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    Summary
    EudraCT Number:2020-004850-31
    Sponsor's Protocol Code Number:C4221016
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2021-03-05
    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 ConcernedGermany - BfArM
    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 MUTATION-POSITIVE METASTATIC OR UNRESECTABLE LOCALLY ADVANCED MELANOMA
    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.
    A.3.2Name or abbreviated title of the trial where available
    The STARBOARD Study
    A.4.1Sponsor's protocol code numberC4221016
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04657991
    A.5.4Other Identifiers
    Name:US IND numberNumber:113850
    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., 66 Hudson Boulevard East, New York, NY 10001
    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 Address66 Hudson Boulevard East
    B.5.3.2Town/ cityNew York
    B.5.3.3Post codeNY 10001
    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.3.4Pharmaceutical 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.3.4Pharmaceutical 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.3.9.3Other descriptive nameMEKTOVI
    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 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.3.4Pharmaceutical 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 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/ml milligram(s)/millilitre
    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 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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    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 placeboFilm-coated tablet
    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
    E.1.1.1Medical condition in easily understood language
    Skin cancer
    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 27.0
    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 27.0
    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 27.0
    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 27.0
    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 27.0
    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 27.0
    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 27.0
    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 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 27.0
    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 27.0
    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
    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 OR by BICR assessment.
    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.

    To characterize the PK of encorafenib and binimetinib when administered 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.

    To assess the efficacy of the Triplet Arm versus the Control Arm.

    To assess 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.
    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.
    6. Documented evidence of a BRAF V600E or V600K mutation in melanoma tumor tissue as previously determined by either PCR or NGS-based local laboratory assay (eg, US FDA-approved test, CE-marked [European conformity] in vitro diagnostic in EU countries, or equivalent), obtained during the course of normal clinical care, in a CLIA- or similarly certified laboratory.
    7. Submission of adequate tumor tissue (archival or newly obtained; block or slides; see protocol section 8.7.2) to the sponsor central laboratory(ies) during the screening period and prior to enrollment (SLI)/randomization (Phase 3).
    Note: Whenever possible, the archival sample should be from the same tumor block that was used for local BRAF V600E/K mutation testing.
    Note: A newly obtained tumour tissue biopsy must be provided prior to enrolment (SLI)/ randomization (Phase 3) for participants unable to provide adequate archival tumour tissue. If a newly obtained biopsy is taken, the biopsy should be taken from a nontarget lesion when possible.
    Note: Confirmation of the BRAF V600E/K mutation from the central laboratory is required (see protocol section 8.7.2). If results from the central laboratory are indeterminate or indicate insufficient tissue, additional samples must be submitted (see protocol section 8.7.2).
    8. SLI Participants: Have not received more than 1 prior systemic therapy for metastatic or locally advanced melanoma.
    Note: Prior neoadjuvant therapy for early-stage disease does not count as prior systemic therapy.
    Note: Participants who receive adjuvant therapy and had evidence of disease recurrence ≤ 6 months after the last dose of adjuvant treatment will be considered as having received prior first line therapy.
    Phase 3 Participants: Have not received prior first-line systemic therapy for metastatic or unresectable locally advanced melanoma.
    Note: Participants with complete surgical resection of locally advanced or metastatic disease (eg, definitive treatment of all sites of metastases), who receive up to 12 months of systemic adjuvant therapy are eligible for the study provided there is no evidence of disease recurrence ≤ 6 months after the last dose of adjuvant treatment.
    Note: Participants who receive any neoadjuvant therapy for early stage disease are eligible for the study.
    Note: Prior adjuvant therapy with a BRAFi and/or MEKi or anti-PD-1 or CTLA-4 agents is permitted.
    Note: Participants who receive adjuvant treatment for up to 12 months, and have evidence of disease recurrence during treatment or ≤ 6 months after the last dose of treatment would be considered as receiving first-line therapy and are therefore not eligible for study participation.
    9. Adequate bone marrow, hepatic and renal function, characterized by screening results specified in protocol section 5.1.
    For a full list please see protocol section 5.1.
    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, 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.
    6. Impairment of GI function or disease which may significantly alter the absorption of oral study intervention (eg, uncontrolled nausea, vomiting or diarrhea, malabsorption syndrome, including malabsorption syndrome secondary to prior GI surgery).
    7. Clinically significant cardiovascular diseases, including any of the following:
    a. History of acute myocardial infarction, acute coronary syndromes (including unstable angina, coronary artery bypass graft, coronary angioplasty or stenting) ≤ 6 months prior to enrollment (SLI)/randomization (Phase 3);
    b. Congestive heart failure requiring treatment (New York Heart Association Grade ≥ 2);
    c. LVEF < 50% as determined by ECHO or MUGA scan;
    d. Uncontrolled hypertension, defined as persistent systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg, despite therapy;
    e. History or presence of clinically significant cardiac arrhythmias (including uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia);
    f. Triplicate average QTcF interval ≥ 480 ms at Screening or a history of prolonged QT syndrome.
    8. History of thromboembolic or cerebrovascular events ≤ 12 weeks prior to enrollment (SLI)/randomization (Phase 3). Examples include transient ischemic attacks, cerebrovascular accidents, hemodynamically significant (ie, massive or sub-massive) deep vein thrombosis or pulmonary emboli.
    9. History or current evidence of RVO or current risk factors for RVO (eg, uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes).
    10. Concurrent neuromuscular disorder that is associated with the potential of elevated CK (eg, inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
    11. Current noninfectious pneumonitis/interstitial lung disease or history of noninfectious pneumonitis/interstitial lung disease requiring steroids, or history of radiation pneumonitis.
    12. Evidence of HBV or HCV infection.
    13. Known history of a positive test for HIV or known AIDS. Testing for HIV must be performed at sites where mandated locally.
    14. Any active infection requiring systemic therapeutic treatment within 2 weeks prior to enrollment (SLI)/ randomization (Phase 3).
    15. Participants with prior or current symptomatic brain metastasis, leptomeningeal disease or other active CNS metastases.
    16. Concurrent or previous other malignancy within 2 years of study entry, except curatively treated basal or squamous cell skin cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, Bowen’s disease and Gleason ≤ 6 prostate cancer. Participants with a history of other curatively treated cancers must be reviewed with the sponsor or designee prior to entering the study.

    For a full list please see section 5.2 of the protocol.
    E.5 End points
    E.5.1Primary end point(s)
    Safety Lead-In:
    Incidence of Dose-limiting toxicities (DLTs)

    Randomised Phase 3:
    OR, defined as confirmed BOR of either CR or PR, as determined by BICR assessment per RECIST v1.1 from randomization to the earliest of PD, start of subsequent anticancer therapy, or death due to any cause.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Throughout the duration of the study
    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.
    -OR, defined as confirmed BOR of either a CR or PR, as determined by investigator assessment per RECIST v1.1.
    -PFS, defined as the time from the date of first dose to the date of first documented disease progression, as determined by investigator assessment per RECIST v1.1, or death due to any cause, whichever occurs first.
    - DC, defined as 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.
    *Unless otherwise noted
    Randomised Phase 3:
    -PFS, defined as the time from the date of randomization to the date of first documented disease progression, as determined by BICR assessment per RECIST v1.1, or death due to any cause, whichever occurs first.
    - 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.
    - OR, defined as confirmed BOR of either CR or PR, as determined by 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..
    - DC, defined as confirmed BOR 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 date of discontinuation of next-line of treatment after first objective disease
    progression by investigator assessment per RECIST v1.1, second objective disease progression after initiation of next-line of treatment, as determined by investigator assessment 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.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Timepoints as outlined in Section 1.3 Schedule of Activities of the Protocol
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    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
    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 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 concerned24
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA116
    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
    Argentina
    New Zealand
    Switzerland
    Ukraine
    Brazil
    Canada
    Israel
    Mexico
    Russian Federation
    Serbia
    South Africa
    United Kingdom
    United States
    Austria
    Belgium
    Bulgaria
    Czechia
    Finland
    France
    Germany
    Greece
    Hungary
    Italy
    Norway
    Poland
    Slovakia
    Spain
    Türkiye
    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 study is defined as the last participant's last visit date, at which time all data collection will be complete. It will occur soon after the analysis of the primary and secondary endpoints of the study are conducted, based on the availability of 128 PFS events by BICR (PCD).
    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 months4
    E.8.9.1In the Member State concerned days9
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial days16
    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: 168
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 72
    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 state96
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 151
    F.4.2.2In the whole clinical trial 240
    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 receive study intervention at the discretion of the investigator and sponsor, considering different available options in accordance with local regulations and requirements, as long as none of the study intervention discontinuation criteria are met.
    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 Decision2021-07-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-07-29
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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