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    Summary
    EudraCT Number:2013-002073-22
    Sponsor's Protocol Code Number:11_DOG12_56
    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:2015-06-01
    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 ConcernedUK - MHRA
    A.2EudraCT number2013-002073-22
    A.3Full title of the trial
    A Phase II Trial of PLX3397 in the Treatment of KIT Mutated Advanced Acral and Mucosal Melanoma( PIANO)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase II Trial of PLX3397 in the Treatment of Tyrosine Kinase Receptor (KIT) Mutated Advanced Acral and Mucosal Melanoma (PIANO trial)
    A.3.2Name or abbreviated title of the trial where available
    PIANO Study - PLX3397 c-KIT in advanced acral and mucosal melanoma
    A.4.1Sponsor's protocol code number11_DOG12_56
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02071940
    A.5.4Other Identifiers
    Name:clinicaltrials.govNumber:NCT02071940
    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 SponsorThe Christie NHS Foundation Trust, R&D
    B.1.3.4CountryUnited Kingdom
    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 supportCancer Research UK
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportThe Christie Charitable Funds The Christie NHS Foundation Trust
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportPlexxikon Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationManchester Academic Health Science Centre-Trials Coordination Unit, The Christie NHS FT
    B.5.2Functional name of contact pointAzad Aziz
    B.5.3 Address:
    B.5.3.1Street AddressWilmslow Road
    B.5.3.2Town/ cityManchester
    B.5.3.3Post codeM20 4BX
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01619187771
    B.5.5Fax number01614468148
    B.5.6E-mailazad.aziz@christie.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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePLX3397([5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3
    D.3.2Product code PLX3397-HCl
    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 INNN/A
    D.3.9.2Current sponsor codePLX3397-HCl
    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 number200 to 00
    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
    In a subset of patients with advanced acral and mucosal melanoma exhibiting Tyrosine Kinase Receptor gene(c-KIT) mutation.
    E.1.1.1Medical condition in easily understood language
    Melanoma - cancer of the skin and mucosal tissues
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    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 19.0
    E.1.2Level PT
    E.1.2Classification code 10025654
    E.1.2Term Malignant melanoma of sites other than 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 19.0
    E.1.2Level LLT
    E.1.2Classification code 10000589
    E.1.2Term Acral lentiginous melanoma 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 19.0
    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 19.0
    E.1.2Level LLT
    E.1.2Classification code 10025667
    E.1.2Term Malignant melanoma site/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 19.0
    E.1.2Level PT
    E.1.2Classification code 10000583
    E.1.2Term Acral lentiginous 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 19.0
    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 19.0
    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.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study is to evaluate the efficacy and safety of PLX3397 in patients with KIT mutated advanced mucosal and acral melanoma. Response to the treatment is measured by tumour progression free survival at 6 months and overall patient survival rate are key objectives of the study.
    E.2.2Secondary objectives of the trial
    The secondary objectives of the study are to evaluate the response rate to treatment, safety and toxicity of PLX3397 and overall survival during the treatment period. The objectives of the translational sub-study include evaluation of the correlation between KIT mutation and response rate to treatment, mechanism of drug response and resistance to it during tumour progression, down stream signalling of KIT mutation and estimation of free tumour cells in the blood taken from patients participating in the translational sub-study. It is anticipated that by screening all potential patients for KIT mutation, a better estimate of the incidence of acral and mucosal melanoma in the UK will be determined as few data are currently reported in the literature.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Male and female patients ≥ 18 years of age with histologically confirmed KIT mutated advanced mucosal or acral melanoma (exons 9, 11, 13 and 17 will be sequenced. For exon 17 only Asp816 (also know as D816X) mutations are excluded- other exon 17 mutations are allowed)
    2.Patients with advanced acral and mucosal melanoma in whom KIT mutations have been confirmed and the mutations are not known to be associated with resistance to PLX3397
    3.Patients must have clinically or radiologically measurable lesion of at least 15mm in size
    4.Unresectable locally advanced or metastatic disease
    5.The capacity to understand the patient information sheet and the ability to provide signed and dated written informed consent prior to any study related procedures
    6.Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other study procedures
    7.ECOG performance status of 0-2
    8.Life expectancy greater than 12 weeks
    9.Serum alanine aminotransaminase (ALT) ≤2.5 x upper limit of normal (ULN) or serum aspartate aminotransferase (AST) ≤2.5 x ULN
    10.Total serum bilirubin ≤1.5 x ULN
    11.Serum creatinine ≤1.5 x ULN
    12.Haemoglobin ≥90 g/L, absolute neutrophil count ≥1.5 x 109/L, platelets ≥100 x 109/L
    13.Prothrombin time (PT) ≤1.5 x ULN
    14.Men and women of childbearing potential must use adequate birth control measures (e.g. abstinence, oral contraceptives, intrauterine device, barrier method with spermicide, implantable or injectable contraceptives or surgical sterilization). Women must be either postmenopausal (no menstrual period for a minimum of 1 year) or have a negative urine or serum pregnancy test on entry in the study (even if surgically sterilised).
    15.At least 28 days since major surgery and 7 days since skin/tumour biopsy
    16.The ability to swallow and retain oral medication
    17.Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other study procedures
    E.4Principal exclusion criteria
    1.Intracranial disease, unless there has been radiological evidence of stable intracranial disease > 6 months. In the case of a solitary brain metastasis, evidence of a disease-free interval of at least 3 months post-surgery. All patients previously treated for brain metastases must be stable and off corticosteroid therapy for at least 28 days
    2.Women who are pregnant, nursing, or planning pregnancy within 3 months after the last treatment
    3.Men who plan to father a child within 3 months of the last dose of treatment
    4.Significant cardiac disease including patients who have or who are at significant risk of developing prolongation of QTc
    5.Severe and/or uncontrolled medical disease
    6.Known chronic liver disease
    7.Known HIV infection
    8.Previous radiotherapy to 25% or more of the bone marrow and/or radiation therapy in the 4 weeks (28 days) prior to study entry
    9.Prior exposure to a KIT inhibitor
    10.Patients with KIT mutations that are known to be associated with PLX3397 resistance
    11.Current use of Chinese or herbal medication
    12.Any malabsorption syndrome (.e. partial gastrectomy, small bowel resection, Crohn’s disease or ulcerative colitis)
    13.Use of any investigational drug within 28 days prior to screening or patients who are involved in current research or have recently been involved in any research or clinical trials are excluded.
    E.5 End points
    E.5.1Primary end point(s)
    The primary objective of this study is to evaluate the efficacy of PLX3397 in KIT mutated advanced mucosal and acral melanoma by measuring the proportion of patients progression free at 6 months.

    Progression free survival is survival during the interval from the day of enrolment into the treatment phase until the first date (following the start of treatment) of either death or confirmed progressive disease according to RECIST (version 1.1). In the absence of RECIST progression clinical date of progression will be used.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Progression free survival times will be measured from the date of enrolment into the treatment phase until the first date (following start of treatment) of either death or confirmed progressive disease according to RECIST Version (1.1). Survival and progression free status are confirmed at each visit which is 4 weekly during first and 8 weekly during second year of treatment and survival status every six month after two years of treatment until confirmation of death or loss of contact with the patient. For patients who discontinue treatment during the trial, they will be followed up for up to 12 month for confirmation of survival status and progress free status.
    E.5.2Secondary end point(s)
    The main secondary endpoints of the trial are as follows:
    1.Evaluation of the response rate at 12 weeks
    2.Evaluation of the overall survival rate
    3.Evaluation of toxicity of the treatment

    In addition to the above enpoints the trial aims to evaluate correlation between frequency of KIT mutation in patients with advance acral and mucosal melanoma. Estimation of mechanism of drug resistance and changes in the circulating tumour cells and or free tumour DNA in the blood are amonge exploratory and secondary objectives of the trial in a subset of patients consenting to optional translational substudy.
    5.Estimation of the changes in the circulating tumour cells (CTCs)and or free tumour DNA.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Survival times will be measured from the date of the treatment phase until the date of death due to any cause or date last seen if still alive. Best overall response of a patient will be defined as the best tumour response that is achieved during or within 30 days after termination of active therapy (according to RECIST (version 1.1).
    Toxicity analyses will be carried out during treatment and interpreted in the light of similar analyses from other studies of PLX3397. Response to treatment, resistance to the drug and survival will be measured during the treatment presented together with their 95% confidence intervals as a guide to the ranges within which these effects might lie. These results will be interpreted in the light of similar analyses from other studies of KIT kinase inhibitors.
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Information not present in EudraCT
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned10
    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 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
    All patients will be followed up every 6 months after the second year of treatment until death of the last patient or for 12 months after the last patient has discontinued the treatment.
    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 months6
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days1
    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: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 18
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 6
    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 state24
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 24
    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)
    It is anticipated that patients will remain on the study drug (PLX3397) during the trial but continuation of treatment with PLX3397 following the end of the trial can not be guaranteed. If a patient continues to derive clinical benefit from using PLX3397, at the end of the trial, based on the clinical findings and at the discretion of the treating physician, applications would be made to Plexxikon for the supply of the drug on compassionate ground, free of charge.
    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 Decision2015-07-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-08-29
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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