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    Summary
    EudraCT Number:2020-004850-31
    Sponsor's Protocol Code Number:C4221016
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-06-08
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2020-004850-31
    A.3Full title of the trial
    A PHASE 3, RANDOMIZED, DOUBLE-BLIND STUDY OF ENCORAFENIB AND BINIMETINIB PLUS PEMBROLIZUMAB VERSUS PLACEBO PLUS PEMBROLIZUMAB IN PARTICIPANTS WITH BRAF V600E/K MUTATIONPOSITIVE METASTATIC OR UNRESECTABLE LOCALLY ADVANCED MELANOMA
    UNO STUDIO DI FASE 3 RANDOMIZZATO IN DOPPIO CIECO SU ENCORAFENIB E BINIMETINIB + PEMBROLIZUMAB RISPETTO A PLACEBO + PEMBROLIZUMAB IN PARTECIPANTI AFFETTI DA MELANOMA METASTATICO O LOCALMENTE AVANZATO NON RESECABILE POSITIVO ALLA MUTAZIONE BRAF V600E/K
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A STUDY OF ENCORAFENIB AND BINIMETINIB PLUS PEMBROLIZUMAB VERSUS PLACEBO PLUS PEMBROLIZUMAB IN PARTICIPANTS WITH IN PARTICIPANTS WITH MELANOMA THAT HAVE A GENETIC ABNORMALITY IN THE BRAF GENE.
    UNO STUDIO SU ENCORAFENIB E BINIMETINIB + PEMBROLIZUMAB RISPETTO A PLACEBO + PEMBROLIZUMAB IN PARTECIPANTI AFFETTI DA MELANOMA METASTATICO CHE HANNO UN'ANORMALITA' NEL GENE BRAF
    A.3.2Name or abbreviated title of the trial where available
    The STARBOARD Study
    Studio STARBOARD
    A.4.1Sponsor's protocol code numberC4221016
    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.
    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
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name 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 name-
    D.3.2Product code [-]
    D.3.4Pharmaceutical form Solution for injection/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.3.9.2Current sponsor code-
    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 number25
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    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 metastatico o localmente avanzato non resecabile positivo alla mutazione BRAF V600E/K
    E.1.1.1Medical condition in easily understood language
    Skin cancer
    Tumore della pelle
    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 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 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 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 21.1
    E.1.2Level LLT
    E.1.2Classification code 10025665
    E.1.2Term Malignant melanoma of skin stage 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 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 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 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 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 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 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 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 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 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.1.2 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.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Safety Lead-In:
    To determine the RP3D of encorafenib and binimetinib when given in combination with pembrolizumab.
    Randomized Phase 3:
    To compare the efficacy of encorafenib and binimetinib plus pembrolizumab (Triplet Arm) versus placebo plus pembrolizumab (Control Arm) with respect to PFS by BICR assessment
    Lead-in di sicurezza:
    Determinare la dose raccomandata di fase 3 (RP3D) di encorafenib e binimetinib se somministrati in combinazione con pembrolizumab.
    Fase 3 randomizzata:
    Confrontare l’efficacia di encorafenib e binimetinib + pembrolizumab (Braccio della tripletta) rispetto a placebo + pembrolizumab (Braccio di controllo) in relazione alla PFS mediante valutazione tramite revisione centrale indipendente e in cieco (BICR).
    E.2.2Secondary objectives of the trial
    Safety Lead-In:
    To assess the overall safety and tolerability of encorafenib and binimetinib plus pembrolizumab.
    To assess the efficacy of encorafenib and binimetinib plus pembrolizumab with respect to objective response rate (ORR), disease control rate (DCR) and time to objective response (TTR)
    To characterize the PK of encorafenib and binimetinib when administered in combination with pembrolizumab.
    Randomized Phase 3:
    To compare the efficacy of the Triplet Arm versus the Control Arm with respect to OS.
    To compare the efficacy of the Triplet Arm versus the Control Arm with respect to PFS by investigator assessment, ORR, DOR, DCR, TTR, PFS2.
    To compare the effect on PROs of the Triplet Arm versus the Control Arm
    To further evaluate the safety and tolerability of the Triplet Arm versus the Control Arm.
    To assess the exposure of encorafenib and binimetinib when administered in combination with pembrolizumab.
    Lead-in di sicurezza:
    Valutare la sicurezza generale e la tollerabilità di encorafenib e binimetinib + pembrolizumab. Valutare l’efficacia di encorafenib e binimetinib + pembrolizumab rispetto alla percentuale di risposta obiettiva (ORR), il tasso di controllo della patologia (DCR) e il Tempo di risposta (TTR). Caratterizzare la farmacocinetica (PK) di encorafenib e binimetinib se somministrati in combinazione con pembrolizumab.
    Fase 3 randomizzata:
    Confrontare l’efficacia del Braccio della tripletta rispetto al Braccio di controllo rispetto alla sopravvivenza globale (OS). Confrontare l’efficacia del Braccio della tripletta rispetto al Braccio di controllo in relazione a PFS tramite valutazione dello sperimentatore, ORR, DOR, DCR, TTR, PFS2. Confrontare l’effetto sugli esiti riferiti dal paziente (PRO) del Braccio della tripletta rispetto al Braccio di controllo. Valutare ulteriormente la sicurezza e la tollerabilità del Braccio della tripletta rispetto al Braccio di controllo.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female participants = 18 years at the time of informed consent. Refer to protocol appendix 4 for reproductive criteria for male (protocol section 10.4.1) and female (protocol section 10.4.2) participants.
    2. Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
    3. Histologically confirmed unresectable (Stage IIIB, IIIC, or IIID) or metastatic (Stage IV) cutaneous melanoma, according to the AJCC 8th edition. Note: Locally advanced disease must not be amenable for treatment with curative intent.
    4. Presence of at least 1 measurable lesion as detected by radiological and/or photographic methods according to RECIST v1.1. Note: Tumor lesions situated in a previously irradiated area, or in an
    area subjected to other locoregional therapy, are not considered measurable unless there has been documented progression of the lesion. Note: If baseline scans from an institution other than the investigational
    site are used, the site must obtain copies of the scans prior to enrolment of the participant, or the scans must be repeated at the investigational site and submitted for independent review (Phase 3 only). Note: Clinical lesions will only be considered measurable when they are superficial and = 10 mm diameter as assessed using calipers (eg, skin nodules). When lesions can be evaluated by both clinical exam and
    imaging, imaging evaluation should be performed and submitted for independent review (Phase 3 only).
    5. ECOG performance status 0 or 1.
    For a full list please see protocol section 5.1
    1 - Partecipanti maschi o femmine di età =18 anni al momento del consenso informato. Fare riferimento all’Appendice 4 del Protocollo per i partecipanti maschi (Sezione 10.4.1 del Protocollo) e femmine (Sezione 10.4.2 del Protocollo).
    2. Partecipanti disposti e in grado di rispettare tutte le visite programmate, il piano di trattamento, i test di laboratorio, le considerazioni sullo stile di vita e altre procedure di studio.
    3. Melanoma cutaneo istologicamente confermato non resecabile (Stadio IIIB, IIIC o IIID) o metastatico (Stadio IV), secondo l’AJCC, 8a edizione. Nota: la malattia localmente avanzata non deve essere idonea al trattamento con intento curativo.
    4. Presenza di almeno 1 lesione misurabile rilevata con metodi radiologici e/o fotografici secondo il RECIST v1.1. Nota: le lesioni tumorali situate in un’area precedentemente irradiata, o in un’area sottoposta ad altre terapie locoregionali, non sono considerate misurabili a meno che non vi sia stata una progressione documentata della lesione. Nota: se vengono utilizzate scansioni al basale da un centro diverso dal centro di sperimentazione, il centro deve ottenere copie delle scansioni prima dell’arruolamento del partecipante o le scansioni devono essere ripetute presso il centro di sperimentazione e sottoposta a controllo indipendente (solo Fase 3). Nota; le lesioni cliniche saranno considerate misurabili solo quando sono superficiali e = di 10 mm di diametro in base a una valutazione con calibri (ad esempio, noduli cutanei). Nel caso di lesioni cutanee, si suggerisce di documentare tramite fotografia a colori, incluso un righello per stimare le dimensioni della lesione. Quando le lesioni possono essere valutate sia dall’esame clinico sia dall’imaging, la valutazione dell’imaging deve essere eseguita e sottoposta a revisione indipendente (solo Fase 3).
    5. Stato di validità secondo il Gruppo cooperativo orientale di oncologia (ECOG) di 0 o 1.
    per l'elenco completo vedere la sezione 5.1 del protocollo
    E.4Principal exclusion criteria
    1. Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study.
    2. Mucosal or ocular melanoma.
    3. Diagnosis of immunodeficiency or an active autoimmune disease that required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Note: Participants with diabetes type I, vitiligo, psoriasis, controlled asthma, Graves' disease, Hashimoto's disease or hypo- or hyperthyroid disease are exceptions and may participate.
    Note: Replacement and symptomatic therapies (eg, levothyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or
    pituitary insufficiency) are not considered a form of immunosuppressive agents and are permitted.
    4. Clinically significant multiple or severe drug allergies, intolerance to topical corticosteroids, or severe post-treatment hypersensitivity reactions (including, but not limited to, erythema multiforme major,
    linear IgA dermatosis, toxic epidermal necrolysis, and exfoliative dermatitis).
    5. Unable to swallow, retain, and absorb oral medications.
    For a full list please see section 5.2 of the protocol.
    1. Altre condizioni mediche o psichiatriche, tra cui idee/comportamenti suicidari recenti (nell’ultimo anno) o attivi o anomalie di laboratorio che possono aumentare il rischio di partecipazione allo studio o, a giudizio dello sperimentatore, rendere il partecipante non idoneo allo studio.
    2. Melanoma mucoso o oculare.
    3. Diagnosi di immunodeficienza o di una malattia autoimmune attiva che richiedeva un trattamento sistemico negli ultimi 2 anni (cioè, con l’uso di agenti modificanti la malattia, corticosteroidi o farmaci immunosoppressori). Nota: i partecipanti con diabete di tipo I, vitiligine, psoriasi, asma controllata, malattia di Graves, malattia di Hashimoto o malattia ipo- o ipertiroidea costituiscono un’eccezione e possono partecipare. Nota: le terapie sostitutive e sintomatiche (ad esempio levotiroxina, insulina o terapia fisiologica di sostituzione con corticosteroidi per insufficienza surrenale o ipofisaria) non sono considerate una forma di agenti immunosoppressori e sono consentite.
    4. Allergie farmacologiche multiple o gravi clinicamente significative, intolleranza a corticosteroidi topici o gravi reazioni di ipersensibilità post-trattamento (tra cui, a titolo esemplificativo, eritema multiforme maggiore, dermatosi a IgA lineari, necrolisi epidermica tossica e dermatite esfoliativa).
    5. Non in grado di inghiottire, trattenere e assorbire farmaci per via orale.
    per l'elenco completo vedere la sezione 5.2 del protocollo.
    E.5 End points
    E.5.1Primary end point(s)
    Safety Lead-In:
    Incidence of Dose-limiting toxicities (DLTs)
    Randomised Phase 3:
    PFS, defined as the interval of time between the date of randomization to the earliest date of disease progression, as determined by BICR assessment per RECIST v1.1, or death due to any cause, whichever
    occurs first.
    Lead-in di sicurezza:
    Incidenza di tossicità dose limitanti (DLT).
    Fase 3 randomizzata:
    PFS definita come il tempo che intercorre tra la data di randomizzazione e la prima progressione documentata della malattia, determinata mediante valutazione BICR secondo i RECIST v1.1, o morte per qualsiasi causa, a seconda di quale delle due eventualità si verifichi per prima.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Throughout the duration of the study
    Per tutta la durata dello studio
    E.5.2Secondary end point(s)
    Safety Lead-In:
    - Incidence and severity of AEs graded according to the NCI CTCAE v4.03 and changes in clinical laboratory parameters, vital signs, and cardiac assessments.
    - ORR, defined as the proportion of participants with a confirmed BOR of either a CR or PR, as determined by investigator assessment per RECIST v1.1.
    - DCR, defined as the proportion of participants with a confirmed BOR of CR, PR or SD, as determined by investigator assessment per RECIST
    v1.1.
    - TTR, defined as the time from the date of first dose to the date of first documented response (CR or PR), as determined by investigator assessment per RECIST v1.1.
    - Plasma concentration-time profiles and PK parameter estimates for encorafenib and binimetinib.
    Randomised Phase 3:
    - OS, defined as the time from date of randomization to the date of death due to any cause.
    - 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.
    - ORR, defined as the proportion of participants with a confirmed best
    overall response of either CR or PR, as determined by BICR and investigator assessment per RECIST v1.1.
    - 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 BICR and investigator assessment per RECIST v1.1, or
    death due to any cause, whichever occurs first..
    - DCR, defined as the proportion of participants with a confirmed best overall response of CR, PR or SD, as determined by BICR and
    investigator assessment per RECIST v1.1.
    - TTR, defined as the time from date of randomization to the date of the first documented response (CR or PR) as determined by BICR and
    investigator assessment per RECIST v1.1.
    - PFS2, defined as the time from the date of randomization to the second objective disease progression per RECIST v1.1, or death from any cause,
    whichever occurs first.
    - EORTC QLQ-C30: change from baseline in the global health status/QoL score.
    - FACT-M: change from baseline in the melanoma subscale score.
    - EQ-5D-5L: change from baseline in the index score and VAS.
    - PGIS: change from baseline in the score.
    - PGIC score.
    - Incidence and severity of AEs graded according to the NCI CTCAE v4.03 and changes in clinical laboratory parameters, vital signs, and cardiac assessments.
    - Plasma concentrations of encorafenib and binimetinib.
    Lead-in di sicurezza:
    - Incidenza e gravità degli eventi avversi (AE) classificati in base ai criteri terminologici comuni per gli eventi avversi (CTCAE) del National Cancer Institute (NCI) v4.03 e cambiamenti di parametri clinici di laboratorio, segni vitali e valutazioni cardiache.
    -ORR, definita come la percentuale di partecipanti con una migliore risposta globale (BOR) confermata, completa (CR) o parziale (PR), come determinato dalla valutazione dello sperimentatore in base ai criteri di valutazione della risposta nei tumori solidi (RECIST) v1.1.
    -DCR, definito come la percentuale di partecipanti con una BOR confermata di CR, PR o malattia stabile (SD), come determinato dalla valutazione dello sperimentatore in base ai RECIST v1.1.
    -TTR, definito come il tempo intercorso dalla data della prima dose alla data della prima risposta documentata (CR o PR), come determinato dalla valutazione dello sperimentatore in base al RECIST v1.1.
    -Profili tempo-concentrazione plasmatica e stime dei parametri PK per encorafenib e binimetinib.
    Fase 3 randomizzata:
    -La OS definita come il tempo che intercorre tra la data di randomizzazione e la data della morte per qualsiasi causa.
    -PFS definita come il tempo che intercorre tra la data di randomizzazione e la prima progressione documentata della malattia determinata mediante valutazione dello sperimentatore secondo i RECIST v1.1, o morte per qualsiasi causa, a seconda di quale delle due eventualità si verifichi per prima.
    -ORR, definita come la percentuale di partecipanti con una BOR confermata completa (CR) o parziale (PR), come determinato dalla valutazione BICR e dello sperimentatore in base ai RECIST v1.1.
    -DOR definita come il tempo che intercorre tra la data della risposta documentata (CR o PR) e la data della prima progressione documentata della malattia, come determinato dalla valutazione BICR e dello sperimentatore secondo i RECIST v1.1, o morte per qualsiasi causa, a seconda di quale delle due eventualità si verifichi per prima.
    -DCR, definita come la percentuale di partecipanti con una BOR confermata di CR, PR o SD, come determinato dalla valutazione BICR e dello sperimentatore in base ai RECIST v1.1.
    -TTR, definito come il tempo intercorso tra la data di randomizzazione e la data della prima risposta documentata (CR o PR), come determinato dalla valutazione BICR e dello sperimentatore in base al RECIST v1.1.
    -PFS2, definita come il tempo che intercorre tra la data di randomizzazione e la data della seconda progressione obiettiva della malattia, come determinato alla valutazione dello sperimentatore in base ai RECIST v1.1, o morte per qualsiasi causa, a seconda di quale dei due eventi si verifichi per primo.
    -Questionario sulla qualità della vita-Core 30 dell’Organizzazione europea per la ricerca e la cura del cancro (EORTC QLQ-C30): cambiamento rispetto al basale nello stato di salute globale/punteggio della qualità della vita (QoL).
    -Valutazione funzionale della terapia antitumorale - Melanoma (FACT-M): cambiamento rispetto al basale nel punteggio della sottoscala del melanoma.
    -Questionario europeo sulla qualità della vita a 5 dimensioni e 5 livelli (EQ-5D-5L): cambiamento rispetto al basale nel punteggio dell’indice e nella Scala analogica visiva (VAS).
    -Impressione complessiva del paziente sulla gravità (PGIS): cambiamento rispetto al basale nel punteggio.
    -Punteggio dell’Impressione globale di cambiamento del paziente (PGIC).
    -Incidenza e gravità degli AE classificati in base ai CTCAE dell’NCI v4.03 e cambiamenti di parametri clinici di laboratorio, segni vitali e valutazioni cardiache.
    -Concentrazioni plasmatiche di encorafenib e binimetinib.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Timepoints as outlined in Section 1.3 Schedule of Activities of the Protocol
    Tempistiche come indicato nella Sezione 1.3 Programma delle attività del Protocollo.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic Yes
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Fase di lead-in di sicurezza (SLI) in aperto
    Open-label Safety Lead-In Phase
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA16
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Brazil
    Canada
    Mexico
    New Zealand
    Russian Federation
    South Africa
    Turkey
    Ukraine
    United States
    Bulgaria
    France
    Germany
    Hungary
    Italy
    Switzerland
    Argentina
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the study will occur when all participants in all participating countries have discontinued all study intervention and/or the LPLV has been performed. Any participants still receiving study intervention at the end of the study will be allowed to continue at the discretion of the investigator and sponsor, and in accordance with local regulations and requirements, as long as none of the study intervention discontinuation criteria are met.
    La fine dello studio avverrà quando tutti i partecipanti in tutti i paesi partecipanti avranno interrotto tutti gli interventi dello studio e / o sarà stata eseguita la LPLV. A tutti i partecipanti che stanno ancora ricevendo l'intervento dello studio alla fine dello studio sarà consentito di continuare, a discrezione dello sperimentatore e dello sponsor e in conformità con le normative e i requisiti locali, purché nessuno dei criteri di interruzione dell'intervento dello studio sia soddisfatto.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years8
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days9
    E.8.9.2In all countries concerned by the trial years8
    E.8.9.2In all countries concerned by the trial months11
    E.8.9.2In all countries concerned by the trial days9
    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: 437
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 187
    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 state16
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 108
    F.4.2.2In the whole clinical trial 624
    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)
    Any participants still receiving study intervention at the end of the study will be allowed to continue at the discretion of the investigator and sponsor, and in accordance with local regulations and
    requirements, as long as none of the study intervention discontinuation criteria are met.
    A tutti i partecipanti che stanno ancora ricevendo l'intervento dello studio alla fine dello studio sarà consentito di continuare a discrezione dello sperimentatore e dello sponsor, e in conformità con le normative locali e
    requisiti, a condizione che nessuno dei criteri di interruzione dell'intervento in studio sia soddisfatto.
    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 Decision2021-06-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-06-09
    P. End of Trial
    P.End of Trial StatusOngoing
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