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    Summary
    EudraCT Number:2021-002177-25
    Sponsor's Protocol Code Number:19-255-03
    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:2021-07-20
    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 number2021-002177-25
    A.3Full title of the trial
    A Phase 1b/2, Open-label, Multicenter, Dose Escalation and Dose Expansion Study of NKTR-255 in Combination with Cetuximab as a Salvage Regimen for Solid Tumors
    Estudio de fase 1b/2, abierto, multicéntrico, de aumento escalonado y ampliación de la dosis de NKTR-255 en combinación con cetuximab como pauta de rescate para tumores sólidos
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study on NKTR-255 in combination with Cetuximab as salvage treatment for Solid Tumors
    Estudio sobre NKTR-255 en combinación con Cetuximab como tratamiento de rescate para tumores sólidos.
    A.4.1Sponsor's protocol code number19-255-03
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04616196
    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 SponsorNektar Therapeutics
    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 supportNektar Therapeutics
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPPD
    B.5.2Functional name of contact pointProject Manager
    B.5.3 Address:
    B.5.3.1Street Address3900 Paramount Parkway
    B.5.3.2Town/ cityMorrisville
    B.5.3.3Post codeNC 27560
    B.5.3.4CountryUnited States
    B.5.4Telephone number+34900834223
    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 nameNKTR-255
    D.3.2Product code NKTR-255
    D.3.4Pharmaceutical form Lyophilisate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNKTR-255
    D.3.9.1CAS number 2361317-09-9
    D.3.9.2Current sponsor codeNKTR-255
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1.0
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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 Yes
    D.2.1.1.1Trade name Erbitux
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Europe B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namecetuximab
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCETUXIMAB
    D.3.9.1CAS number 205923-56-4
    D.3.9.4EV Substance CodeSUB01178MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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
    Relapsed or refractory (R/R) head and neck squamous cell carcinoma (HNSCC) or colorectal carcinoma (CRC)
    Carcinoma escamoso de cabeza y cuello (CECC) o carcinoma colorrectal (CCR) recidivante o resistente (R/R)
    E.1.1.1Medical condition in easily understood language
    Head and neck squamous cell cancer or colorectal cancer which has spread to other part of body
    Cáncer epidermoide de cabeza y cuello o cáncer colorrectal que se ha extendido a otra parte del cuerpo
    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 LLT
    E.1.2Classification code 10009963
    E.1.2Term Colon carcinoma recurrent
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10007336
    E.1.2Term Carcinoma colon recurrent
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 22.0
    E.1.2Level LLT
    E.1.2Classification code 10082179
    E.1.2Term Squamous cell carcinoma of head and neck metastatic
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10060121
    E.1.2Term Squamous cell carcinoma of head and neck
    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
    Phase 1b (Dose Escalation):
    • To evaluate the safety, tolerability, and define the maximum tolerated dose (MTD), and/or RP2D of NKTR-255 in combination with cetuximab in R/R metastaticHNSCC or CRC.
    Phase 2 (Dose Expansion):
    • To evaluate the safety and tolerability of NKTR-255 in patients with R/R metastatic HNSCC or CRC.
    • To evaluate the efficacy of NKTR-255 in combination with cetuximab in R/R metastatic HNSCC or CRC by assessing the objective response rate (ORR) by RECIST 1.1.
    Fase Ib (aumento escalonado de la dosis):
    • Evaluar la seguridad y la tolerabilidad y definir la dosis máxima tolerada (DMT) y/o la DRF2 de NKTR-255 en combinación con cetuximab en el CECC o CCR R/R metastásico.
    Fase 2 (ampliación de la dosis):
    • Evaluar la seguridad y la tolerabilidad de NKTR-255 en pacientes con CECC o CCR R/R metastásico.
    • Evaluar la eficacia de NKTR-255 en combinación con cetuximab en el CECC o CCR R/R metastásico mediante la evaluación de la tasa de respuesta objetiva (TRO) conforme a los criterios RECIST 1.1.
    E.2.2Secondary objectives of the trial
    • To evaluate the anti-tumor activity of the combination of NKTR-255 and cetuximab by assessing progression-free survival(PFS) and overall survival (OS).
    • To characterize the pharmacodynamic (PD) effects and change from baseline in immune cell populations (natural killer [NK], CD8+ cells, and other immune populations), tumor cells, cytokine levels, and changes in gene expression after administration of NKTR-255 in combination with cetuximab.
    • To characterize the pharmacokinetics (PK) of NKTR-255 and cetuximab.
    • To assess development of anti-drug antibodies against NKTR-255.
    • Evaluar la actividad antitumoral de la combinación de NKTR-255 y cetuximab mediante la evaluación de la supervivencia sin progresión (SSP) y la supervivencia global (SG).
    • Caracterizar los efectos farmacodinámicos (FD) y los cambios con respecto a los valores basales de poblaciones de células inmunitarias (linfocitos citolíticos naturales [natural killer, NK], linfocitos CD8+ y otras poblaciones inmunitarias), células tumorales, niveles de citocinas y los cambios en la expresión génica tras la administración de NKTR-255 en combinación con cetuximab.
    • Caracterizar la farmacocinética (FC) de NKTR-255 y cetuximab.
    • Evaluar el desarrollo de anticuerpos antifármaco contra NKTR-255.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion Criteria for All Patients
    1. Patients must be at least 18 years of age at study entry
    2. Patients must be capable of understanding and providing a written informed consent.
    3. Women of childbearing potential (WCBP) must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) at Screening and a negative serum or urine pregnancy test within 24 hours prior to dosing. Women of childbearing potential and men who are sexually active with women of childbearing potential must commit to use contraception.
    4. Histologically confirmed diagnosis of a locally advanced (not amenable to curative therapy such as surgical resection) or metastatic cancer of the following histologies: HNSCC or CRC
    5. Patients who have previously received cetuximab or other EGFR-directed therapies are excluded from Phase 2 of the trial, unless cetuximab was given as part of a primary treatment approach, with no progressive disease for at least 4 months following the end of prior cetuximab treatment.
    6. Life expectancy > 12 weeks as determined by the Investigator
    7. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
    8. Measurable disease per RECIST 1.1
    9. Patients must have demonstrated adequate organ function during Screening:
    a. Estimated glomerular filtration rate ≥ 40 mL/min/1.73m2 calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Creatinine Equation
    Inclusion Criteria for Specific Tumor Types
    • Head and Neck Cancer
    1. Patients must have histologically or cytologically confirmed advanced, recurrent, or metastatic HNSCC that could not be treated with curative intent. “Advanced” is defined as either locally advanced HNSCC not amenable to curative surgery or radiotherapy or with distant metastases.
    2. Progression (or toxicity precluding additional treatment) on any first or second line platinum-based chemotherapy and/or anti-PD-1 or programmed death-ligand 1 (anti-PD-L1) (together termed "anti-PD-(L)1") antibody
    3. Patients who have undergone treatment with anti-PD-(L)1 antibody must have had the last dose of antibody at least 4 weeks prior and evidence of tumor progression before they can be enrolled into this study.
    4. Ineligible for platinum-based (either cisplatin or carboplatin) chemotherapy or chemoradiation due to decline in renal function and/or patient's intolerance
    5. Must have known status by pathology for human papillomavirus (HPV) and Epstein-Barr virus (EBV) in HNSCC, either metastatic or recurrent disease.
    • Colorectal Cancer
    1. Patients must have a histologically or cytologically confirmed diagnosis of advanced CRC; patients in Phase 2 must have confirmed KRAS wild type EGFR-expressing advanced CRC. “Advanced” is defined as either locally advanced unresectable cancer or metastatic disease.
    2. Patients must have received or were intolerant to at least 2 prior cancer therapy regimens administered for metastatic disease.
    3. Patients with high microsatellite instability (MSI-H) or mismatched repair disease (dMMR) tumors must have been exposed to checkpoint inhibitors such as anti-PD-(L)1 or anticytotoxic T-lymphocyte-associated protein (CTLA)-4 antibody.
    Criterios de inclusión para todos los pacientes
    1. Los pacientes deben tener al menos 18 años en el momento de incorporarse al estudio.
    2. Los pacientes deben ser capaces de comprender y otorgar el consentimiento informado por escrito.
    3. Las mujeres en edad fértil (MEF) deberán tener una prueba de embarazo en suero negativa (sensibilidad mínima de 25 UI/l o unidades equivalentes de gonadotropina coriónica humana [HCG]) en la selección y una prueba de embarazo en suero u orina negativa en las 24 horas previas a la administración. Las mujeres en edad fértil y los varones que mantengan relaciones sexuales con mujeres en edad fértil deberán comprometerse a utilizar métodos anticonceptivos.
    4. Diagnóstico confirmado histológicamente de un cáncer localmente avanzado (no susceptible de tratamiento curativo, como la resección quirúrgica) o metastásico de las siguientes histologías: CECC o CCR.
    5. Los pacientes que hayan recibido previamente cetuximab u otros tratamientos dirigidos contra el EGFR quedan excluidos de la fase 2 del ensayo, a menos que el cetuximab se haya administrado como parte de una estrategia de tratamiento primario y no haya habido progresión de la enfermedad durante al menos 4 meses después del final del tratamiento previo con cetuximab.
    6. Esperanza de vida >12 semanas, determinada por el investigador.
    7. Estado funcional de 0 o 1 del Eastern Cooperative Oncology Group (ECOG).
    8. Enfermedad mensurable conforme a los criterios RECIST 1.1.
    9. Los pacientes deberán haber mostrado una función orgánica adecuada durante la selección:
    a. Filtración glomerular estimada ≥40 ml/min/1,73 m2 calculada mediante la ecuación de creatinina de la Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI).
    Criterios de inclusión para cada tipo de tumor específico
    • Cáncer de cabeza y cuello
    1. Los pacientes deben tener CECC avanzado, recurrente o metastásico, confirmado histológica o citológicamente, que no pueda tratarse con intención curativa. “Avanzado” se define como un CECC localmente avanzado no susceptible de cirugía ni radioterapia curativas o con metástasis a distancia.
    2. Progresión (o toxicidad que impida el tratamiento adicional) con cualquier quimioterapia basada en platino de primera o segunda línea y/o con anticuerpos anti-PD-1 o anti-PD-L1 (ligando 1 de muerte celular programada), denominados conjuntamente anti-PD-(L)1.
    3. Los pacientes que hayan sido tratados con anticuerpos anti-PD-(L)1 deberán haber recibido la última dosis del anticuerpo al menos 4 semanas antes y presentar signos de progresión tumoral antes de poder ser incluidos en este estudio.
    4. Pacientes que no sean aptos para quimioterapia basada en platino (cisplatino o carboplatino) o quimiorradioterapia debido a deterioro de la función renal y/o intolerancia del paciente.
    5. Deben tener un estado conocido mediante anatomía patológica en relación con el virus del papiloma humano (VPH) y el virus de Epstein-Barr (VEB) en el CECC, ya sea metastásico o recurrente.
    • Cáncer colorrectal
    1. Los pacientes deben tener un diagnóstico de CCR avanzado confirmado histológica o citológicamente; los pacientes de la fase 2 deberán tener un CCR avanzado con expresión de EGFR y KRAS no mutado confirmado. “Avanzado” se define como cáncer irresecable localmente avanzado o enfermedad metastásica.
    2. Los pacientes deben haber recibido o no haber tolerado al menos dos tratamientos antineoplásicos previos administrados para la enfermedad metastásica.
    3. Los pacientes con tumores que presenten inestabilidad de microsatélites alta (MSI-H) o deficiencia en la reparación de errores de emparejamiento (dMMR) deben haber estado expuestos a inhibidores de puntos de control, como anticuerpos anti-PD-(L)1 o anti-proteína asociada a los linfocitos T citotóxicos-4 (CTLA-4).
    E.4Principal exclusion criteria
    1.Use of an IMP or an investigational device within 28 days before administration of first dose of study drug(s)
    2.Active, known, or suspected autoimmune disease. Patients requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease that requires systemic corticosteroids or immunosuppressive.
    3.History of allergy or known hypersensitivity to murine protein or study drug components
    4.History of organ transplant that requires ongoing use of immunosuppressive agents
    5.Patients who have been previously treated with IL-2 or IL-15
    6.Patients with HNSCC who require treatment with anticoagulation therapy are not eligible.
    7.Contraindication to or unable to receive cetuximab
    8.Patient has had prior Grade 4 IRR to cetuximab
    9.Unresolved toxicity from previous anti-cancer therapy, unless resolved to Grade ≤ 1; or resolved to Grade 2; or resulting from incomplete recovery from surgery
    10.Prior surgery or radiotherapy within 14 days of initiating study drug(s). Patients must have recovered from all radiation-related toxicities.
    11.Patients participating in observational studies should be discussed with the Medical Monitor to confirm eligibility.
    12.Patients who have had < 28 days since the last anti-cancer treatment, chemotherapy or biological therapy, or < 14 days from approved tyrosine kinase inhibitor therapy, or systemic or inhaled steroid therapy at doses greater than 10 mg of prednisone or equivalent before administration of the first dose of study drug(s).
    13.Patients who have received systemic interferon alpha within the previous 6 months prior to enrollment in the study are not eligible.
    14.Active infection requiring systemic therapy within 7 days prior to dosing
    15.Evidence of clinically significant interstitial lung disease or active, noninfectious pneumonitis
    16.Known immunodeficiency or active human immunodeficiency virus (HIV)
    17.Known to be seropositive or active for hepatitis B or hepatitis C
    18.QTcF> 450 ms for men and > 470 ms for women at Screening
    19. History of unstable or deteriorating cardiac disease within the previous 6 months prior to Screening
    20.Has a known additional malignancy that is progressing or requires active treatment, exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cervical cancer.
    21.Patient has any of the following laboratory test results during Screening:
    a.AST and ALT level ≥ 2.5 times ULN;
    b.Alkaline phosphatase level ≥ 2.5 × ULN;
    c.Total bilirubin level ≥ 2 × ULN;
    d.Potassium level < 3.0 mEq/L; or
    e.Corrected serum calcium > 14.0 mg/dL (3.5 mmol/L)
    22.Patient is a woman who is pregnant or breastfeeding or planning to become pregnant while enrolled in this study or within 4 weeks after the last dose of NKTR-255 or within 2 months after the last dose of cetuximab.
    23.Active brain metastases or leptomeningeal metastases patients with brain metastases are eligible if these have been treated and there is no radiographic evidence of progression for at least 4 weeks after treatment is complete. There must also be no requirement for immunosuppressive doses of systemic corticosteroids for at least 4 weeks prior to study treatment. Stable dose of anticonvulsants is required within 14 days prior to study treatment. Treatment for central nervous system metastases may include stereotactic radiosurgery or neurosurgical resection. Patients who received whole brain radiation therapy are not eligible.
    24.Patients with hypertension must be on a stable anti-hypertensive regimen for the 14 days prior to study treatment; Screening blood pressure must be < 150 mmHg for systolic blood pressure and < 90 mmHg for diastolic blood.
    25.Known current drug or alcohol abuse
    26.Any condition including medical, emotional, psychiatric, or logistical that, in the opinion of the Investigator, would preclude the patient from adhering to the protocol
    1. Uso de un PEI o un dispositivo en investigación en los 28 días previos a la administración de la primera dosis de los fármacos del estudio.
    2. Confirmación o sospecha de enfermedad autoinmunitaria activa. Pacientes que hayan precisado tratamiento sistémico en los últimos 3 meses o que tengan antecedentes documentados de una enfermedad autoinmunitaria clínicamente grave con necesidad de corticosteroides sistémicos o inmunosupresores.
    3. Antecedentes de alergia o hipersensibilidad conocida a proteínas murinas o a los componentes del fármaco del estudio.
    4. Antecedentes de trasplante de órgano que obliga a seguir usando inmunosupresores.
    5. Pacientes tratados previamente con IL-2 o IL-15.
    6. No serán elegibles los pacientes con CECC que necesiten tratamiento anticoagulante.
    7. Contraindicación o imposibilidad de recibir cetuximab.
    8. El paciente ha tenido una RRI de grado 4 previa a cetuximab.
    9. Toxicidad no resuelta de un tratamiento antineoplásico previo, a menos que haya mejorado hasta un grado ≤1, haya mejorado hasta un grado 2 o sea consecuencia de una recuperación incompleta de la intervención quirúrgica.
    10. Cirugía o radioterapia previa en los 14 días previos al inicio de los fármacos del estudio. Los pacientes deberán haberse recuperado de todas las toxicidades relacionadas con la radioterapia.
    11. En los pacientes que estén participando en estudios observacionales, se deberá comentar el caso con el monitor médico para confirmar la elegibilidad.
    12. Pacientes para los que hayan transcurrido menos de 28 días desde el último tratamiento antineoplásico, quimioterapia o tratamiento biológico, o menos de 14 días desde el tratamiento aprobado con inhibidores de la tirosina cinasa o el tratamiento con esteroides sistémicos o inhalados en dosis superiores a 10 mg de prednisona o equivalente antes de la administración de la primera dosis del fármaco o fármacos del estudio.
    13. No serán elegibles los pacientes que hayan recibido interferón alfa sistémico en los 6 meses previos a la inclusión en el estudio.
    14. Infección activa con necesidad de tratamiento sistémico en los 7 días previos a la administración.
    15. Signos de enfermedad pulmonar intersticial o neumonitis no infecciosa activa clínicamente importantes.
    16. Inmunodeficiencia conocida o virus de la inmunodeficiencia humana (VIH) activo.
    17. Seropositividad o infección activa por hepatitis B o C conocidas.
    18. QTcF >450 ms en varones y >470 ms en mujeres en el momento de la selección.
    19. Antecedentes de cardiopatía inestable o en deterioro en los 6 meses previos a la selección.
    20. Presencia de otra neoplasia maligna conocida que esté en progresión o precise tratamiento activo; son excepciones el carcinoma basocelular de piel, el carcinoma espinocelular de piel para el que se haya recibido un tratamiento potencialmente curativo y el cáncer de cuello uterino in situ.
    21. El paciente presenta alguno de los siguientes resultados analíticos durante la selección:
    a. Concentración de AST y ALT ≥2,5 veces el LSN.
    b. Concentración de fosfatasa alcalina ≥2,5 veces el LSN.
    c. Concentración de bilirrubina total ≥2 veces el LSN.
    d. Concentración de potasio <3,0 mEq/l; o
    e. Calcio sérico corregido >14,0 mg/dl (3,5 mmol/l).
    22. El paciente es una mujer que está embarazada o en periodo de lactancia o que planea quedarse embarazada durante su participación en este estudio o en las 4 semanas siguientes a la última dosis de NKTR-255 o en los 2 meses siguientes a la última dosis de cetuximab.
    23. Los pacientes con metástasis cerebrales o metástasis leptomeníngeas activas con metástasis cerebrales podrán participar si han recibido tratamiento y no hay signos radiológicos de progresión durante al menos 4 semanas después de finalizar el tratamiento. Tampoco debe haber necesidad de dosis inmunosupresoras de corticosteroides sistémicos durante al menos 4 semanas antes del tratamiento del estudio. Es obligatoria una dosis estable de antiepilépticos en los 14 días previos al tratamiento del estudio. El tratamiento para las metástasis del sistema nervioso central puede incluir radiocirugía estereotáctica o resección neuroquirúrgica. No podrán participar los pacientes que hayan recibido radioterapia cerebral total.
    24. Los pacientes con hipertensión deben estar recibiendo un régimen antihipertensivo estable durante los 14 días previos al tratamiento del estudio; en la selección, la presión arterial sistólica debe ser <150 mm Hg y la presión arterial diastólica <90 mm Hg.
    25. Alcoholismo o toxicomanía actuales conocidos.
    26. Cualquier trastorno médico, emocional o psiquiátrico o problema logístico que, en opinión del investigador, impida al paciente cumplir el protocolo.
    E.5 End points
    E.5.1Primary end point(s)
    1. Incidence of Treatment-Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) of NKTR-255 with Cetuximab:
    Safety and tolerability of NKTR-255 in combination with cetuximab as evaluated by dose limiting toxicities, incidence of drug-related Adverse Events (AEs), SAEs, and AEs leading to discontinuation, deaths, and clinical laboratory abnormalities per CTCAE 5.0

    2.Efficacy of NRTR-255 with Cetuximab:
    Efficacy of NKTR-255 in combination with cetuximab in R/R metastatic HNSCC or CRC by assessing the objective response rate (ORR) by RECIST 1.1
    1. Incidencia de acontecimientos adversos aparecidos durante el tratamiento (AAAT) y acontecimientos adversos graves (AAG) de NKTR-255 con cetuximab:
    Seguridad y tolerabilidad de NKTR-255 en combinación con cetuximab, evaluadas mediante toxicidades limitante de la dosis, incidencia de acontecimientos adversos (AA) relacionados con el fármaco, AAG y AA que motiven la suspensión del tratamiento, muertes y anomalías analíticas según los CTCAE 5.0.

    2. Eficacia de NKTR-255 con cetuximab:
    Eficacia de NKTR-255 en combinación con cetuximab en el CECC o CCR metastásico R/R mediante la evaluación de la tasa de respuesta objetiva (TRO) conforme a los criterios RECIST 1.1.
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Safety and tolerability: throughout the trial till 60 days after the last dose of study treatment
    2. Efficacy: Through study completion, an expected average of 1 year
    1. Seguridad y tolerabilidad: durante todo el ensayo y hasta 60 días después de la última dosis del tratamiento del estudio.
    2. Eficacia: Hasta la finalización del estudio; se prevé una duración media de 1 año (TRO).
    E.5.2Secondary end point(s)
    Efficacy of NKTR-255 with Cetuximab:
    Evaluate the anti-tumor activity of the combination of NKTR-255 and cetuximab by assessing progression-free survival (PFS) and overall survival (OS).
    Eficacia de NKTR-255 con cetuximab: Evaluar la actividad antitumoral de la combinación de NKTR-255 y cetuximab mediante la evaluación de la supervivencia libre de progresión (SLP) y la supervivencia global (SG).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Through study completion, an expected average of 1 year
    Hasta la finalización del estudio; se prevé una duración media de 1 año.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    1b
    1b
    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 Yes
    E.8.1.7.1Other trial design description
    ESCALADA DE DOSIS Y AMPLIACIÓN DE LA DOSIS
    DOSE ESCALATION AND DOSE EXPANSION
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA8
    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
    United States
    France
    Italy
    Spain
    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
    End of study is defined as no more than 2 years after the last patient received his or her last dose of NKTR-255 or Sponsor decision to terminate the study, whichever comes first.
    El final del estudio se define como un máximo de 2 años después de que el último paciente reciba su última dosis de NKTR-255 o como la decisión del promotor de poner fin al estudio, lo que ocurra antes.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 51
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 27
    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 state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 12
    F.4.2.2In the whole clinical trial 78
    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 Decision2021-11-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-09-22
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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