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    Summary
    EudraCT Number:2021-003640-24
    Sponsor's Protocol Code Number:C4221023
    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:2023-03-24
    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 number2021-003640-24
    A.3Full title of the trial
    A PHASE 2, RANDOMIZED, OPEN-LABEL STUDY OF ENCORAFENIB AND BINIMETINIB PLUS PEMBROLIZUMAB VERSUS NIVOLUMAB AND IPILIMUMAB IN PARTICIPANTS WITH BRAF V600E/K MUTATION-POSITIVE MELANOMA WHO PROGRESSED DURING OR AFTER PRIOR TREATMENT WITH ANTI−PD-1 THERAPY
    ESTUDIO DE FASE II, ALEATORIZADO, ABIERTO, DE ENCORAFENIB Y BINIMETINIB MÁS PEMBROLIZUMAB FRENTE A NIVOLUMAB E IPILIMUMAB EN ARTICIPANTES CON MELANOMA POSITIVO PARA LA MUTACIÓN V600E/K EN BRAF QUE PROGRESÓ DURANTE O DESPUÉS DE UN TRATAMIENTO PREVIO CON ERAPIA ANTI-PD-1
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 2 Study of Encorafenib and Binimetinib Plus Pembrolizumab in Participants With BRAF V600E/K Mutation-Positive Melanoma Who Progressed During
    or After Prior Treatment with Anti−PD-1 Therapy
    Estudio de fase II de encorafenib y binimetinib más pembrolizumab en participantes con melanoma positivo para la mutación V600E/K en BRAF que progresó durante o después de un tratamiento previo con terapia anti-PD-1
    A.3.2Name or abbreviated title of the trial where available
    Portside
    A.4.1Sponsor's protocol code numberC4221023
    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 SponsorPfizer 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 supportPfizer Inc., 235 East 42nd Street, New York, NY 10017
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPfizer Inc.
    B.5.2Functional name of contact pointClinical Trials.gov Call Centre
    B.5.3 Address:
    B.5.3.1Street Address235 East 42nd Street
    B.5.3.2Town/ cityNew York
    B.5.3.3Post codeNY 10017
    B.5.3.4CountryUnited States
    B.5.4Telephone number+18007181021
    B.5.6E-mailClinicalTrials.gov_Inquiries@pfizer.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 Yes
    D.2.1.1.1Trade name BRAFTOVI®
    D.2.1.1.2Name of the Marketing Authorisation holderPierre Fabre Médicament
    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 nameEncorafenib
    D.3.2Product code PF-07263896
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNEncorafenib
    D.3.9.1CAS number 1269440-17-6
    D.3.9.2Current sponsor codePF-07263896
    D.3.9.4EV Substance CodeSUB177218
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number75
    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 Yes
    D.2.1.1.1Trade name MEKTOVI®
    D.2.1.1.2Name of the Marketing Authorisation holderPierre Fabre Médicament
    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 nameBinimetinib
    D.3.2Product code PF-06811462
    D.3.4Pharmaceutical form 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 INNBinimetinib
    D.3.9.1CAS number 606143-89-9
    D.3.9.2Current sponsor codePF-06811462
    D.3.9.4EV Substance CodeSUB179942
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP 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 KEYTRUDA®
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme 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 namePembrolizumab
    D.3.4Pharmaceutical form Concentrate 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 INNPembrolizumab
    D.3.9.1CAS number 1374853-91-4
    D.3.9.4EV Substance CodeSUB167136
    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 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: 4
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name 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 Concentrate 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 INNNivolumab
    D.3.9.1CAS number 946414-94-4
    D.3.9.4EV Substance CodeSUB122750
    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 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: 5
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Yervoy
    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 nameIpilimumab
    D.3.4Pharmaceutical form Concentrate 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 INNIpilimumab
    D.3.9.1CAS number 477202-00-9
    D.3.9.4EV Substance CodeSUB29397
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin 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: 6
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Yervoy
    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 nameIpilimumab
    D.3.4Pharmaceutical form Concentrate 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 INNIpilimumab
    D.3.9.1CAS number 477202-00-9
    D.3.9.4EV Substance CodeSUB29397
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin 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
    metastatic or unresectable locally advanced BRAF V600E/K mutation-positive melanoma
    Melanoma localmente avanzado irresecable o metastásico con mutación V600E/K de BRAF
    E.1.1.1Medical condition in easily understood language
    BRAF V600E/K Mutation-Positive Melanoma
    Melanoma positivo a la mutación V600/K de BRAF
    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 10040891
    E.1.2Term Skin 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 20.0
    E.1.2Level HLT
    E.1.2Classification code 10027156
    E.1.2Term Skin melanomas (excl ocular)
    E.1.2System Organ Class 100000004858
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10025671
    E.1.2Term Malignant melanoma stage IV
    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 21.1
    E.1.2Level LLT
    E.1.2Classification code 10025655
    E.1.2Term Malignant melanoma of skin
    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 10066600
    E.1.2Term Melanoma 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 21.1
    E.1.2Level PT
    E.1.2Classification code 10025670
    E.1.2Term Malignant melanoma stage III
    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 10027480
    E.1.2Term Metastatic 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 20.0
    E.1.2Level LLT
    E.1.2Classification code 10027150
    E.1.2Term Melanoma malignant
    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 LLT
    E.1.2Classification code 10048434
    E.1.2Term Melanoma malignant aggravated
    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 10027155
    E.1.2Term Melanoma skin
    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 10027152
    E.1.2Term Melanoma of skin (malignant)
    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 LLT
    E.1.2Classification code 10025658
    E.1.2Term Malignant melanoma of skin of eyelid, including canthus
    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 10025661
    E.1.2Term Malignant melanoma of skin of other and unspecified parts of face
    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 LLT
    E.1.2Classification code 10025663
    E.1.2Term Malignant melanoma of skin of trunk, except scrotum
    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 LLT
    E.1.2Classification code 10025660
    E.1.2Term Malignant melanoma of skin of lower limb, including hip
    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 LLT
    E.1.2Classification code 10025659
    E.1.2Term Malignant melanoma of skin of lip
    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 LLT
    E.1.2Classification code 10025656
    E.1.2Term Malignant melanoma of skin of ear and external auditory canal
    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 10025662
    E.1.2Term Malignant melanoma of skin of scalp and neck
    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 LLT
    E.1.2Classification code 10025664
    E.1.2Term Malignant melanoma of skin of upper limb, including shoulder
    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 10025653
    E.1.2Term Malignant melanoma of other specified sites of skin
    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 10027153
    E.1.2Term Melanoma of skin, site unspecified
    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 10025657
    E.1.2Term Malignant melanoma of skin of ear and external auricular canal
    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 10027481
    E.1.2Term Metastatic 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 20.0
    E.1.2Level LLT
    E.1.2Classification code 10027154
    E.1.2Term Melanoma of trunk and head
    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 LLT
    E.1.2Classification code 10025666
    E.1.2Term Malignant melanoma of the anus
    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 LLT
    E.1.2Classification code 10053571
    E.1.2Term 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 21.1
    E.1.2Level LLT
    E.1.2Classification code 10056768
    E.1.2Term Malignant melanoma of skin of lower limb, incl hip
    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 LLT
    E.1.2Classification code 10056767
    E.1.2Term Malignant melanoma of skin of eyelid, incl canthus
    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 LLT
    E.1.2Classification code 10056769
    E.1.2Term Malignant melanoma of skin of upper limb, incl shoulder
    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 LLT
    E.1.2Classification code 10056792
    E.1.2Term Malignant melanoma of skin of trunk, excl scrotum
    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 10077160
    E.1.2Term Central nervous system melanoma
    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 compare the efficacy of encorafenib and binimetinib plus pembrolizumab (Triplet Arm) versus nivolumab and ipilimumab (Control Arm) with respect to
    ORR.
    Comparar la eficacia de encorafenib y binimetinib más pembrolizumab (grupo del triplete) frente a nivolumab e ipilimumab (grupo de control) con respecto a la TRG
    E.2.2Secondary objectives of the trial
    - To compare the efficacy of the Triplet Arm versus the Control Arm with respect to PFS.
    - To compare the efficacy of the Triplet Arm versus the Control Arm with respect to OS.
    - Comparar la eficacia del grupo del triplete frente al grupo de control con respecto a la SSP.
    - Comparar la eficacia del grupo del triplete frente al grupo de control con respecto a la SG
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Participants must meet the following key inclusion criteria to be eligible for enrollment into the study:
    - Male or female participants ≥18 years of age at the time of informed consent.
    - Histologically confirmed unresectable (Stage IIIB, IIIC, or IIID) or metastatic
    (Stage IV) cutaneous melanoma, according to the AJCC 8th edition.
    - Documented evidence of a BRAF V600E or V600K mutation.
    - Submission of adequate tumor tissue for central laboratory testing of BRAF V600E/K mutation and biomarkers is required for all participants during the screening period and prior to randomization.
    - Must have received only 1 prior line of systemic therapy for melanoma (either adjuvant therapy or first-line anti-PD-1 monotherapy (ie, nivolumab or
    pembrolizumab).
    - Must have anti-PD-1 resistant disease (primary or secondary) with confirmed disease
    progression per RECIST v1.1 either during or after receipt of an approved anti-PD-1
    monotherapy (ie, nivolumab or pembrolizumab) for melanoma, defined according to
    the SITC Immunotherapy Resistance Taskforce (Kluger et al, 2020).
    - Have at least 1 measurable lesion per RECIST v1.1.
    - ECOG PS of 0-1, and adequate organ and cardiac function, including LVEF ≥50%
    by cardiac imaging.
    Los participantes deberán cumplir los siguientes criterios de inclusión clave para ser aptos para su inclusión en el estudio:
    • Participantes de ambos sexos #18 años en el momento del consentimiento informado.
    • Melanoma cutáneo irresecable (estadio IIIB, IIIC o IIID) o metastásico (estadio IV) confirmado histológicamente, de acuerdo con la 8.a edición del JCC.
    • Evidencia documentada de una mutación V600E o V600K de BRAF.
    • Es necesario enviar tejido tumoral adecuado para los análisis de la mutación V600E/K de BRAF y biomarcadores del laboratorio central de todos los participantes durante la fase de selección y antes de la aleatorización.
    • Deben haber recibido solo 1 línea previa de tratamiento sistémico para el melanoma (ya sea un tratamiento adyuvante o una monoterapia de primera línea con anti-PD-1, es decir, nivolumab o pembrolizumab).
    • Deben tener enfermedad resistente a anti-PD-1 (primaria o secundaria) con progresión confirmada de la enfermedad según los RECIST v1.1 durante o después de recibir una monoterapia aprobada con anti-PD-1 (es decir, nivolumab o pembrolizumab) para el melanoma, definida según el Grupo de Trabajo de la Resistencia a la Inmunoterapia (Immunotherapy Resistance Taskforce) de la SITC (Kluger et al., 2020).
    • Tener al menos 1 lesión medible según los RECIST v1.1. • EF del ECOG de 0-1 y función orgánica y cardíaca adecuadas, incluida una FEVI #50 % según las pruebas de imagen cardíacas.
    E.4Principal exclusion criteria
    Participants with any of the following key characteristics/conditions will be excluded:
    - Mucosal or ocular melanoma.
    - Diagnosis of immunodeficiency or an active autoimmune disease that required
    systemic treatment with chronic systemic steroid therapy or any other form of
    immunosuppressive therapy within the past 2 years.
    - Clinically significant cardiovascular diseases.
    - History of thromboembolic or cerebrovascular events ≤12 weeks prior to randomization.
    - History or current evidence of RVO or current risk factors for RVO.
    - Concurrent neuromuscular disorder that is associated with the potential of elevated CK.
    - Active bacterial, fungal, or viral infection requiring systemic therapeutic treatment within 2 weeks prior to randomization.
    - Current noninfectious pneumonitis/ILD or history of noninfectious pneumonitis/ILD requiring steroids.
    - Prior or current symptomatic brain metastasis, leptomeningeal disease or other active CNS metastases.
    - Participants who permanently discontinued prior anti-PD-1 therapy due to toxicity or will be unable to tolerate combination therapy based on investigator judgement are excluded.
    - Prior treatment with ipilimumab; prior combined immunotherapy blockade with anti- PD-1/L-1; prior treatment with a BRAFi and/or MEKi; or previous administration of an investigational anticancer agent for the adjuvant or first-line treatment of
    melanoma prior to randomization.
    - Previous participation in the Pfizer C4221016 STARBOARD Study.
    Se excluirá a los participantes con alguna de las siguientes características/afecciones clave:
    • Melanoma mucoso u ocular.
    • Diagnóstico de inmunodeficiencia o enfermedad autoinmunitaria activa que haya requerido tratamiento sistémico con corticoesteroides sistémicos prolongados o cualquier otra forma de tratamiento inmunosupresor en los últimos 2 años.
    • Enfermedades cardiovasculares clínicamente significativas.
    • Antecedentes de acontecimientos tromboembólicos o cerebrovasculares #12 semanas antes de la aleatorización.
    • Antecedentes o evidencia actual de OVR o factores de riesgo actuales de OVR.
    • Trastorno neuromuscular concomitante relacionado con la posible elevación de la CK.
    • Infección bacteriana, fúngica o vírica activa que requiera tratamiento terapéutico sistémico en las 2 semanas anteriores a la aleatorización.
    • Neumonitis/EPI no infecciosa actual o antecedentes de neumonitis/EPI no infecciosa que requieran corticoesteroides.
    • Metástasis cerebral sintomática previa o actual, enfermedad leptomeníngea u otras metástasis activas del SNC.
    • Se excluye a los participantes que interrumpieron permanentemente el tratamiento previo con anti-PD-1 debido a toxicidad o que no puedan tolerar el tratamiento combinado a criterio del investigador.
    • Tratamiento previo con ipilimumab; bloqueo previo de la inmunoterapia combinada con anti-PD-1/L-1; tratamiento previo con un
    iBRAF o iMEK o administración previa de un fármaco antineoplásico en investigación para el tratamiento adyuvante o de primera línea del melanoma antes de la aleatorización.
    • Participación previa en el estudio C4221016 STARBOARD de Pfizer.
    E.5 End points
    E.5.1Primary end point(s)
    ORR, defined as the proportion of participants with a confirmed best overall response of either CR or PR, as determined by investigator assessment per
    RECIST v1.1 from randomization to the earliest of PD, start of subsequent anticancer therapy, or death due to any cause.
    TRG, definida como la proporción de participantes con una mejor respuesta global confirmada de RC o RP, determinada por el investigador según los RECIST v1.1 desde la aleatorización hasta la PE, el inicio de un tratamiento antineoplásico posterior o la muerte por cualquier causa, lo que ocurra primero.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Throughout the duration of the study; the analysis of ORR and PFS will be both performed at the time on the achievement of the required number of PFS events (88) to run the PFS analysis: assuming non-uniform enrollment over 14 months, 88 PFS events are anticipated to occur approximately 21 months after the first participant is randomized
    A lo largo de la duración del estudio; el análisis de TRG y SSP se realizará en el momento en que se logre la cantidad requerida de eventos de SSP (88) para ejecutar el análisis de SSP: suponiendo una inscripción no uniforme durante 14 meses, se prevé que ocurran 88 eventos de SSP aproximadamente 21 meses después de la asignación aleatoria del primer participante
    E.5.2Secondary end point(s)
    1. PFS, defined as the interval of time between the date of randomization to the earliest date of disease progression, as determined by investigator assessment per RECIST v1.1, or death due to any cause, whichever occurs first.
    2. OS, defined as the time from date of randomization to the date of death due to any cause or the last known alive date.
    3. DOR, defined as the time from the date of the first documented response (CR or PR) to the earliest date of disease progression, as determined by investigator assessment per RECIST v1.1, or death due to any cause.
    4. DCR, defined as the proportion of participants with a confirmed best overall response of CR, PR or SD, as determined by investigator assessment per
    RECIST v1.1.
    5. TTR, defined as the time from the date of randomization to the date of first documented response (CR or PR), as determined by investigator assessment per RECIST v1.1.
    6. PFS2, defined as the time from the date of
    randomization to the date of discontinuation of next-line treatment after first objective disease progression by investigator assessment per RECIST v1.1, second objective disease progression after initiation of next-line treatment, as determined by investigator assessment, or death due to any cause, whichever occurs first.
    7. Incidence and severity of AEs, and changes in clinical laboratory parameters, vital signs, and cardiac assessments.
    8. EORTC QLQ-C30: change from baseline in the global health status/QoL score and all other subscales scores.
    9. EQ-5D-5L: change from baseline in the index score and VAS.
    10. BRAF V600E/K VAF and/or overall mean VAF from ctDNA analysis of plasma samples collected at baseline and on treatment.
    1. SSP, definida como el intervalo de tiempo entre la fecha de aleatorización y la fecha más temprana de progresión de la enfermedad, determinada por el investigador según los RECIST v1.1, o la muerte por cualquier causa, lo que ocurra primero.
    2. SG, definida como el tiempo desde la aleatorización hasta la fecha de la muerte por cualquier causa o la última fecha en que se supo que estaban vivos.
    3. DdR, definida como el tiempo transcurrido desde la fecha de la primera respuesta documentada (RC o RP) hasta la fecha más temprana de progresión de la enfermedad, determinada por el investigador según los RECIST v1.1, o la muerte por cualquier causa.
    4. TCE, definida como la proporción de participantes con una mejor respuesta global confirmada de RC, RP o EE, determinada por el
    investigador según los RECIST v1.1.
    5. TTR, definido como el tiempo transcurrido desde la fecha de la aleatorización hasta la fecha de la primera respuesta documentada (RC o RP), determinado por el investigador según los RECIST v1.1.
    6. SSP2, definida como el tiempo transcurrido desde la fecha de aleatorización hasta la fecha de la interrupción del tratamiento de siguiente línea después de la primera progresión objetiva de la enfermedad determinada por el investigador según los RECIST v1.1, la segunda progresión objetiva de la enfermedad después del inicio del tratamiento de siguiente línea, determinada por el investigador o la muerte por cualquier causa, lo que ocurra primero.
    7. Incidencia e intensidad de los AA y alteraciones de los parámetros analíticos clínicos, las constantes vitales y las evaluaciones cardíacas.
    8. EORTC QLQ-C30: cambio desde el inicio en la puntuación del estado de salud global/CdV y todas las demás puntuaciones de las subescalas.
    9. EQ-5D-5L: cambio con respecto al inicio en la puntuación del índice y la EVA.
    10. Frecuencia de las variantes alélicas (VAF) de V600E/K de BRAF o VAF media global a partir del análisis de ADNtc de las muestras de plasma
    recogidas al inicio y durante el tratamiento.
    E.5.2.1Timepoint(s) of evaluation of this end point
    throughout the study
    a lo largo del estudio
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    tolerabilidad
    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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group 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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned11
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA66
    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
    Canada
    Israel
    United States
    Switzerland
    Austria
    Bulgaria
    Czechia
    France
    Germany
    Italy
    Poland
    Slovakia
    Spain
    United Kingdom
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the study is defined as the point at which all participants have had the opportunity to be followed for at least 32 months after the randomization date of the last participant enrolled and at least 63% of total participants have had an OS event (or were lost to follow-up).
    El fin del estudio se define como el momento en el que todos los participantes han tenido la oportunidad de ser objeto de seguimiento durante un mínimo de 32 meses tras la fecha de aleatorización del último participante inscrito y al menos el 63 % del total de los participantes han experimentado un acontecimiento de SG (o se han perdido para el seguimiento).
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months11
    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: 110
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    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 state26
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 121
    F.4.2.2In the whole clinical trial 150
    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)
    At the end of study, participants in the Triplet Arm who are still deriving clinical benefit from study intervention will be provided with an option for continued study intervention (eg, continuation study), in accordance with local regulations and requirements. (Treatment with Pembrolizumab and Nivolumab has a maximum duration of 2 years).
    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 Decision2023-03-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2023-02-27
    P. End of Trial
    P.End of Trial StatusOngoing
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