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    Summary
    EudraCT Number:2011-001841-34
    Sponsor's Protocol Code Number:PLUTO2011
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-11-21
    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 number2011-001841-34
    A.3Full title of the trial
    A Randomised Phase II study investigating pazopanib vs weekly paclitaxel in relapsed or progressive Transitional Cell Carcinoma (TCC) of the urothelium.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    PLUTO - (pazopanib versus paclitaxel in relapsed urothelial tumours) A Randomised Phase II study investigating pazopanib vs weekly paclitaxel in relapsed or progressive Transitional Cell Carcinoma (TCC) of the urothelium
    A.3.2Name or abbreviated title of the trial where available
    PLUTO (PAZOPANIB VERSUS PACLITAXEL IN RELAPSED UROTHELIAL TUMOURS)
    A.4.1Sponsor's protocol code numberPLUTO2011
    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 SponsorNHS Greater Glasgow Health Board
    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 supportGlaxoSmithKline Research & Development Limited
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNHS Greater Glasgow & Clyde
    B.5.2Functional name of contact pointResearch & Development
    B.5.3 Address:
    B.5.3.1Street AddressTennent Institute, 38 Church Street, Western Infirmary
    B.5.3.2Town/ cityGlasgow
    B.5.3.3Post codeG11 6NT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01412111789
    B.5.6E-mailR&DIMP@ggc.scot.nhs.uk
    B.Sponsor: 2
    B.1.1Name of SponsorUniversity of Glasgow
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 Votrient
    D.2.1.1.2Name of the Marketing Authorisation holderGlaxo Group Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 namePazopanib Hydrochloride (Votrient)
    D.3.2Product code GW786034B
    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 INNPazopanib Hydrochloride
    D.3.9.1CAS number 635702-64-6
    D.3.9.2Current sponsor codeNot applicable
    D.3.9.3Other descriptive nameNot applicable
    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
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPazopanib Hydrochloride
    D.3.9.1CAS number 635702-64-6
    D.3.9.2Current sponsor codeNot applicable
    D.3.9.3Other descriptive nameNot applicable
    D.3.9.4EV Substance CodeAS5
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number400
    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 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 Information not present in EudraCT
    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 namePaclitaxel
    D.3.2Product code Not Applicable
    D.3.4Pharmaceutical form Concentrate for 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 INNPaclitaxel
    D.3.9.1CAS number 33069-62-4
    D.3.9.2Current sponsor codeNot applicable
    D.3.9.3Other descriptive nameNot applicable
    D.3.9.4EV Substance CodeAS4
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6
    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.3.11.13.1Other medicinal product typeantineoplastic
    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
    Relapsed or progressive Transitional Cell Carcinoma (TCC) of the urothelium
    E.1.1.1Medical condition in easily understood language
    Relapsed or progressive Transitional Cell Carcinoma (TCC) of the urothelium
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.0
    E.1.2Level LLT
    E.1.2Classification code 10044426
    E.1.2Term Transitional cell carcinoma urethra
    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 14.0
    E.1.2Level LLT
    E.1.2Classification code 10044420
    E.1.2Term Transitional cell carcinoma of the bladder 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 14.0
    E.1.2Level PT
    E.1.2Classification code 10044407
    E.1.2Term Transitional cell cancer of the renal pelvis and ureter
    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 the study is to investigate whether pazopanib increases the overall survival time for patients with relapsed or progressive disease; in comparison to the current standard treatment, paclitaxel.
    E.2.2Secondary objectives of the trial
    The secondary objectives of the study are to measure the following for pazopanib in comparison to the current standard treatment, paclitaxel: -Toxicity -Clinical benefit at 12 weeks -Progression free survival time -Clinical benefit at 24 weeks -Quality of Life
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Histologically or cytologically confirmed TCC (bladder, renal pelvis, ureter, urethra), which is locally advanced or metastatic (T4b and/or N1-3 and/or M1). Patients with mixed or differentiation pattern pathology will be permitted entry providing that TCC is a component pathology. 2.Progressive disease during or after one prior platinum-based chemotherapy regimen for advanced disease or as peri-operative therapy for muscle-invasive / node positive disease (if completed < 12 months prior to documented disease progression). The regimen must have included either cisplatin or carboplatin. Patients who have had two platinum containing regimens are eligible if one of these was given peri-operatively, and provided that there was a chemotherapy-free interval of at least 12 months between completing the 1st course and commencing the second course of chemotherapy. Chemotherapy given during radical radiotherapy as a radiosensitizer will not be considered as a chemotherapy treatment for the purposes of study eligibility. 3.Age ≥ 18 years. 4.Measurable disease by RECIST 1.1. 5.Adequate organ function as defined by the following criteria: •Total serum bilirubin ≤1.5 x upper level of normal (ULN). •Serum transaminases <2.5 x ULN. Concomitant elevations of transaminases and bilirubin are not permitted. •Creatinine clearance >30ml/min (calculated by Cockcroft Gault equation) or Creatinine ≤1.5 x ULN. •Absolute neutrophil count (ANC) ≥1500/mm3 without growth factor support •Platelets ≥ 100,000/mm3 •Urine protein to creatinine ratio (UPC) < 110 mg/mmol (1g/g) (or total urinary protein < 1g/24hrs) •Activated partial thromboplastin time (APTT) ≤1.2 x ULN •International normalised ratio (INR)≤ 1.2 6.Signed and dated informed consent indicating that the patient has been informed of all the pertinent aspects of the trial prior to enrolment. 7.A negative pregnancy test for women of childbearing potential. 8.Life expectancy of 3 months or more. 9.Willingness and ability to comply with scheduled visits, treatment plans and laboratory tests and other study procedures. 10.ECOG performance status of 0 or 1.
    E.4Principal exclusion criteria
    1.Congestive heart failure, myocardial infarction, coronary artery bypass graft or thrombotic cerebrovascular event in the previous six months, or ongoing severe or unstable arrhythmia requiring medication. Patients with rate controlled atrial fibrillation are permitted to enter the study. 2.History of clinically significant bleeding in the 6 months prior to study initiation (including haemoptysis, cerebrovascular bleed or haematemesis; patients with haematuria are permitted entry as long as there is no indication for intervention). 3.Major surgery or trauma within 28 days prior to first dose of investigational product and/or presence of any unhealed wound, fracture, or ulcer (procedures such as catheter placement not considered to be major surgery). 4.Cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or deep venous thrombosis (DVT) within the past 6 months. Note: Subjects with recent DVT who have been therapeutically anti-coagulated for at least 6 weeks are eligible. 5.History of another malignancy in the last 5 years (other than treated squamous/basal cell skin cancer, treated early stage cervical cancer or treated / biochemically stable, organ confined prostate cancer). 6.Ongoing major gastrointestinal disease including unstable inflammatory bowel disease or bleeding peptic ulcer disease. 7.Known endobronchial lesions which have a high risk of pulmonary haemorrhage . 8.Previously identified brain, or central nervous system (CNS) metastases at baseline, with the exception of those subjects who have previously-treated CNS metastases (surgery ± radiotherapy, radiosurgery, or gamma knife) and who meet both of the following criteria: a) are asymptomatic and b) have no requirement for steroids or enzyme-inducing anticonvulsants in prior 28 days. 9.Pregnant or breastfeeding. Patients must be surgically sterile or be postmenopausal, or must agree to use effective contraception during the period of therapy. Male patients must be surgically sterile or agree to use effective contraception. 10.Administration of any investigational drug within 28 days or 5 half lives, whichever is longer, prior to receiving the first dose of study treatment 11.Treatment with any of the following anti-cancer therapies: Radiation therapy, surgery or tumour embolisation within 14 days prior to the first dose of study medication Chemotherapy, immunotherapy, biologic therapy, investigational therapy within 28 days or 5 half-lives of a drug (whichever is longer) prior to the first dose of study medication. 12.Peripheral neuropathy of grade 2 or more. 13.Any on-going toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is progressing in severity, except alopecia. 14.Other severe or uncontrolled systemic disease or evidence of any other significant clinical disorder or lab finding that makes it undesirable for the patient to participate in the study. 15.Any psychological, familial, sociological or geographical consideration potentially hampering compliance with the study protocol and follow up schedule; those considerations should be discussed with the patient before registration in the trial. 16.Known HIV or other chronic immunosuppressive disease. 17. QTc that is immeasurable or >480 msec on screening ECG. (Note: If a subject has a QTc interval >480 msec on screening ECG, the screening ECG may be repeated twice (at least 24 hours apart). The average QTc from the three screening ECGs must be <480 msec in order for the subject to be eligible for the study.) Patients who are receiving a drug that has a risk of Torsades de Pointes are excluded if QTc is ≥ 460 msec. Note: the method for estimating QTc must be consistent between all time points for any individual patient. 18.History of symptomatic peripheral vascular disease within 6 months prior to trial entry. 19.Uncontrolled hypertension (blood pressure (BP) >150/90 at screening visit – if screening value is higher than this, then study entry will be permitted if there is evidence documented by a trained healthcare professional of controlled blood pressure during the 4 weeks prior to study entry). 20.Evidence of active bleeding or bleeding diathesis. 21.Recent haemoptysis (greater than or equal to ½ teaspoon of red blood within 8 weeks before first dose of study drug). 22.Patients who are unable or unwilling to withdraw potent CYP3A4 inhibitors, inhibitors of P-glycoprotein or BCRP (see Appendix VI). 23.Prior hypersensitivity to cremophor or known sensitivity to any component of pazopanib. 24.Prior treatment with paclitaxel or pazopanib
    E.5 End points
    E.5.1Primary end point(s)
    Overall survival.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary endpoint is overall survival. Data relating to any patient death that occurs throughout the study period will be captured via the Case Report Form (CRFs), both during the treatment period and active follow up.
    E.5.2Secondary end point(s)
    The secondary end points of the study are to measure the following for pazopanib in comparison to the current standard treatment, paclitaxel: -Toxicity -Clinical benefit at 12 weeks -Progression free survival time -Clinical benefit at 24 weeks -Quality of Life
    E.5.2.1Timepoint(s) of evaluation of this end point
    -Toxicity will be assessed at all study visits while the patient is receiving treatment and until any ongoing toxicity is resolved. -Clinical benefit will be assessed after 12 and 24 weeks on treatment. Assessment will be by CT scans/MRI as appropriate and the tumour response (stable disease (SD), partial response (PR) or complete response (CR) will be reported in accordance with RECIST 1.1. -Progression free survival will be assessed on an ongoing basis, by radiology and/or any other means of idenitification, or the opinion of the investigator. -Quality of Life (QoL)will be assessed continuously throughout the trial. QoL questionnaires will be collected at baseline (Week 1), and at Weeks 9, 17, 25, 37, 49, 61, 73, 85 and 97.
    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 No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    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) 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 concerned30
    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
    For the purpose of the Clinical Trial Authorisation the trial is deemed to have ended 30 days after the last patient remaining on treatment receives the last dose of pazopanib. For the purposes of the main REC approval, the study end date is deemed to be the date of the last data capture.
    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 months8
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months8
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number 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: 42
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 98
    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 state140
    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)
    Patients randomised to receive paclitaxel will receive 24 weeks of treatment (maximum), unless their disease progresses, the patient dies, or the patient discontinues treatment due to toxicity. Patients randomised to receive pazopanib will receive study treatment until their disease progresses, death or until they discontinue treatment due to toxicity. No provision has been made for patients to receive pazopanib beyond the end of the study at 103 weeks since…..
    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 Decision2012-01-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-11-07
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-09-01
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