing loss.
    23. CTCAE (v4.0 or later) Grade ≥ 2 neuropathy.
    24. If female, is pregnant or nursing (lactating), where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotrophin urine or blood laboratory test.
    25. Have known microsatellite instability-high (MSI-H) disease and the decision is made by the treating investigator that an alternative, non-study therapy is warranted according to standard of care.
    1. Haber recibido tratamiento antineoplásico sistémico por colangiocarcinoma irresecable, recurrente o metastásico. Se permite el tratamiento neoadyuvante o adyuvante previo si se ha completado > 6 meses antes de la primera dosis del fármaco del estudio.
    2. Antecedentes de trasplante de hígado.
    3. Haber recibido tratamiento previo o actual con un inhibidor de MEK o un inhibidor selectivo de FGFR.
    4. Presentar síntomas neurológicos relacionados con la enfermedad subyacente que requieran dosis crecientes de corticosteroides
    5. Tener antecedentes de otra neoplasia maligna primaria en los 3 años previos, excepto carcinoma in situ de cuello uterino debidamente tratado o carcinoma de piel distinto del melanoma o cualquier otra neoplasia maligna tratada curativamente que no se prevea que requiera tratamiento por recidiva durante el estudio.
    6. Presentar cualquier otro trastorno médico que impida la participación del sujeto en el estudio clínico debido a problemas de seguridad o de cumplimiento de los procedimientos del estudio clínico.
    7. Presentar signos de queratopatía/trastorno corneal o retiniano, tal como queratopatía bullosa/en banda, abrasión corneal, inflamación/ulceración, queratoconjuntivitis, confirmado por exploración oftalmológica.
    8. Tener antecedentes y/o signos actuales de calcificación extensa de tejidos, incluidos, entre otros, tejidos blandos, riñones, intestino, miocardio, sistema vascular y pulmón,
    9. Presentar alguna disfunción o enfermedad GI que pueda alterar significativamente la absorción de infigratinib oral .
    10. Presentar indicios actuales de alteraciones endocrinas de la homeostasis del calcio/fosfato, como trastornos paratiroideos, antecedentes de paratiroidectomía, lisis tumoral, calcinosis tumoral, etc.
    11. Estar recibiendo actualmente tratamiento con fármacos que son inductores o inhibidores potentes conocidos de la CYP3A4 y medicamentos que aumentan la concentración sérica de fósforo y/o calcio.
    12. Haber consumido pomelo, zumo de pomelo, híbridos de pomelo, granada, carambola, naranjas amargas o productos que contengan zumo de estas frutas en los 7 días previos a la primera dosis del fármaco del estudio.
    13. Haber utilizado medicamentos que prolongan el intervalo QT y/o que se asocian a un riesgo de taquicardia helicoidal 7 días antes de la primera dosis del fármaco del estudio.
    14. Haber utilizado amiodarona en los 90 días previos a la primera dosis del fármaco del estudio.
    15. Estar utilizando en la actualidad dosis terapéuticas de warfarina sódica o de cualquier otro anticoagulante cumarínico, o inhibidores directos de la trombina o inhibidores del factor Xa que son metabolizados principalmente por la CYP3A4.
    16.Tener una función insuficiente de la médula ósea:
    a.RAN < 1.000/mm3 (1,0 × 109/l)
    b.Plaquetas < 100.000/mm3 (< 100 ×109/l)
    c.Hemoglobina < 9,0 g/dl.
    17.Tener insuficiencia hepática o renal:
    a.Bilirrubina total > 1,5 × LSN
    b. (AST/SGOT) y alanina aminotransferasa/transaminasa glutámico-pirúvica sérica (ALT/SGPT) >2,5 × LSN (AST y ALT > 5 × LSN en presencia de afectación hepática por el colangiocarcinoma)
    c.Aclaramiento de creatinina calculado o medido < 45 ml/min
    18.Tener amilasa o lipasa > 2,0 × LSN.
    19.Tener una homeostasis anormal del calcio-fosfato:
    a.Fósforo inorgánico fuera de los límites normales del laboratorio local
    b.Calcio sérico corregido total fuera de los límites normales del laboratorio local.
    20.Tener una cardiopatía clínicamente significativa, como alguna de las siguientes:
    a.Insuficiencia cardíaca congestiva con necesidad de tratamiento (grado ≥ 2 de la New York Heart Association), fracción de eyección ventricular izquierda (FEVI) < 50% o límite inferior de la normalidad local determinado por ventriculografía isotópica en equilibrio (MUGA) o ecocardiograma, o hipertensión no controlada
    b.Presencia de arritmias ventriculares, fibrilación auricular, bradicardia o anomalía de la conducción de grado ≥ 2.
    c.Angina de pecho inestable o infarto agudo de miocardio ≤ 3 meses antes de la primera dosis del fármaco del estudio.
    d.QTcF > 470 ms
    e.Antecedentes conocidos de síndrome de QT prolongado congénito.
    21.Haber sufrido recientemente (≤ 3 meses antes de la primera dosis de fármaco del estudio) un accidente isquémico transitorio o un ictus.
    22.Pérdida auditiva de grado ≥ 2 según los CTCAE
    23.Neuropatía de grado ≥ 2 según los CTCAE
    24.Mujeres embarazadas o en período de lactancia, definido el embarazo como el estado de la mujer desde la concepción hasta el final de la gestación, confirmado por un resultado positivo en el análisis de gonadotropina coriónica humana en orina o sangre.
    25.Tener enfermedad con inestabilidad de microsatélites elevada conocida y decisión del investigador responsable del tratamiento de que está justificado un tratamiento alternativo, ajeno al estudio, con arreglo a la práctica asistencial habitual.
    E.5 End points
    E.5.1Primary end point(s)
    Progression-free survival (from date of randomization until date of progression as determined by independent central read or death due to any cause).
    SSP (desde la fecha de la aleatorización hasta la fecha de progresión determinada por una evaluación centralizada independiente o la muerte por cualquier causa).
    E.5.1.1Timepoint(s) of evaluation of this end point
    From date of randomization until date of progression as determined by independent central read or death due to any cause.
    desde la fecha de la aleatorización hasta la fecha de progresión determinada por una evaluación centralizada independiente o la muerte por cualquier causa
    E.5.2Secondary end point(s)
    1. Overall survival (from date of randomization until date of death).
    2. Progression-free survival (PFS) as determined by the investigator.
    3. Overall response rate (ORR) assessed centrally according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.
    4. ORR assessed by the investigator according to RECIST Version 1.1.
    5. Best overall response (BOR), disease control rate (partial response [PR] + complete response [CR] + stable disease [SD]), and duration of response (only for subjects who have a response) assessed centrally and by the investigator according to RECIST 1.1.
    6. Type, frequency, and severity of adverse events (AEs) and serious AEs (SAEs), laboratory abnormalities, and other safety findings.
    •SG (desde la fecha de la aleatorización hasta la fecha de la muerte).
    •SSP determinada por el investigador.
    •TRG evaluada de forma centralizada según los Criterios de evaluación de la respuesta en tumores sólidos (RECIST), versión 1.1.
    •TRG evaluada por el investigador según los criterios RECIST, versión 1.1.
    •MRG, tasa de control de la enfermedad (respuesta parcial [RP] + respuesta completa [RC] + enfermedad estable [EE]) y duración de la respuesta (solo en los sujetos con respuesta) evaluadas de forma centralizada y por el investigador con arreglo a los criterios RECIST 1.1.
    •Tipo, frecuencia e intensidad de los acontecimientos adversos (AA) y los AA graves (AAG), anomalías analíticas y otros hallazgos de seguridad.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. From date of randomization until date of death every 3 months; every 3 months after disease progression
    2. Every 8 weeks
    3. Every 8 weeks
    4. Every 8 weeks
    5. Every 8 weeks
    6. From randomization until 30 days after the last dose of study drug
    Desde la fecha de la asignación al azar hasta la fecha de la muerte cada 3 meses; cada 3 meses después de la progresión de la enfermedad
    2. Cada 8 semanas
    3. Cada 8 semanas
    4. Cada 8 semanas
    5. Cada 8 semanas
    6. Desde la aleatorización hasta 30 días después de la última dosis del fármaco del estudio
    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 No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Assessment of Biomarkers and genetic mutation
    Evaluación de biomarcadores y mutación genética.
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    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 Yes
    E.8.2.3.1Comparator description
    Gemcitabine and Cisplatin
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned12
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA45
    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
    Belgium
    Canada
    Chile
    China
    France
    Germany
    Hungary
    Italy
    Korea, Republic of
    Spain
    Taiwan
    Thailand
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of trial (study) is defined as up to 1 year after the time at which 251 centrally confirmed PFS events are reached.
    El final de la prueba (estudio) se define como hasta 1 año después del momento en que se alcanzan los 251 eventos de SLP confirmados centralmente.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial 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: 65
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 66
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 45
    F.4.2.2In the whole clinical trial 131
    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)
    Best standard of care at investigator’s discretion
    Mejor atención por práctica habitual a discreción del investigador
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-01-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-12-18
    P. End of Trial
    P.End of Trial StatusOngoing
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