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    Summary
    EudraCT Number:2018-001437-40
    Sponsor's Protocol Code Number:KO-TIP-007
    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:2018-11-23
    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 number2018-001437-40
    A.3Full title of the trial
    The AIM-HN and SEQ-HN Study: A 2 Cohort, Non-comparative, Pivotal Study Evaluating the Efficacy of Tipifarnib in Patients with Head and Neck Squamous Cell Carcinoma (HNSCC) with HRAS Mutations (AIM-HN) and the Impact of HRAS Mutations on Response to First Line Systemic Therapies for HNSCC (SEQ-HN)
    El estudio AIM-HN y SEQ-HN: Estudio pivotal no comparativo de 2 cohortes para evaluar la eficacia de tipifarnib en pacientes con carcinoma de células escamosas de cabeza y cuello (CCECC) con mutaciones de HRAS (AIM-HN) y el impacto de las mutaciones de HRAS en la respuesta a las terapias sistémicas de primera línea para el CCECC (SEQ-HN).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The AIM-HN and SEQ-HN Study: A 2 Cohort Study to Evaluate the Safety and Efficacy of Tipifarnib in Patients with Head and Neck Cancer with HRAS Mutations (Cohort 1) and the Impact of HRAS Mutations on Response to Treatment (Cohort 2)
    El estudio AIM-HN y SEQ-HN: un estudio de 2 cohortes para evaluar la seguridad y la eficacia de Tipifarnib en pacientes con cáncer de cabeza y cuello con mutación en HRAS (cohorte 1) y el impacto de las mutaciones en HRAS en la respuesta al tratamiento (cohorte 2).
    A.4.1Sponsor's protocol code numberKO-TIP-007
    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 SponsorKura Oncology, 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 supportKura Oncology, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKura Oncology, Inc.
    B.5.2Functional name of contact pointClinical Trials Mailbox
    B.5.3 Address:
    B.5.3.1Street Address3033 Science Park Road, Suite 220
    B.5.3.2Town/ citySan Diego
    B.5.3.3Post codeCA 92121
    B.5.3.4CountryUnited States
    B.5.6E-mailprivacy@kuraoncology.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 nameTipifarnib 300 mg
    D.3.2Product code R115777
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTipifarnib
    D.3.9.1CAS number 192185-72-1
    D.3.9.2Current sponsor code089408
    D.3.9.3Other descriptive nameTIPIFARNIB
    D.3.9.4EV Substance CodeSUB22236
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 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 nameTipifarnib 100 mg
    D.3.2Product code R115777
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTipifarninb
    D.3.9.1CAS number 192185-72-1
    D.3.9.2Current sponsor code089408
    D.3.9.3Other descriptive nameTIPIFARNIB
    D.3.9.4EV Substance CodeSUB22236
    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.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
    Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) with HRAS Mutations
    Carcinoma de células escamosas de cabeza y cuello (CCECC) recurrente o metastásico con mutaciones en HRAS
    E.1.1.1Medical condition in easily understood language
    Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) with HRAS Mutations
    Carcinoma de células escamosas de cabeza y cuello (CCECC) recurrente o metastásico con mutaciones en HRAS
    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 10063569
    E.1.2Term Metastatic squamous cell carcinoma
    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 determine the ORR of tipifarnib in subjects with HNSCC with HRAS mutations as assessed by IRF.
    Determinar la tasa de respuesta objetiva (TRO) de tipifarnib en pacientes con carcinoma de células escamosas de cabeza y cuello (CCECC) con mutaciones de HRAS, evaluada por un recurso independiente de revisión (RIR).
    E.2.2Secondary objectives of the trial
    To determine the anti-tumor activity of tipifarnib in terms of: time to response, DOR, TTP, PFS, one year progression free rate, one year survival and OS
    To investigate the safety and tolerability of tipifarnib according to the NCI CTCAE v5.0
    To assess population PK of tipifarnib in subjects with HNSCC with HRAS mutations
    Determinar la actividad antitumoral de tipifarnib en términos de: tiempo transcurrido hasta la respuesta, duración de la respuesta (DdR), tiempo transcurrido hasta la progresión (TTP), supervivencia sin progresión (SSP), tasa sin progresión en un año, supervivencia en un año y supervivencia global (SG).
    Investigar la seguridad y tolerabilidad de tipifarnib de acuerdo con los criterios terminológicos comunes para acontecimientos adversos del National Cancer Institute versión 5.0 (CTCAE de NCI v5.0).
    Evaluar las características farmacocinéticas (FC) de tipifarnib en pacientes con CCECC con mutaciones de HRAS.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Observational cohort SEQ-HN. Study title:
    The AIM-HN and SEQ-HN Study: A 2 Cohort, Non-comparative, Pivotal Study Evaluating the Efficacy of Tipifarnib in Patients with Head and Neck Squamous Cell Carcinoma (HNSCC) with HRAS Mutations (AIM-HN) and the Impact of HRAS Mutations on Response to First Line Systemic Therapies for HNSCC (SEQ-HN).
    Version Protocol Amendment 1 dated 25 July 2018.
    Objective of SEQ-HN is to help facilitate HRAS testing in HNSCC, preferentially as HNSCC patients initiate first line systemic treatment for recurrent or metastatic disease.
    El estudio AIM-HN y SEQ-HN: Estudio pivotal no comparativo de 2 cohortes para evaluar la eficacia de tipifarnib en pacientes con carcinoma de células escamosas de cabeza y cuello (CCECC) con mutaciones de HRAS (AIM-HN) y el impacto de las mutaciones de HRAS en la respuesta a las terapias sistémicas de primera línea para el CCECC (SEQ-HN).
    Protocolo versión enmienda 1 de 25 de julio de 2018.
    El obetivo del subestudio SEQ-HN es facilitar la evaluación de HRAS en pacientes con CCECC, preferentemente cuando los pacientes con CCECC inicien la terapia sistémica de primera línea para la enfermedad recurrente o metastásica.
    E.3Principal inclusion criteria
    AIM-HN
    1.At least 18 years of age.
    2.Histologically confirmed head and neck cancer (oral cavity, pharynx, larynx, sinonasal, nasopharyngeal, or unknown primary) of squamous histology not amenable to local therapy with curative intent (surgery or radiation therapy with or without chemotherapy). Enrollment may proceed with local diagnosis but all subjects must consent to provide tumor tissue for a central pathology review.
    3.Documented tumor progression or recurrence from at least one prior platinum-containing regimen in the primary, neoadjuvant, adjuvant, advanced, recurrent or metastatic setting. Subjects must have progressed or have recurred from a prior platinum containing regimen but there is no limit in the number of prior lines of therapy. Subjects without prior platinum treatment who, at the judgment of the investigator, are considered unsuitable to receive standard therapy with a platinum-containing regimen due to auditory deficit or hypersensitivity to platinum may be also enrolled.
    4.Known tumor missense HRAS mutation. HRAS status may be assessed on tumor obtained at primary diagnosis or at later stages of disease. Enrollment may proceed with the identification of a missense HRAS mutation using a test preferred by the site and approved by the Sponsor but all subjects must consent to provide tumor tissue for central HRAS testing. Tumor tissue may be obtained from prior archival diagnostic biopsies. If no archival biopsy is available, a new biopsy will be required.
    5.Measurable disease by RECIST v1.1 that meets the criteria for selection as a target lesion according to RECIST v1.1. The presence of at least one measurable target lesion per RECIST v1.1 must be confirmed by local radiology prior to subject entry.
    6.At least 2 weeks since the last systemic therapy regimen prior to Cycle 1 Day 1. Subjects must have recovered to NCI CTCAE v5.0 < Grade 2 from all acute toxicities (excluding Grade 2 toxicities that are not considered a safety risk by the Sponsor and Investigator) or toxicity must be deemed irreversible by the Investigator.
    7.At least 2 weeks since last radiotherapy. Subjects must have recovered from all acute toxicities from radiotherapy.
    8.ECOG perform. status of 0-2.
    9.Acceptable liver function:
    a)Bilirubin less or equal 1.5 times upper limit of normal (x ULN); does not apply to subjects with Gilbert’s syndrome diagnosed as per institutional guidelines.
    b)AST (SGOT) and ALT (SGPT) less or equal 1.5 x ULN;
    10.Acceptable renal function with either serum creatinine less or equal 1.5 x ULN or a calculated creatinine clearance ≥ 60 mL/min using the Cockcroft-Gault or Modification of Diet in Renal Disease (MDRD) formulas.
    11.Acceptable hematol. status:
    a)ANC ≥ 1000 cells/μL.
    b)Platelet count ≥ 75,000/μL.
    c)Hemoglobin ≥ 8.0 g/dL.
    12.Female subjects must be:
    a)Of non-child-bearing potential (surgically sterilized or at least 2 years post-menopausal); or
    b)If of child-bearing potential, subject must use a highly effective method of contraception, such as combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner or sexual abstinence. Both females and male subjects with female partners of child-bearing potential must agree to use a highly effective method of contraception from the first dose of tipifarnib, during tipifarnib treatment, and at least 28 days after last dose of tipifarnib for females and 90 days for males. Female subjects must have a negative serum or urine pregnancy test within 72 hours prior to start of trial medication.
    c)Not breast feeding at any time during the study.
    13.Written and voluntary informed consent understood, signed and dated.

    SEQ-HN
    1.At least 18 years of age.
    2.Histologically confirmed head and neck cancer (oral cavity, pharynx, larynx, sinonasal, nasopharyngeal, or unknown primary) of squamous histology.
    3.Known tumor HRAS status using a test preferred by the site and approved by the Sponsor or through central HRAS testing. HRAS status may be assessed on tumor obtained at primary diagnosis or at later stages of disease.
    4.Will or has received at least one systemic anti-cancer therapy for recurrent or metastatic HNSCC for which there is available outcome information in terms of ORR, or the latter can be estimated based on the subject’s records. Subjects who have not yet received or completed at least one systemic anti-cancer therapy for recurrent or metastatic HNSCC must consent to the collection of treatment outcome information and additional follow up contact in order to participate in the SEQ-HN portion of the study.
    5.Written and voluntary informed consent understood, signed and dated.
    AIM-HN
    1.Tener 18 años o más.
    2.Cáncer de cuello y cabeza con confirmación histológica de histología escamosa, no susceptible de tratamiento local con intención curativa .
    3.Progresión tumoral o recidiva documentada como mínimo después de un régimen que contenga platino en el contexto primario, neoadyuvante, adyuvante, avanzado, recurrente o metastásico.
    4.Mutación confirmada de HRAS con cambio de sentido. El estado de HRAS podrá evaluarse en muestras tumorales obtenidas en el momento del diagnóstico primario o en etapas posteriores de la enfermedad. En la selección, será posible identificar una mutación de HRAS con cambio de sentido mediante el uso de una prueba preferida por el centro y aprobada por el promotor, pero todos los pacientes deberán dar su consentimiento para proporcionar tejido tumoral destinado a pruebas centralizadas de HRAS.
    5.Enfermedad medible por RECIST v1.1 que cumpla los criterios para la selección como lesión diana según RECIST v1.1. Antes de la entrada del paciente en el estudio, debe confirmarse mediante radiología la presencia de al menos una lesión diana medible según RECIST v1.1.
    6.Al menos 2 semanas desde el último régimen terapéutico sistémico antes del día 1 del ciclo 1. Los pacientes deberán haberse recuperado hasta NCI-CTCAE v5.0 < grado 2 de todas las toxicidades agudas (con exclusión de las toxicidades de grado 2 que el promotor y el investigador no consideren un riesgo para la seguridad) o el investigador deberá juzgar irreversible la toxicidad.
    7.Al menos 2 semanas desde la última sesión de radioterapia. Los pacientes deben haberse recuperado de todas las toxicidades agudas derivadas de la radioterapia.
    8.Escala de valoración del ECOG de 0-2.
    9.Función hepática aceptable:
    a)Bilirrubina 1,5 veces el límite superior de la normalidad (x LSN); no se aplicará a los pacientes con síndrome de Gilbert diagnosticado según las pautas institucionales.
    b)AST (TGO sérica) y ALT (GPT sérica)  1.5 x LSN
    10.Función renal aceptable con creatinina en suero  1,5 x LSN o aclaramiento de creatinina calculado ≥ 60 ml/min utilizando las fórmulas de Cockcroft-Gault o de modificación de la dieta en enfermedad renal (MDER).
    11.Estado hematológico aceptable
    12. Las mujeres:
    a)o deben tener posibilidad de quedarse embarazadas (sometidas a una esterilización quirúrgica o que lleven al menos dos años en estado posmenopáusico); o
    b)si tienen capacidad para quedarse embarazadas, las pacientes deben utilizar un método anticonceptivo de alta eficacia, como anticoncepción hormonal combinada (con estrógeno y progesterona) asociada a la inhibición de la ovulación, anticoncepción hormonal solo con progesterona asociada a la inhibición de la ovulación, dispositivo intrauterino, sistema de liberación de hormonas intrauterino, oclusión de trompas bilateral, pareja vasectomizada o abstinencia sexual. Tanto las mujeres como los hombres con parejas femeninas que tengan posibilidad de quedarse embarazadas deben estar de acuerdo en utilizar un método anticonceptivo de alta eficacia desde la primera dosis de tipifarnib, durante el tratamiento con tipifarnib y al menos durante los 28 días siguientes a la administración de la última dosis de tipifarnib para las mujeres y 90 días para los hombres. Las mujeres deberán disponer de una prueba de embarazo en suero u orina con resultado negativo en las 72 horas previas al inicio del tratamiento con el medicamento del ensayo.
    c)No deberán estar en periodo de lactancia en ningún momento del estudio.
    13.Consentimiento informado por escrito, voluntario, comprendido, firmado y fechado.
    SEQ-HN
    1.Tener 18 años o más.
    2.Cáncer de cabeza y cuello (de cavidad oral, faringe, laringe, de senos paranasales y cavidad nasal, nasofaríngeo o desconocido primario) con confirmación histológica de histología escamosa.
    3.Estado tumoral de HRAS confirmado mediante el uso de una prueba preferida por el centro y aprobada por el promotor o a través de pruebas centralizadas de HRAS. El estado de HRAS podrá evaluarse a partir de tejido tumoral obtenido en el diagnóstico primario o en etapas posteriores de la enfermedad.
    4.Ir a recibir o haber recibido al menos una terapia sistémica contra el CCECC recurrente o metastásico sobre cuyo resultado en términos de TRO se disponga de información, o que pueda valorarse a partir de los expedientes médicos del paciente. Los pacientes que aún no hayan recibido o completado al menos una terapia sistémica contra el CCECC recurrente o metastásico deberán dar su consentimiento para la recopilación de información sobre su resultado y para un contacto adicional de seguimiento a fin de participar en la porción SEQ-HN del estudio.
    5.Consentimiento informado por escrito, voluntario, comprendido, firmado y fechado.
    E.4Principal exclusion criteria
    AIM-HN
    1.Has disease that is suitable for local therapy administered with curative intent.
    2.Histologically confirmed salivary gland, thyroid, (primary) cutaneous squamous or nonsquamous histologies (e.g. mucosal melanoma).
    3.Known additional malignancy that is progressing or requires active treatment (excluding non-melanoma skin cancer, adjuvant hormonal therapy for breast cancer and hormonal treatment for castration sensitive prostate cancer).
    4.Ongoing treatment with an anticancer agent not contemplated in this protocol (excluding adjuvant hormonal therapy for breast cancer and hormonal treatment for castration sensitive prostate cancer).
    5.Prior treatment (at least 1 full treatment cycle) with a farnesyltransferase inhibitor (FTI).
    6.Any use of investigational therapy within 2 weeks of Cycle 1 Day 1 or 5 half-lives (whichever is longer).
    7.Received treatment for unstable angina within prior year, myocardial infarction within the prior year, cerebro-vascular attack within the prior year, history of New York Heart Association grade III or greater congestive heart failure, or current serious cardiac arrhythmia requiring medication except atrial fibrillation.
    8.Non-tolerable Grade 2 or ≥ Grade 3 neuropathy or evidence of unstable neurological symptoms within 4 weeks of Cycle 1 Day 1. Non-tolerable Grade 2 toxicities are defined as those with moderate symptoms that the subject is not able to endure for the conduct of instrumental activities of daily life or that persists ≥ 7 days.
    9.Major surgery, other than diagnostic surgery, within 2 weeks prior to Cycle 1 Day 1, without complete recovery.
    10.Active, uncontrolled bacterial, viral or fungal infections requiring systemic therapy. Known history of infection with human immunodeficiency virus or an active infection with hepatitis B or hepatitis C.
    11. Received treatment for non-cancer related liver disease within prior year.
    12.Subjects who have exhibited allergic reactions to tipifarnib or structural compounds similar to tipifarnib or to its excipients. This includes hypersensitivity to imidazoles, such as clotrimazole, ketoconazole, miconazole and others in this drug class. Subjects with hypersensitivity to these agents will be excluded from enrollment.
    13.Required use of concomitant medications classified as strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4, Table 7) or UDP-glucuronosyltransferase (UGT).
    14.Concomitant disease or condition that could interfere with the conduct of the study or that would, in the opinion of the investigator, pose an unacceptable risk to the subject in this study.
    15.Dementia or significantly altered mental status that would limit the understanding or rendering of informed consent and compliance with the requirements of this protocol. Unwillingness or inability to comply with the study protocol for any reason.
    16.The subject has legal incapacity or limited legal capacity.

    SEQ-HN
    1.Histologically confirmed salivary gland, thyroid, (primary) cutaneous squamous or nonsquamous histologies (e.g. mucosal melanoma).
    2.Concomitant disease or condition that could interfere with the conduct of the study or that would, in the opinion of the investigator, pose an unacceptable risk to the subject in this study.
    3.The subject has legal incapacity or limited legal capacity.
    1. Tener enfermedad idónea para terapia local administrada con propósito curativo.
    2. Histologías confirmadas de glándula salival, tiroides, escamosa o no escamosa cutánea (primario) (p. ej., melanoma de mucosa).
    3. Malignidad adicional confirmada que esté progresando o requiera tratamiento activo (con exclusión del cáncer de piel distinto del melanoma, la terapia hormonal adyuvante para el cáncer de mama y el tratamiento hormonal para el cáncer de próstata sensible a la castración).
    4. Tratamiento en curso con un agente contra el cáncer no contemplado en este protocolo (con exclusión de la terapia hormonal adyuvante para el cáncer de mama y del tratamiento hormonal para el cáncer de próstata sensible a la castración).
    5. Tratamiento previo (1 ciclo de tratamiento completo como mínimo) con un inhibidor de la farnesil transferasa (IFT).
    6. El uso de cualquier terapia experimental en las 2 semanas previas al día 1 del ciclo 1 o 5 semividas (lo que sea más largo).
    7. Tratamiento recibido para la angina inestable en el año anterior, infarto de miocardio en el año anterior, accidente cerebrovascular en el año anterior, antecedentes de insuficiencia cardiaca congestiva de grado III o superior según la clasificación de la New York Heart Association o arritmia cardiaca grave en curso que requiera medicación, salvo fibrilación auricular.
    8. Neuropatía de grado 2 no tolerable o ≥ grado 3 o evidencia de síntomas neurológicos inestables en las 4 semanas previas al día 1 del ciclo 1. Las toxicidades de grado 2 no tolerables se definen como las que presentan síntomas moderados que el paciente no pueda soportar para la realización de las actividades instrumentales de la vida cotidiana o que persisten ≥ 7 días.
    9. Intervención quirúrgica importante, excepto cirugía diagnóstica, en las 2 semanas previas al día 1 del ciclo 1, sin recuperación completa.
    10. Infecciones activas bacterianas, víricas o fúngicas no controladas que requieran terapia sistémica. Antecedentes confirmados de infección por el virus de la inmunodeficiencia humana o infección activa por el virus de la hepatitis B o la hepatitis C.
    11. Tratamiento recibido para enfermedad hepática no relacionada con el cáncer en el año anterior.
    12. Pacientes que hayan mostrado reacciones alérgicas a tipifarnib o componentes estructurales similares a tipifarnib o a sus excipientes. Esas reacciones alérgicas incluirán la hipersensibilidad a los imidazoles, como clotrimazol, ketoconazol, miconazol y otras sustancias pertenecientes a este grupo farmacológico. No podrá incluirse a los pacientes con hipersensibilidad a esos agentes.
    13. Uso necesario de medicamentos concomitantes clasificados como inhibidores o inductores potentes del citocromo P450 3A4 (CYP3A4, Tabla 7) o UPD-glucoronosiltransferasa (UGT).
    14. Enfermedad o afección simultáneas que puedan interferir en la realización del estudio o que, en opinión del investigador, puedan suponer un riesgo inaceptable para el sujeto del estudio.
    15. Demencia o alteraciones significativas del estado mental que limitarían la comprensión o prestación del consentimiento informado y el cumplimiento de los requisitos de este protocolo. Renuencia o incapacidad para cumplir con el protocolo del estudio por cualquier motivo.
    16. El paciente presenta incapacidad legal o capacidad legal limitada.
    SEQ-HN
    1. Histologías confirmadas de glándula salival, tiroides, escamosa o no escamosa cutánea (primario) (p. ej., melanoma de mucosa).
    2. Enfermedad o afección simultáneas que puedan interferir en la realización del estudio o que, en opinión del investigador, puedan suponer un riesgo inaceptable para el sujeto del estudio.
    3. El paciente presenta incapacidad legal o capacidad legal limitada.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the proportion of subjects with confirmed Objective Response (OR), defined as either Complete Response (CR) or Partial Response (PR), calculated using the mITT analysis set.
    Determinar la tasa de respuesta objetiva (TRO) de tipifarnib en pacientes con carcinoma de células escamosas de cabeza y cuello (CCECC) con mutaciones de HRAS, evaluada por un recurso independiente de revisión (RIR).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Tumor response assessment visit
    Visita de valoración de respuesta tumoral.
    E.5.2Secondary end point(s)
    •Time to response
    •Duration of response (DOR)
    •Time to progression (TTP)
    •Progression-free survival (PFS)
    •1-year progression-free rate and 1-year survival rate
    •Overall survival rate (OS)
    •Adverse Events
    •Population PK parameters of tipifarnib
    •Laboratory test results
    •Vital Signs
    •ECG results
    Tiempo de respuesta
    Duración de la respuesta
    Tiempo hasta progresión
    Supervivencia libre de progresión
    Tasa de supervivencia sin progresión en 1 año y tasa de supervivencia en 1 año
    Tasa de supervivencia global
    Acontecimientos adversos
    Carácterísticas farmacocinéticas de la población
    Resultados de laboratorio
    Constantes vitales
    Resultados ECG
    E.5.2.1Timepoint(s) of evaluation of this end point
    Tumor response assessment visit
    End of response assessment visit
    Follow up visit
    Visita de valoración de respuesta tumoral
    Visita de fin de valoración de fin de respuesta tumoral
    Visita de seguimiento
    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 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.8.3 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 concerned15
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA51
    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
    Austria
    Belgium
    Canada
    Denmark
    France
    Germany
    Greece
    Italy
    Malaysia
    Netherlands
    Norway
    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 this clinical study is defined as 2 years from enrollment of the last enrolled study subject in AIM-HN. If the last enrolled study subject discontinues treatment within 2 years of study enrollment, the End of Study will occur no earlier than the date of the last enrolled subject’s safety follow-up assessment (End of Treatment visit) performed approximately 30 days after treatment discontinuation or until initiation of another anti-cancer therapy, whichever occurs first.
    La finalización del ensayo se define como 2 años desde la inclusión del último paciente en el estudio AIM-HN. Si el último paciente incluido discontinúa el tratamiento dentro de los 2 años del periodo de reclutamiento, el fin de ensayo ocurrirá no antes de la fecha de valoración de seguimiento de la seguridad del último paciente incluido (visita fin de tratamiento) realizada aproximadamente 30 días después de la discontinuación o hasta el inicion de otra terapia anticaner. Lo que antes ocurra.
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    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: 84
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 200
    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 state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 152
    F.4.2.2In the whole clinical trial 284
    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)
    None
    Ninguno
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-03-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-01-11
    P. End of Trial
    P.End of Trial StatusOngoing
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