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    Summary
    EudraCT Number:2020-005016-21
    Sponsor's Protocol Code Number:FW-2020-1
    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:2021-07-30
    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 number2020-005016-21
    A.3Full title of the trial
    A Phase 1/2 Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of CM24 in combination with nivolumab in adults with advanced solid tumours
    Estudio de fase I/II para evaluar la seguridad, tolerabilidad, farmacocinética, farmacodinámica y eficacia de CM24 en combinación con nivolumab en adultos con tumores sólidos avanzados
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to evaluate CM24 in combination with nivolumab in adults with solid tumours
    Estudio para evaluar CM24 en combinación con nivolumab en adultos con tumores sólidos
    A.4.1Sponsor's protocol code numberFW-2020-1
    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 SponsorFamewave Ltd.
    B.1.3.4CountryIsrael
    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 supportFamewave Ltd.
    B.4.2CountryIsrael
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFamewave Ltd.
    B.5.2Functional name of contact pointMichael Schickler
    B.5.3 Address:
    B.5.3.1Street Address4 Oppenheimer Street, Science Park
    B.5.3.2Town/ cityRehovot
    B.5.3.3Post code7670104
    B.5.3.4CountryIsrael
    B.5.4Telephone number+97239333121
    B.5.6E-mailmichaels@purple-biotech.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.3.2Product code CM24
    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 INNCM24
    D.3.9.3Other descriptive nameHumanised IgG4k monoclonal antibody against Carcinoembryonic antigen-related cell adhesion molecule 1
    D.3.9.4EV Substance CodeSUB224042
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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 Opdivo®
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    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 nameNivolumab
    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 INNNivolumab
    D.3.9.3Other descriptive nameNIVOLUMAB
    D.3.9.4EV Substance CodeSUB122750
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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: 3
    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 ABRAXANE®
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene 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 nameNab-paclitaxel
    D.3.4Pharmaceutical form Powder for suspension for injection
    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 INNNab-paclitaxel
    D.3.9.3Other descriptive namePACLITAXEL ALBUMIN-BOUND
    D.3.9.4EV Substance CodeSUB127678
    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 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
    Part A- Recurrent and metastatic non-small cell lung cancer (NSCLC), pancreatic cancer, ovarian cancer, papillary thyroid cancer, colorectal adenocarcinoma and melanoma
    Part B- Recurrent or metastatic immune checkpoint refractory NSCLC
    Part C- Metastatic pancreatic cancer
    Parte A- Cáncer de pulmón no microcítico (CPNM) metastásico y recurrente, cáncer de páncreas, cáncer de ovario, cáncer papilar tiroideo, adenocarcinoma colorrectal y melanoma
    Parte B- CPNM resistente a los puntos de control inmunitario recurrente o metastásico
    Parte C- Cáncer de páncreas metastásico
    E.1.1.1Medical condition in easily understood language
    Different types of cancers
    Diferentes tipos de cánceres
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10033604
    E.1.2Term Pancreatic cancer
    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 PT
    E.1.2Classification code 10033128
    E.1.2Term Ovarian cancer
    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 21.1
    E.1.2Level PT
    E.1.2Classification code 10061873
    E.1.2Term Non-small cell lung cancer
    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 24.0
    E.1.2Level PT
    E.1.2Classification code 10033701
    E.1.2Term Papillary thyroid cancer
    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 21.1
    E.1.2Level PT
    E.1.2Classification code 10025650
    E.1.2Term Malignant melanoma
    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 10052360
    E.1.2Term Colorectal adenocarcinoma
    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
    Part A
    • To assess the safety, tolerability and the maximum tolerated dose (MTD) of CM24 in combination with 480mg nivolumab in adults with selected recurrent or metastatic solid tumors.
    • Determine the recommended Phase 2 dose level (RP2D) of CM24 in combination with nivolumab

    Part B
    To assess the efficacy of the recommended phase 2 dose (RP2D) of CM24 in combination with nivolumab in adults with immune-checkpoint refractory recurrent or metastatic NSCLC based on Objective Response Rate (ORR).

    Part C
    To assess the efficacy of CM24 in combination with nivolumab and nabpaclitaxel in adults with metastatic pancreatic cancer based on Objective Response Rate.
    Parte A
    • Evaluar la seguridad, la tolerabilidad y la dosis máxima tolerada (DMT) de CM24 en combinación con 480 mg de nivolumab en adultos con determinados tumores sólidos recidivantes o metastásicos.
    • Determinar el nivel de dosis recomendado para la fase II (DRF2) de CM24 en combinación con nivolumab.

    Parte B
    Evaluar la eficacia de la dosis recomendada para la fase II (DRF2) de CM24 en combinación con nivolumab en adultos con CPNM metastásico o recidivante resistente a los puntos de control inmunológico según la tasa de respuesta objetiva.

    Parte C
    Evaluar la eficacia de CM24 en combinación con nivolumab y nabpaclitaxel en adultos con cáncer de páncreas metastásico en función de la tasa de respuesta objetiva.
    E.2.2Secondary objectives of the trial
    Part A
    1. Characterize the pharmacokinetic profile of CM24 in combination with nivolumab.
    2. Characterize the immunogenicity of CM24 in combination with nivolumab.
    3. To assess the preliminary efficacy of different dose levels of CM24 in combination with nivolumab:
    o Objective response rate (ORR)
    o Disease control rate (DCR)
    o Median duration of response (DoR)
    o Median time to response
    o 6, 12 and 18 month and median progression free survival (PFS)
    o 6, 12, 18 months and median overall survival (OS)

    Part B
    1. To further assess the efficacy of the RP2D of CM24 in combination with nivolumab based on, but not limited to:
    o Disease control rate (DCR)
    o Median duration of response (DoR)
    o Median time to response

    Part C
    1. To further assess the efficacy of CM24 in combination with nivolumab and nab-paclitaxel based on, but not limited to:
    o Disease control rate (DCR)
    Parte A
    1. Caracterizar el perfil farmacocinético de CM24 en combinación con nivolumab. 2. Caracterizar la inmunogenicidad de CM24 en combinación con nivolumab. 3. Evaluar la eficacia preliminar de diferentes niveles de dosis de CM24 en combinación con nivolumab:
    o Tasa de respuesta objetiva (TRO)
    o Tasa de control de la enfermedad (TCE)
    o Mediana de duración de la respuesta (DR)
    o Mediana del tiempo hasta la respuesta (THR)
    o 6, 12 y 18 meses y mediana de supervivencia sin progresión (SSP)
    o 6, 12, 18 meses y mediana de supervivencia global (SG)

    Parte B
    1. Evaluar más a fondo la eficacia de la DRF2 de CM24 en combinación con nivolumab en función de, pero no limitado a:
    o La tasa de control de la enfermedad (TCE)
    o La duración media de la respuesta
    o El tiempo medio hasta la respuesta

    Parte C
    1. Evaluar más a fondo la eficacia de CM24 en combinación con nivolumab y nab-paclitaxel en función de, pero no limitado a:
    o La tasa de control de la enfermedad (TCE)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Part A
    1. Previously treated subjects with recurrent and metastatic NSCLC, pancreatic cancer, ovarian cancer, papillary thyroid cancer, colorectal adenocarcinoma and melanoma with documented progression/intolerance following at least one previous therapy (and not more than 2 previous regimens).
    2. Adequate safety lab results at Screening and at Baseline (Day 1) for those tests that require repeating at Baseline, including the following:
    a. Albumin ≥3 g/dL;
    b. Bilirubin ≤1.5 times the upper limit of normal (ULN) or <3 times the ULN in the case of Gilbert Syndrome;
    c. Aspartate aminotransaminase (AST), alanine aminotransaminase (ALT), and alkaline phosphatase ≤3 times the ULN;
    d. Serum creatinine ≤1.5xULN and creatinine clearance >40 mL/minute based on the Cockcroft-Gault equation [creatinine clearance in mL/min = (140 – age in years) x body weight (kg)/72 x serum creatinine (mg/dL); multiplied by 0.85 for women];
    e. White blood cell (WBC) count ≥2000/uL; neutrophils ≥1500/uL; hemoglobin ≥9 g/dL; platelets ≥100x103/uL.
    3. Brain metastases should be stable following radiosurgery with at least 4 weeks since the end of definitive therapy (i.e., radiotherapy) and without need for steroid therapy as evidenced by imaging performed after completion of any CNS directed therapy demonstrating radiographic stability of CNS lesions.
    4. Must have at least 1 measurable lesion per RECIST1.1 with progressing or new tumors since last antitumor therapy.
    5. Age ≥18 years at the time of signing ICF;

    Part B
    1. Subjects with histologically confirmed metastatic or locally advanced non-small cell lung cancer (NSCLC) with documented progression following anti-PD-1/PD-L1 containing therapy; Subjects must have confirmation of progression of disease that is consistent with iCPD during or within 3 months of prior anti-PD1/PDL1 with either two radiographic scans showing disease progression or documented clinical progression (e.g., worsening of symptoms).
    2. Subjects could have had a maximum of 1 prior treatment regimen.
    3. Adequate safety lab results at Screening and at Baseline (Day 1) for those tests that require repeating at Baseline, including the following:
    a. Albumin ≥3 g/dL;
    b. Bilirubin ≤1.5 times the upper limit of normal (ULN) or <3 times the ULN in the case of Gilbert Syndrome;
    c. Aspartate aminotransaminase (AST), alanine aminotransaminase (ALT), and alkaline phosphatase ≤3 times the ULN;
    d. Serum creatinine ≤1.5xULN and Creatinine clearance >40 mL/minute based on the Cockcroft-Gault equation [creatinine clearance in mL/min = (140 – age in years) x body weight (kg)/72 x serum creatinine (mg/dL); multiplied by 0.85 for women];
    e. White blood cell (WBC) count ≥2000/uL; neutrophils ≥1500/uL; hemoglobin ≥9 g/dL; platelets ≥100x103/uL.
    4. Brain metastases should be stable following radiosurgery with at least 4 weeks since the end of definitive therapy (i.e., radiotherapy) and without need for steroid therapy as evidenced by imaging performed after completion of any CNS directed therapy demonstrating radiographic stability of CNS lesions.
    5. Must have at least 1 measurable lesion per RECIST1.1 with progressing or new tumors since last antitumor therapy.

    Part C
    1. Subjects with histologically confirmed metastatic pancreatic adenocarcinoma as defined by NCCN Guidelines; Subjects with islet cell neoplasms are excluded.
    2. Subjects with a maximum of 1 prior treatment regimen for metastatic disease excluding nab-paclitaxel containing regimens and up to 8 weeks from last chemotherapy treatment; nab-paclitaxel completed more than 6 month prior to study is allowed.
    3. Adequate safety lab results at Screening and at Baseline (Day 1) for those tests that require repeating at Baseline, including the following:
    a. Albumin ≥3 g/dL;
    b. Bilirubin ≤1.5 times the upper limit of normal (ULN) or <3 times the ULN in the case of Gilbert Syndrome;
    c. Aspartate aminotransaminase (AST), alanine aminotransaminase (ALT), and alkaline phosphatase ≤3 times the ULN;
    d. Serum creatinine ≤1.5xULN and Creatinine clearance >40 mL/minute based on the Cockcroft-Gault equation [creatinine clearance in mL/min = (140 – age in years) x body weight (kg)/72 x serum creatinine (mg/dL); multiplied by 0.85 for women];
    e. White blood cell (WBC) count ≥2000/uL; neutrophils ≥1500/uL; hemoglobin ≥9 g/dL; platelets ≥100x103/uL.
    Parte A
    1. Sujetos tratados previamente con CPNM recidivante y/o metastásico, cáncer de páncreas, cáncer de ovario, cáncer papilar de tiroides, adenocarcinoma colorrectal y melanoma con progresión o intolerancia documentada después de al menos un tratamiento previo (y no más de 2 pautas previas).
    2. Resultados analíticos de seguridad adecuados en la selección y en el momento basal (día 1) para las pruebas que requieran una repetición en el momento basal, incluidos los siguientes:
    a. Albúmina ≥3 g/dl.
    b. Bilirrubina ≤1,5 veces el límite superior de la normalidad (LSN) o <3 veces el LSN en caso de síndrome de Gilbert.
    c. Aspartato aminotransferasa (AST), alanina aminotransferasa (ALT) y fosfatasa alcalina <3 veces el LSN.
    d. Creatinina sérica ≤1,5 veces el LSN y aclaramiento de creatinina >40 ml/min según la ecuación de Cockcroft-Gault [aclaramiento de creatinina en ml/min = (140 - edad en años) x peso corporal (kg)/72 x creatinina sérica (mg/dl) multiplicado por 0,85 en las mujeres].
    e. Recuento de leucocitos ≥2000/μl; neutrófilos ≥1500/μl; hemoglobina ≥9 g/dl; plaquetas ≥100 x 103/μl.
    3. Las metástasis cerebrales deben permanecer estables después de la radiocirugía con al menos 4 semanas desde el final del tratamiento definitivo (radioterapia) y sin necesidad de tratamiento con esteroides, como demuestran los estudios de imagen realizados después de finalizar cualquier tratamiento dirigido al SNC que demuestren la estabilidad radiológica de las lesiones del SNC.
    4. Presencia de al menos una lesión mensurable, conforme a los criterios RECIST 1.1, con tumores en progresión o nuevos desde el último tratamiento antitumoral.
    5. Edad ≥18 años en el momento de firmar el DCI.

    Parte B
    1. Sujetos con cáncer de pulmón no microcítico (CPNM) metastásico o localmente avanzado confirmado histológicamente con progresión documentada después de un tratamiento que contenga anti-PD-1/PD-L1. Los sujetos deberán tener confirmación de la progresión de la enfermedad ocurrida durante el tratamiento, o en el plazo de los 3 meses siguientes, anti-PD-1/PD-L1 previo con dos estudios radiológicos que muestren progresión de la enfermedad o progresión clínica documentada (p. ej., empeoramiento de los síntomas).
    2. Los sujetos podían haber recibido un máximo de 1 pauta de tratamiento previa.
    3. Resultados analíticos de seguridad adecuados en la selección y en el momento basal (día 1) para las pruebas que requieran una repetición en el momento basal, incluidos los siguientes:
    a. Albúmina ≥3 g/dl.
    b. Bilirrubina ≤1,5 veces el límite superior de la normalidad (LSN) o <3 veces el LSN en caso de síndrome de Gilbert.
    c. Aspartato aminotransferasa (AST), alanina aminotransferasa (ALT) y fosfatasa alcalina ≤3 veces el LSN.
    d. Creatinina sérica <1,5 veces el LSN y aclaramiento de creatinina >40 ml/min según la ecuación de Cockcroft-Gault [aclaramiento de creatinina en ml/min = (140 - edad en años) x peso corporal (kg)/72 x
    creatinina sérica (mg/dl); multiplicado por 0,85 en las mujeres].
    e. Recuento de leucocitos ≥2000/μl; neutrófilos ≥1500/μl; hemoglobina ≥9 g/dl; plaquetas ≥100 x 103/μl.
    4. Las metástasis cerebrales deben permanecer estables después de la radiocirugía con al menos 4 semanas desde el final del tratamiento definitivo (radioterapia) y sin necesidad de tratamiento con esteroides, como demuestran los estudios de imagen realizados después de finalizar cualquier tratamiento dirigido al SNC que demuestren la estabilidad radiológica de las lesiones del SNC.
    5. Presencia de al menos una lesión mensurable, conforme a los criterios RECIST 1.1, con tumores en progresión o nuevos desde el último tratamiento antitumoral.

    Parte C
    1. Sujetos con adenocarcinoma de páncreas metastásico confirmado histológicamente conforme a las directrices de la NCCN; quedan excluidos los sujetos con neoplasias de células de los islotes.
    2. Sujetos con un máximo de 1 pauta de tratamiento previa para la enfermedad metastásica, excluidas las pautas que contengan nab-paclitaxel, y hasta 8 semanas después del último tratamiento quimioterápico; se permite la administración de nab-paclitaxel más de 6 meses antes del estudio.
    3. Resultados analíticos de seguridad adecuados en la selección y en el momento basal (día 1) para las pruebas que requieran una repetición en el momento basal, incluidos los siguientes:
    a. Albúmina ≥3 g/dl.
    b. Bilirrubina ≤1,5 veces el límite superior de la normalidad (LSN) o <3 veces el LSN en caso de síndrome de Gilbert.
    c. Aspartato aminotransferasa (AST), alanina aminotransferasa (ALT) y fosfatasa alcalina ≤3 veces el LSN.
    d. Creatinina sérica <1,5 veces el LSN y aclaramiento de creatinina >40 ml/min según la ecuación de Cockcroft-Gault [aclaramiento de creatinina en ml/min = (140 - edad en años) x peso corporal (kg)/72 x
    creatinina sérica (mg/dl); multiplicado por 0,85 en las mujeres].
    e. Recuento de leucocitos ≥2000/μl; neutrófilos ≥1500/μl; hemoglobina ≥9 g/dl; plaquetas ≥100 x 103/μl.
    E.4Principal exclusion criteria
    Part A
    1. History of weight loss >10% over the 2 months prior to Screening.
    2. Received more than two prior systemic regimens for the metastatic disease.
    3. Unresolved AEs > Grade 1 from prior anticancer therapy. Exempted are effects that are often non-reversible or require a prolonged time for reversal (e.g., alopecia, hypothyroidism, neuropathy).
    4. Concurrent malignancy requiring treatment. Participants with a previously treated malignancy are eligible if treatment was completed at least 2 years before study start and the patient has no evidence of disease. Participants who have a concurrent malignancy that is clinically stable and does not require tumor-directed treatment or with a history of prior early stage basal/squamous cell skin cancer or non-invasive or in situ cancers that have undergone definitive treatment at any time are also eligible.
    5. Active, untreated central nervous system (CNS) metastases.
    6. Subjects previously treated with an anti PD-1/PD-L1 targeting agent with history immune mediated toxicity of ≥ Grade 3, treatment of their toxicity with systemic corticosteroids, or any hypersensitivity to PD-1/PDL-1 targeting agents or any other antibody or drug specifically targeting T cell co-stimulation or immune checkpoint pathways.
    7. Severely immunocompromised as defined by white blood cell (WBC) count <2000/mm3 and/or CD4+ lymphocyte count ≤200/mm3.
    8. History of allergy or hypersensitivity to any of the study treatment components
    9. Major surgery within 4 weeks of study administration.
    10. Participants who have received a live / attenuated vaccine within 30 days of first treatment;
    11. Subjects with serious or uncontrolled medical disorders other than the metastatic disease;
    12. Any condition which, in the opinion of the PI, places the subject at unacceptable risk if he/she were to participate in the study.

    Parts B and C
    1. History of weight loss >10% over the 2 months prior to Screening;
    2. Received more than 1 prior systemic regimens for the advanced/recurrent and/or metastatic disease;
    3. Unresolved AEs > Grade 1 from prior anticancer therapy. Exempted are effects that are often non-reversible or require a prolonged time for reversal (e.g., alopecia, hypothyroidism, neuropathy).
    4. Concurrent malignancy requiring treatment. Participants with a previously treated malignancy are eligible if treatment was completed at least 2 years before study start and the patient has no evidence of disease. Participants who have a concurrent malignancy that is clinically stable and does not require tumor-directed treatment or with a history of prior early stage basal/squamous cell skin cancer or non-invasive or in situ cancers that have undergone definitive treatment at any time are also eligible.
    5. Active and/or untreated central nervous system (CNS) metastases including leptomeningeal metastases;
    6. Severely immunocompromised as defined by white blood cell (WBC) count <2000/mm3 and/or CD4+ lymphocyte count ≤200/mm3.
    7. History of allergy or hypersensitivity to any of the study treatment components; subjects previously treated with an anti PD-1/PD-L1 targeting agent with history of immune-mediated toxicity of ≥ Grade 3 treatment of their toxicity with systemic corticosteroids, or any hypersensitivity to PD-1/PD-L1 targeting agents or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways.
    8. Major surgery within 4 weeks of study administration;
    9. Participants who have received a live / attenuated vaccine within 30 days of first treatment.
    10. Subjects with serious or uncontrolled medical disorders other than the recurrent/metastatic disease.
    11. Any condition which, in the opinion of the PI, places the subject at unacceptable risk if he/she were to participate in the study.
    Parte A
    1. Antecedentes de pérdida de peso >10 % en los 2 meses previos a la selección.
    2. Haber recibido más de dos tratamientos sistémicos previos para la enfermedad metastásica.
    3. EA no resueltos de grado >1 con el tratamiento antineoplásico previo. Se excluyen los efectos que a menudo sean irreversibles o que requieran un tiempo prolongado para revertir la reacción (p. ej., alopecia, hipotiroidismo, neuropatía).
    4. Neoplasia maligna concurrente con necesidad de tratamiento. Podrán participar pacientes con una neoplasia maligna tratada previamente si el tratamiento se completó al menos 2 años antes del comienzo del estudio y el paciente no presenta signos de enfermedad. También podrán participar pacientes con una neoplasia maligna concurrente que se encuentre clínicamente estable y no requiera tratamiento dirigido al tumor, o con antecedentes de cáncer basocelular o espinocelular de piel en estadio inicial previo o cánceres no invasivos o in situ que se hayan sometido a tratamiento definitivo en cualquier momento.
    5. Metástasis activas en el sistema nervioso central (SNC) no tratadas
    6. Sujetos tratados previamente con un fármaco dirigido contra PD- 1/PD-L1 que tengan antecedentes de toxicidad inmunitaria de grado ≥3 con corticosteroides sistémicos, o cualquier hipersensibilidad a fármacos dirigidos contra PD-1/PD-L1 o a cualquier otro anticuerpo o fármaco dirigido específicamente contra la coestimulación de los linfocitos T o las vías de los puntos de control inmunológico.
    7. Inmunodepresión grave, definida como un recuento de leucocitos <2000/mm3 o un recuento de linfocitos CD4+ ≤200/mm3.
    8. Antecedentes de alergia o hipersensibilidad a cualquiera de los componentes del tratamiento del estudio.
    9. Intervención de cirugía mayor en las 4 semanas previas a la administración del fármaco del estudio.
    10. Participantes que hayan recibido una vacuna de microorganismos vivos/atenuados en los 30 días previos al primer tratamiento.
    11. Sujetos con trastornos médicos graves o no controlados distintos de la enfermedad metastásica.
    12. Cualquier trastorno que, en opinión del IP, suponga un riesgo inaceptable para el paciente si participase en el estudio.

    Partes B y C
    1. Antecedentes de pérdida de peso >10 % en los 2 meses previos a la selección.
    2. Haber recibido más de 1 tratamiento sistémico previos para la enfermedad recidivante/metastásica.
    3. EA no resueltos de grado >1 con el tratamiento antineoplásico previo. Se excluyen los efectos que a menudo sean irreversibles o que requieran un tiempo prolongado para revertir la reacción (p. ej., alopecia, hipotiroidismo, neuropatía).
    4. Neoplasia maligna concurrente con necesidad de tratamiento. Podrán participar pacientes con una neoplasia maligna tratada previamente si el tratamiento se completó al menos 2 años antes del comienzo del estudio y el paciente no presenta signos de enfermedad. También podrán participar pacientes con una neoplasia maligna concurrente que se encuentre clínicamente estable y no requiera tratamiento dirigido al tumor, o con antecedentes de cáncer basocelular o espinocelular de piel en estadio inicial previo o cánceres no invasivos o in situ que se hayan sometido a tratamiento definitivo en cualquier momento.
    5. Metástasis activas y/o no tratadas en el sistema nervioso central (SNC), incluidas metástasis leptomeníngeas.
    6. Inmunodepresión grave, definida como un recuento de leucocitos <2000/mm3 o un recuento de linfocitos CD4+ ≤200/mm3.
    7. Antecedentes de alergia o hipersensibilidad a cualquiera de los componentes del tratamiento del estudio. Sujetos tratados previamente con fármacos dirigidos contra PD-1/PD-L1 que hayan tenido antecedentes de toxicidad inmunitaria de grado ≥3, tratamiento de la toxicidad con corticosteroides sistémicos, o hipersensibilidad a fármacos dirigidos contra PD-1/PD-L1 o a cualquier otro anticuerpo o fármaco dirigido específicamente contra la coestimulación de los linfocitos T o vías de puntos de control inmunológico.
    8. Intervención de cirugía mayor en las 4 semanas previas a la administración del fármaco del estudio.
    9. Participantes que hayan recibido una vacuna de microorganismos vivos/atenuados en los 30 días previos al primer tratamiento.
    10. Sujetos con trastornos médicos graves o no controlados distintos de la enfermedad recidivante/metastásica.
    11. Cualquier trastorno que, en opinión del IP, suponga un riesgo inaceptable para el paciente si participase en el estudio.
    E.5 End points
    E.5.1Primary end point(s)
    Part A
    Safety and tolerability

    Parts B and C
    Objective response rate (ORR) based on RECIST Version 1.1
    Parte A
    Seguridad y tolerabilidad

    Partes B y C
    Tasa de respuesta objetiva (TRO) basada en RECIST versión 1.1
    E.5.1.1Timepoint(s) of evaluation of this end point
    Part A
    Following study drug administration on Day 1 and within 100 days of the last dose of CM24, nivolumab or nab-paclitaxel (whichever is last).

    Parts B and C
    Tumor imaging (either CT, PET/CT or MRI) will be performed at Screening, within 1 week following the completion of Cycle 2 (i.e., between 8 and 9 weeks from start of treatment) and approximately every 8 weeks (+1 week) thereafter up to 24 months from last treatment.
    Parte A
    Después de la administración del fármaco del estudio el día 1 y en los 100 días posteriores a la última dosis de CM24, nivolumab o nabpaclitaxel (el que sea último).

    Partes B y C
    Las imágenes tumorales (ya sea TAC, TEP/TAC o RM) se realizarán en la selección, en el plazo de 1 semana tras la finalización del ciclo 2 (es decir, entre 8 y 9 semanas desde el inicio del tratamiento) y aproximadamente cada 8 semanas (+1 semana) a partir de entonces hasta 24 meses desde el último tratamiento.
    E.5.2Secondary end point(s)
    Part A
    1. Serum PK parameters for CM24 following administration of CM24 in combination with nivolumab on Day 1 and Day 15 will be calculated if measurable serum levels are observed, and will include Cmax, Tmax, AUC0-T, AUC0-∞, t1/2, CL, and Vd.
    2. Serum ADA parameters for CM24 of on Day 1 of Cycle 1, 2 and 5 and the Study Follow up Visits; the proportion of subjects developing ADA will be determined. Positive ADA samples will be characterized for their ability to neutralize binding of CM24 to CEACAM1.
    3. Efficacy endpoints at different dose levels of CM24 in combination with nivolumab will include the following analyses (per dose level):
    o Objective response rate (ORR)
    o Disease control rate (DCR)
    o Median duration of response (DoR)
    o Median time to response (TTR)
    o 6, 12 and 18 month and median progression free survival (PFS)
    o 6, 12, 18 months and median overall survival (OS)

    Part B
    1. Efficacy based on disease control rate (DCR), duration of response (DoR) and time to response (TTR), median progression free survival (PFS) as well as 6, 12 and 18 month PFS and 6, 12, 18 month and median overall survival (OS). ORR, DCR, DoR, TTR and PFS endpoints will be determined based on CR, PR, SD and PD as defined by RECIST Version 1.1. Exploratory analyses of efficacy will be done based on iCR, iPR, iSD and iCPD as defined by iRECIST.
    2. Safety based on the same primary and secondary assessments described for the dose escalation phase, minus the MTD determination.
    Parte A
    1. Los parámetros FC séricos de CM24 tras su administración en combinación con nivolumab los días 1 y 15 se calcularán si se observan concentraciones séricas mensurables, e incluirán Cmáx, Tmáx, AUC0-T, AUG0-∞, t1/2, CL y Vd.
    2. Parámetros de ACF en suero correspondientes a CM24 el día 1 de los ciclos 1, 2 y 5 y en las visitas de seguimiento del estudio; se determinará la proporción de sujetos que presenten ACF. Las muestras positivas para ACF se caracterizarán por su capacidad para neutralizar la unión de CM24 a CEACAM1.
    3. Los criterios de valoración de la eficacia con diferentes niveles de dosis de CM24 en combinación con nivolumab incluirán los siguientes análisis (por nivel de dosis):
    o Tasa de respuesta objetiva (TRO)
    o Tasa de control de la enfermedad (TCE)
    o Mediana de duración de la respuesta (DR)
    o Mediana del tiempo hasta la respuesta (THR)
    o 6, 12 y 18 meses y mediana de supervivencia sin progresión (SSP)
    o 6, 12, 18 meses y mediana de supervivencia global (SG)

    Parte B
    1. Eficacia basada en la tasa de control de la enfermedad (TCE), la duración de la respuesta (DR) y el tiempo hasta la respuesta (THR), la mediana de la supervivencia sin progresión (SSP), así como la SSP a los 6, 12 y 18 meses, y la mediana de la supervivencia global (SG) a los 6, 12 y 18 meses. Los criterios de valoración de TRO, TCE, DR, THR y SSP se determinarán basándose en la RC, RP, EE y PE, según lo definido por los criterios RECIST, versión 1.1. Se realizarán análisis exploratorios de la eficacia basados en la RCi, RPi, EEi y PECi conforme a los criterios iRECIST.
    2. Seguridad basada en las mismas evaluaciones principales y secundarias descritas para la fase de aumento escalonado de la dosis, menos la determinación de la DMT.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Part A
    1. Cycle 1 Day 1, predose, within 5min postdose, 1.5 & 3h postdose, Day 2, 4, 8 & 15 predose, Day 15 within 5 min & 1.5h post dose; Day 1 on Cycle 2, 3, 5, 6, 7, 9, 13, 17, 21, 24 & on study follow up visits 30, 60 & 100 days post last treatment.
    2. Day 1 of Cycles 1, 2, 3, 5, 9, 13, 17, 21, 24.
    3. Screening, within 1 week following completion of Cycle 2 & approx. every 8 weeks thereafter.

    Part B
    1. Screening, within 1 week following the completion of Cycle 2 & every 8 weeks thereafter.
    2. Following study drug administration on Day 1 & within 100 days of the last dose.
    Parte A
    1. Día 1 del ciclo 1, antes de la dosis, en los 5 min posteriores a la dosis, 1,5 y 3 h después de la dosis, días 2, 4, 8 y 15 antes de la dosis, día 15 en los 5 min y 1,5 h después de la dosis; día 1 en los ciclos 2, 3, 5, 6, 7, 9, 13, 17, 21, 24 y en las visitas de seguimiento del estudio 30, 60 y 100 días después del último tratamiento.
    2. Día 1 de los ciclos 1, 2, 3, 5, 9, 13, 17, 21, 24.
    3. Selección, en el plazo de 1 semana tras la finalización del ciclo 2 y aproximadamente cada 8 semanas a partir de entonces.

    Parte B
    1. Selección, en el plazo de 1 semana tras la finalización del ciclo 2 y cada 8 semanas a partir de entonces.
    2. Después de la administración del fármaco del estudio el día 1 y dentro de los 100 días posteriores a la última dosis.
    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 No
    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
    Efficacy
    Eficacia
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States No
    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
    Israel
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    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 months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months4
    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: 60
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 14
    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 state22
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 22
    F.4.2.2In the whole clinical trial 74
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Following the last CM24 and/or nivolumab and/or nab-paclitaxel treatment, (whichever is last) an Investigational Site staff member will continue to follow up participants for survival via monthly (4 weeks ± 7 days) telephone calls for up to two years. These 24 months will include also the period during which the Study Follow up Visits will be performed.
    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 Decision2021-11-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-09-21
    P. End of Trial
    P.End of Trial StatusOngoing
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