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    Summary
    EudraCT Number:2013-003595-12
    Sponsor's Protocol Code Number:ADVL1322-VEG116731
    Clinical Trial Type:Outside EU/EEA
    Date on which this record was first entered in the EudraCT database:2013-09-04
    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
    H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED
    Expand All   Collapse All
    A. Protocol Information
    A.2EudraCT number2013-003595-12
    A.3Full title of the trial
    A Phase II Study of Pazopanib in Children, Adolescents and Young Adults with Refractory Solid Tumors.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study of pazopanib in children, adolescents and young adults with cancer that has come back after treatment or is difficult to treat.
    A.4.1Sponsor's protocol code numberADVL1322-VEG116731
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/191/2012
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorGlaxoSmithKline
    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 supportGlaxoSmithKline
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGlaxoSmithKline Research & Development Ltd
    B.5.2Functional name of contact pointClinical Trials Helpdesk
    B.5.3 Address:
    B.5.3.1Street AddressIron Bridge Road, Stockley Park West
    B.5.3.2Town/ cityUxbridge, Middlesex
    B.5.3.3Post codeUB11 1BU
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+4402089904466
    B.5.5Fax number+4402089901234
    B.5.6E-mailGSKClinicalSupportHD@gsk.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 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
    D.3.2Product code GW786034
    D.3.4Pharmaceutical form Tablet and powder for oral solution
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPOral use
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    relapsed solid tumours in children, adolescents and young adults.
    E.1.1.1Medical condition in easily understood language
    solid cancers in children, adolescents and young adults.
    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 determine the investigator assessed objective response rate of pazopanib in children, adolescents and young adults (subjects) with relapsed or refractory rhabdomyosarcoma, non-rhabdomyosarcomatous soft tissue sarcomas, and
    Ewing sarcoma.
    E.2.2Secondary objectives of the trial
    1.Determine the investigator assessed objective response rate of pazopanib in children, adolescents, and young adults with relapsed or refractory osteosarcoma, neuroblastoma (measurable and/or evaluable) and hepatoblastoma
    2.Further define and describe the toxicities of oral pazopanib in subjects with recurrent/refractory solid tumors
    3.Determine progression free survival in subjects with relapsed or refractory solid tumors
    4.Determine the time to progression in subjects with relapsed or refractory solid tumors
    5.Determine the therapeutic activity (a confirmed complete or partial response or stable disease for at least 4 cycles) per stratum
    6.Further examine the biologic relationship between tumor response and angiogenic cytokines
    7.Further assess VEGF and KDR genotype/phenotype relationships in subjects with cancer treated with pazopanib
    8.Further explore pazopanib pharmacokinetic/ pharmacodynamic relationships with
    biomarkers and clinical outcomes, including hypertension
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Age: Patients must be at least 1 and less than or equal to 18 years of age at the time of study entry.
    Diagnosis: Patients must have had histologic verification of one of the malignancies listed below at original diagnosis or at relapse.
    a) Rhabdomyosarcoma
    b) Non-rhabdomyosarcomatous Soft Tissue Sarcoma (including desmoplastic small round cell tumor)
    c) Ewing Sarcoma/Peripheral PNET
    d) Osteosarcoma
    e) Neuroblastoma (Measurable)
    f) Neuroblastoma (Evaluable)
    g) Hepatoblastoma
    Body Surface Area (for subjects taking tablet formulation only): Patients who will be receiving the tablet formulation must have a BSA > 0.48 m2 at the time of study enrollment.
    Disease Status: Patients must have radiographically measurable disease. Patients with neuroblastoma who do not have measurable disease but have MIBG+ evaluable disease are eliglble
    Performance Level: Patients must have a Lansky or Karnofsky performance status score of ≥ 50,
    corresponding to ECOG categories 0, 1 or 2. Use Karnofsky for patients >16 years of age and Lansky for patients ≤ 16 years of age
    Prior Therapy: Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering
    this study.
    Organ Function Requirements:
    Adequate Bone Marrow Function defined as; Peripheral absolute neutrophil count (ANC) >1000/uL; Platelet count >75,000/uL (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment); and Hemoglobin >8.0 g/dL (may receive RBC transfusions).
    Adequate Renal and Metabolic Function defined as:
    a. Creatinine clearance or radioisotope GFR >70mL/min/1.73 m2 or
    b. A serum creatinine based on age/gender.
    c. Urine protein: creatinine ratio of <1 or a urinalysis that is negative for protein; or, 24-hour urine protein level < 1000 mg/dL
    d. No more than Grade 1 abnormalities of potassium, calcium (confirmed by ionized calcium), magnesium and phosphorous (supplementation allowed).
    Adequate Liver Function defined as:
    a. Total bilirubin equal to less than 1.5 x upper limit of normal (ULN) for age;
    b. SGPT (ALT) equal to less than 2.5 x ULN (for the purpose of this study, the ULN for SGPT is 45 U/L);
    c. Serum albumin equal to more than 2 g/dL.
    Adequate Cardiac Function defined as:
    a. Shortening fraction of equal to more than 27% by echocardiogram (while not receiving medications for cardiac function), or
    b. Ejection fraction of ≥ 50% by gated radionuclide study (while not receiving medications for cardiac function)
    c. QTc < 450 msec
    d. Must not have a history of myocardial infarction, severe or unstable angina, peripheral vascular disease or familial QTc prolongation.
    Adequate Blood Pressure Control defined as:
    A blood pressure (BP) ≤ the 95th percentile for age, height, and gender measured.
    - Patients on stable doses of no more than one anti-hypertensive medication, with a baseline BP ≤ 95th percentile for age, height and gender, will be eligible.
    Central Nervous System Function defined as:
    a. Patients with a known history of seizures must have well-controlled seizures and may not be receiving enzyme-inducing anti-convulsants
    b. CNS toxicity ≤ Grade 2.
    Adequate Coagulation defined as:
    PT and PTT ≤ 1.2 x upper limit of normal and an INR ≤ 1.2.
    E.4Principal exclusion criteria
    1.Pregnancy or Breast-Feeding:
    Pregnant or breast-feeding women are not eligible for this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies. Negative pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method beginning at the signing of the informed consent until at least 30 days after the last dose of the study drug. The definition of adequate contraception will be based on the judgment of the principal investigator or a designated associate. Study drug may also potentially be secreted in milk and therefore breastfeeding women are excluded.
    2.Concomitant Medications
    Corticosteroids: Patients requiring corticosteroids who have not been on a stable or decreasing dose of corticosteroid for the 7 days prior to enrollment are not eligible.
    Investigational Drugs: Patients who are currently receiving another investigational drug are not eligible.
    Anti-Cancer Agents or Radiation Therapy: Patients who are currently receiving other anti-cancer agents or radiation therapy are not eligible.
    Anti-hypertensives: Patients who are currently receiving more than one anti-hypertensive medication (Grade 3) or whose blood pressure is not well controlled are not eligible for study enrollment.
    Anticoagulation: Patients must not be on therapeutic anticoagulation (Warfarin (coumadin®) and/or low molecular weight heparin are prohibited.) Prophylactic anticoagulation (ie intralumenal heparin) of venous or arterial access devices is allowed.
    Anti-inflammatory and anti-platelet agents: Patients currently receiving aspirin, and/or ibuprofen, or other NSAIDs are not eligible.
    CYP3A4 Substrates and drugs causing QTc prolongation: Patients receiving drugs metabolized through several of the specific P450 cytochrome isoforms and those receiving drugs with a known risk of torsades de pointes are not eligible. List includes grapefruit juice for 14 days prior to enrollment.
    3.Thyroid Replacement Therapy: Patients who require thyroid replacement therapy are not eligible if they have not been receiving a stable replacement dose for at least 4 weeks prior to study enrollment.
    Patients who are unable to swallow tablets or liquid are not eligible.
    4.Infection: Patients who have an uncontrolled infection are not eligible.
    5.Bleeding and Thrombosis: Patients will be excluded if any of the following are present:
    Evidence of active bleeding, intratumoral hemorrhage, or bleeding diathesis.
    History (within 6 months prior to study enrollment) of arterial thromboembolic events, including transient ischemic attack (TIA) or cerebrovascular accident (CVA).
    History (within 6 months prior to study enrollment) of pulmonary embolism, DVT, or other venous thromboembolic event.
    History of hemoptysis within 6 weeks prior to study enrollment.
    6.Patients with known involvement of the CNS by malignancy will be excluded.
    7.Surgery: Patients who have had or are planning to have the following invasive procedures will be excluded:
    a. Major surgical procedure, laparoscopic procedure, open biopsy or significant traumatic injury within 28 days prior to Day 1 therapy. (Subcutaneous port placement or central line placement is not considered major surgery but must be placed greater than 48 hours from planned Day 1 of therapy.)
    b. Core biopsy within 7 days prior to Day 1 therapy. Note: Routine bone marrow aspirate and biopsy for the purposes of disease staging are not part of these exclusion guidelines.
    c. Fine needle aspirate or central line placement within 48 hours prior to Day 1 therapy.
    8.Patients with serious or non-healing wound, ulcer, or bone fracture.
    9.History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days of study enrollment.
    10.Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible.
    E.5 End points
    E.5.1Primary end point(s)
    Primary Endpoint: Objective response rate in subjects with rhabdomyosarcoma, non-rhabdomyosarcomatous soft tissue sarcomas and Ewing sarcoma:
    This is defined as the percentage of subjects achieving either a confirmed complete or partial tumor response determined by the investigator as per response criteria (dependent upon tumor type). Subjects with unknown or missing response will be treated as non-responders, i.e. they will be included in the denominator when calculating the percentage. 90% confidence intervals will be provided and the data will be presented for each stratum.
    E.5.1.1Timepoint(s) of evaluation of this end point
    From randomization until the time of the first documented evidence of a confirmed complete response or partial response. It is estimated that the analysis will occur in November 2015.
    E.5.2Secondary end point(s)
    Secondary Endpoints:
    1) Objective response rate in subjects with osteosarcoma, neuroblastoma and hepatoblastoma:
    The analysis method will be the same as that described for the primary endpoint. If recruitment is stopped in a non-primary histology group(s) and it has less than 10 subjects, the response data will display summary statistics. The analysis method will be the same as that described for PFS.

    2) Define and describe toxicities of oral pazopanib:
    Analyses will include evaluations of the frequency of adverse events (AEs), serious adverse events (SAEs) and AEs that results in a pazopanib dose modification or discontinuation, along with evaluations of clinical laboratory parameters and vital signs. AEs and hematology, coagulation parameters and clinical chemistry will be summarized using NCI-CTCAE v4.0.

    3) Progression free survival (PFS):
    This is defined as the interval between the date of study entry and the earliest date of disease progression or death due to any cause. Subjects are considered to have progressive disease if they have documented progression based on radiologic assessment as determined by investigator review. For subjects who do not progress or die PFS will be censored at the time of initiation of alternative anticancer therapy or date of last adequate assessment.
    PFS will be summarized using a Kaplan-Meier survival curve. For the pazopanib treatment group, the Kaplan-Meier estimate for the median progression-free survival time and the first and third quartiles will be presented, along with a naive approximate 93% confidence interval if there are a sufficient number of progressions or deaths.

    4) Time to progression (TTP):
    This is defined as the interval between the date of study entry and the earliest date of disease progression or death due to disease under study. Subjects are considered to have progressive disease if they have documented progression based on radiologic assessment as determined by investigator review.

    5) Therapeutic activity (clinical benefit):
    This is defined as the percentage of subjects achieving either a complete or partial tumor response or stable disease for at least 16 weeks. 90% confidence intervals will be produced to characterize the variability around the point estimate.
    E.5.2.1Timepoint(s) of evaluation of this end point
    For the secondary objectives listed above, the timepoints are:

    1) From randomization until the time of the first documented evidence of a confirmed complete response or partial response. It is estimated that the analysis will occur in Nov 2015.

    2) From randomization until the end of the treatment period (up to cycle 24). It is estimated that the analysis will occur in Nov 2015.

    3) and 4) From randomization until the first documented sign of investigator-assessed disease progression or death. It is estimated that the analysis will occur in Nov 2015.

    5) From randomization until the time of the first documented evidence of a confirmed complete response, partial response or stable disease. It is estimated that the analysis will occur in Nov 2015.
    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 No
    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 Yes
    E.6.13.1Other scope of the trial description
    Examine biologic markers
    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 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 No
    E.8.3 Will this trial be conducted at a single site globally? No
    E.8.4 Will this trial be conducted at multiple sites globally? Yes
    E.8.6 Trial involving sites outside the EEA
    E.8.6.2Trial being conducted completely outside of the EEA Yes
    E.8.6.3Specify the countries outside of the EEA in which trial sites are planned
    Canada
    United States
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.2In all countries concerned by the trial years2
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 154
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 154
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 154
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 154
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 154
    F.1.3Elderly (>=65 years) No
    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 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 Yes
    F.3.3.7.1Details of other specific vulnerable populations
    Children, adolescents and young adults
    F.4 Planned number of subjects to be included
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 154
    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 who are removed from protocol therapy are to be followed for a maximum of five years or until they meet at least one of the criteria for Off Study (Death, Lost to follow-up, Entry into another study with tumor therapeutic intent, Withdrawal of consent for any further data submission, the study is closed for any reason). Follow-up data will be required unless consent was withdrawn.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation CHILDREN'S ONCOLOGY GROUP
    G.4.3.4Network Country United States
    H.4 Third Country in which the Trial was first authorised
    H.4.1Third Country in which the trial was first authorised: United States
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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