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    Summary
    EudraCT Number:2016-005228-27
    Sponsor's Protocol Code Number:INTERIM17
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2017-08-02
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2016-005228-27
    A.3Full title of the trial
    INTERIM: a randomised phase II feasibility study of INTERmittent versus continuous dosing of oral targeted combination therapy In patients with BRAFV600 mutant stage 3 unresectable or metastatic Melanoma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A trial to compare giving chemotherapy intermittently to chemotherapy administered continuously to patients with inoperable or metastatic melanoma.
    A.3.2Name or abbreviated title of the trial where available
    INTERIM
    A.4.1Sponsor's protocol code numberINTERIM17
    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 SponsorCambridge University Hospitals NHS Foundation Trust
    B.1.3.4Country
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNational Institute for Health Research
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCCTU
    B.5.2Functional name of contact pointMrs Carrie Bayliss
    B.5.3 Address:
    B.5.3.1Street AddressCambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital
    B.5.3.2Town/ cityLevel 6, Coton House, Box 401
    B.5.3.3Post codeCB2 0QQ
    B.5.4Telephone number01223 348158
    B.5.5Fax number01223 256763
    B.5.6E-mailcctu@addenbrookes.nhs.uk
    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 Information not present in EudraCT
    D.2.1.1.1Trade name dabrafenib
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited, Frimley Business Park, Camberley, GU16 7SR, United Kingdom
    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 namedabrafenib
    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 INNdabrafenib
    D.3.9.1CAS number 1195765-45-7
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50mg & 75mg
    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 Information not present in EudraCT
    D.2.1.1.1Trade name trametinib
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited, Frimley Business Park, Camberley, GU16 7SR, United Kingdom
    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 nametrametinib
    D.3.4Pharmaceutical form Film-coated 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 INNtrametinib
    D.3.9.1CAS number 871700-17-3
    D.3.9.4EV Substance CodeAS3
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.5mg & 2.0mg
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    BRAFV600 mutant stage 3 unresectable or metastatic melanoma
    E.1.1.1Medical condition in easily understood language
    Advanced melanoma (skin cancer) which has an abnormal gene called BRAF.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • To assess recruitment rate and treatment compliance of the intermittent dosing schedule as a measure of acceptance of intermittent dosing to patients and physicians
    • To evaluate the impact on overall QoL with intermittent dosing using European Organisation for Research and Treatment of Cancer (EORTC)QLQ-C30
    • To estimate the size of clinical efficacy of intermittent dosing over continuous dosing, measured by PFS
    E.2.2Secondary objectives of the trial
    Secondary objectives
    • To evaluate safety, objective response rate, time to treatment failure and overall survival
    • To evaluate skin toxicity as assessed by clinicians and patients using patient reported outcome measures (Skindex-16 and patient-reported outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE))
    • To assess factors which influence patients’ decision to enter/decline entering the trial
    • To assess patient experience of participation in this trial (using mixed methods)
    • To determine the QoL and cost-effectiveness of intermittent dosing compared with standard continuous dosing

    Exploratory Objectives
    • To explore emergence of resistance by means of ctDNA collected from patients during the course of their treatment
    • To determine the role of ctDNA as a useful biomarker for therapeutic monitoring
    • In a subset of patients (up to 20), explore pharmacokinetics of standard versus intermittent dosing schedules
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Signed informed consent
    • Age ≥18 years old
    • Histologically or cytologically confirmed BRAFV600 mutant stage 3 unresectable or metastatic melanoma
    • Measurable disease by RECIST
    • ECOG performance status 0-2
    • Minimum life expectancy 12 weeks
    • Adequate bone marrow, renal and liver function
    • Received no prior BRAF or MEK inhibitor therapy for metastatic disease
    • Willing and able to comply with the scheduled visits, treatment plans, laboratory tests, completion of QoL questionnaires and other study procedures
    • Archival tumour tissue sample available
    • Women of child-bearing potential and all sexually active male patients must agree to use effective contraception methods throughout treatment
    E.4Principal exclusion criteria
    • Concomitant immunotherapy being administered to treat advanced melanoma
    • Other invasive malignancies diagnosed within the last year which are not in complete remission, or for which additional therapy is required
    • Significant acute or chronic medical or psychiatric condition, disease or laboratory abnormality which in the judgment of the investigator would place the patient at undue risk or interfere with the trial
    • Women who are pregnant, plan to become pregnant or are lactating during the trial period
    • Other investigational anti-cancer drugs
    • Use of strong inducers and inhibitors of CYP3A or CYP2C8
    E.5 End points
    E.5.1Primary end point(s)
    • Recruitment rate will be measured as the average number of patients recruited per site per 2 months

    • Treatment compliance is defined as the percentage of patients completing the allocated treatment at 6 months from the date of randomisation. Although the primary aim is to assess the compliance of the intermittent dosing schedule, compliance of the standard continuous dosing schedule will also be assessed and compared with the experimental arm in an exploratory manner

    • Overall QoL is defined as the global health status score derived from the standard EORTC QLQ-C30 questionnaire at 6 months from date of randomisation

    • PFS is calculated as the duration from date of randomisation to the date of first progression or death from any cause, whichever occurs first. Progression is assessed according to standard Response Evaluation Criteria In Solid Tumours (RECIST v1.1)
    E.5.1.1Timepoint(s) of evaluation of this end point
    • Recruitment rate will be assessed once the trial has been recruiting for 15 months, or when 15 sites have been open for 6 months, whichever is sooner.

    • Treatment compliance at 6 months from the date of randomisation.

    • QoL at 6 months from date of randomisation.

    • PFS is calculated as the duration from date of randomisation to the date of first progression or death from any cause, whichever occurs first.
    E.5.2Secondary end point(s)
    • Safety is assessed using the standard cancer National Cancer institute (NCI) CTCAE v4.03 criteria

    • Objective Response Rate is assessed according to RECIST v1.1 (Appendix 1)

    • Time to treatment failure is the time from starting drug treatment with dabrafenib+trametinib on day 1 of cycle 1 until the date of day 1 of the last cycle +28 days; if a patient receives any other anti-cancer treatment including surgery they will be censored at the date of last treatment prior to this

    • Overall survival is calculated as the duration from the date of randomisation to the date of death from any cause

    • Objective Response Rate is assessed according to RECIST v1.1 (Appendix 1)

    • Patient reported outcomes focussing on skin toxicity evaluation is assessed using skin-specific patient reported outcome measures (PROM) – the Skindex-16 and NCI PRO-CTCAE items

    • Patient experience is assessed by a) patient experience survey of patients in each arm of the trial and b) semi-structured interviews of patient volunteers

    • QoL & Health Economic Evaluation: the EORTC QLQ-C30 and EQ5D generic measure of health status which will be used for the cost-effectiveness analysis.
    E.5.2.1Timepoint(s) of evaluation of this end point
    • Safety evaluated throughout trial

    • Objective Response Rate evaluated throughout trial

    • Time to treatment failure evaluated throughout trial

    • Overall survival evaluated throughout trial

    • Patient reported outcomes evaluated throughout trial

    • Patient experience evaluated 9 months from randomisation

    • QoL & Health Economic Evaluation evaluated throughout trial
    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 No
    E.6.12Pharmacoeconomic No
    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) 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) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Standard dosing regimen vs Intermittent dosing regimen
    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 concerned22
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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 trial will be considered closed for regulatory purposes 9 months from the date of randomisation of the last patient. Further observational follow-up on survival of all patients enrolled in the trial will be performed for a minimum of 9 months to a maximum of 5 years from the date of randomisation of the last patient. This will initially be via hospitals and clinics, but in the longer term may exploit national registers.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days29
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months8
    E.8.9.2In all countries concerned by the trial days29
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 10
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state150
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 150
    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)
    As dabrafenib+trametinib is fully commissioned, patients may continue to receive treatment for as long as they are benefitting from it, as per NICE guidance.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-08-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-10-05
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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