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    Summary
    EudraCT Number:2018-004591-35
    Sponsor's Protocol Code Number:ADVL1211
    Clinical Trial Type:Outside EU/EEA
    Date on which this record was first entered in the EudraCT database:2018-12-14
    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
    H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED
    Expand All   Collapse All
    A. Protocol Information
    A.2EudraCT number2018-004591-35
    A.3Full title of the trial
    A PHASE 1 STUDY OF XL184 (CABOZANTINIB, IND# 116059) IN CHILDREN AND ADOLESCENTS WITH RECURRENT OR REFRACTORY SOLID TUMORS, INCLUDING CNS TUMORS
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Cabozantinib S-Malate in Treating Younger Patients With Recurrent or Refractory Solid Tumors
    A.4.1Sponsor's protocol code numberADVL1211
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/134/2016
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNational Cancer Institute Cancer Therapy Evaluation Program (NCI/CTEP)
    B.1.3.4CountryUnited States
    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 supportNCI/CTEP
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIpsen
    B.5.2Functional name of contact pointIpsen Medical Director
    B.5.3 Address:
    B.5.3.1Street Address5 avenue du Canada
    B.5.3.2Town/ cityLes Ulis
    B.5.3.3Post code91940
    B.5.3.4CountryFrance
    B.5.6E-mailclinical.trials@ipsen.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.2.1.1.2Name of the Marketing Authorisation holderIpsen Pharma
    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 nameCabozantinib
    D.3.2Product code XL184
    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 INNCabozantinib
    D.3.9.1CAS number 1140909-48-3
    D.3.9.3Other descriptive nameCABOZANTINIB
    D.3.9.4EV Substance CodeSUB93452
    D.3.10 Strength
    D.3.10.1Concentration unit U unit(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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
    Patients with relapsed or refractory solid tumors including CNS tumors and malignant melanoma
    E.1.1.1Medical condition in easily understood language
    Patients with cancer that has recurred or are not responding to treatment including cancer of the nervous system such as brain and some forms of cancer of the skin
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 dose of XL184 (cabozantinib) administered orally to children with refractory solid tumors including CNS tumors.
    To define and describe the toxicities of XL184 (cabozantanib) administered on this schedule.
    To characterize the pharmacokinetics of XL184 (cabozantanib) in children with refractory solid tumors.
    E.2.2Secondary objectives of the trial
    To preliminarily define the antitumor activity of XL184 (cabozantanib) within the confines of a Phase 1 study.
    To assess the biologic activity of XL184 (cabozantanib).
    To assess the biomarker response (CEA and calcitonin) in patients with medullary thyroid cancer treated with XL184.
    To evaluate overall survival from study entry through a five-year follow-up period.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Patients must have a body surface area >= 0.44 m^2 when enrolling on dose level -1; patients must have a body surface area >= 0.35 m^2 when enrolling on dose level 1, 2, or 3
    • PART A: Patients with relapsed or refractory solid tumors (excluding medullary thyroid cancer) including CNS tumors and malignant melanoma are eligible; patients must have had histologic verification of malignancy at original diagnosis or relapse except in patients with intrinsic brain stem tumors, optic pathway gliomas, or patients with pineal tumors and elevations of cerebrospinal fluid (CSF) or serum tumor markers including alpha-fetoprotein or beta-human chorionic gonadotropin (HCG)
    • Part B: Patients with medullary thyroid cancer (MTC), with or without bone marrow involvement, will be eligible for Part B; these patients will be enrolled at dose level 2, the recommended phase 2 dose determined in the dose escalation part of the study
    • Patients must have either measurable or evaluable disease
    • Patient's current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life
    • Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age
    • Patients must have fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy
    • For patients with solid tumors without known bone marrow involvement:
    • Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
    • Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
    • Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions); these patients will not be evaluable for hematologic toxicity; at least 5 of every cohort of 6 patients with a solid tumor must be evaluable for hematologic toxicity in the dose-escalation part of the study; if dose-limiting hematologic toxicity is observed, all subsequent patients enrolled must be evaluable for hematologic toxicity
    • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
    ◦2 to < 6 years: 0.8 mg/dL
    ◦6 to < 10 years: 1 mg/dL
    ◦10 to < 13 years: 1.2 mg/dL
    ◦13 to < 16 years: 1.5 mg/dL (male), 1.4 mg/dL (female)
    ◦>= 16 years: 1.7 mg/dL (male), 1.4 mg/dL (female)
    • Urine protein: =< 30 mg/dl in urinalysis or =< 1+ on dipstick, unless quantitative protein is < 1000 mg in a 24 hour (h) urine sample
    • Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age
    •S erum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 110 U/L; for the purpose of this study, the ULN for SGPT is 45 U/L
    • Serum albumin >= 2.8 g/dL
    • Prothrombin time (PT) and international normalized ratio (INR) =< 1.5 x ULN
    • Serum amylase =< 1.5 x ULN
    • Serum lipase =< 1.5 x ULN
    • A blood pressure (BP) =< the 95th percentile for age, height, and gender, and not receiving medication for treatment of hypertension; please note that 3 serial blood pressures should be obtained and averaged to determine baseline BP
    • Central nervous system function defined as: patients with seizure disorder may be enrolled if receiving non-enzyme inducing anticonvulsants and well controlled
    • No history of congenital prolonged corrected QT interval (QTc) syndrome, New York Heart Association (NYHA) class III or IV congestive heart failure (CHF)
    • No clinically significant cardiac arrhythmias, stroke or myocardial infarction within 6 months prior to enrollment
    • QTc =< 480 msec; Note: patients with grade 1 prolonged QTc (450-480 msec) at the time of study enrollment should have correctable causes of prolonged QTc addressed if possible (i.e. electrolytes, medications)
    • All patients and/or their parents or legally authorized representatives must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines
    • Archival tumor tissue slides from either initial diagnosis or relapse must be sent; if tumor tissue is unavailable, the study chair must be notified prior to enrollment
    E.4Principal exclusion criteria
    • Pregnant or breast-feeding women will not be entered on this study; 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 two methods of birth control - a medically accepted barrier method of contraceptive method (e.g., male or female condom) and a second effective contraceptive method of birth control - during protocol therapy and for at least 4 months after the last dose of XL184; abstinence is an acceptable method of birth control
    • Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible
    • Patients who are currently receiving another investigational drug are not eligible
    • Patients who are currently receiving other anti-cancer agents are not eligible
    • Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial
    • Patients must not be receiving any of the following potent cytochrome P450 family 3, subfamily A, polypeptide 4 cytochrome (CYP3A4) inducers or inhibitors: erythromycin, clarithromycin, ketoconazole, azithromycin, itraconazole, grapefruit juice or St. John's wort
    • Patients who are receiving systemic treatment anticoagulation are not eligible; patients receiving prophylactic systemic anticoagulation will be allowed as long as eligibility PT/INR requirements are met
    • Patients must not have received enzyme-inducing anticonvulsants within 14 days prior to enrollment
    • Patients who are receiving drugs that prolong QTc are not eligible
    • Patients must be able to swallow intact tablets; patients who cannot swallow intact tablets are not eligible
    • Patients with active bleeding are not eligible; specifically, no clinically significant gastrointestinal (GI) bleeding, GI perforation, intra-abdominal abscess or fistula for 6 months prior to enrollment, no hemoptysis or other signs of pulmonary hemorrhage for 3 months prior to enrollment
    • Patients with evidence of an acute intracranial or intratumoral hemorrhage on computed tomography (CT) or magnetic resonance imaging (MRI) are not eligible (patients with evidence of resolving hemorrhage will be eligible)
    • Patients who have had or are planning to have the following invasive procedures are not eligible:
    ◦Major surgical procedure, laparoscopic procedure, open biopsy or significant traumatic injury within 28 days prior to enrollment
    ◦Central line placement or subcutaneous port placement is not considered major surgery but must be placed at least 3 days prior to enrollment for external lines (e.g. Hickman or Broviac) and at least 7 days prior to enrollment for subcutaneous port
    ◦Core biopsy within 7 days prior to enrollment
    ◦Fine needle aspirate within 7 days prior to enrollment
    ◦Surgical or other wounds must be adequately healed prior to enrollment
    •Patients on antihypertensive therapy for control of blood pressure at the time of enrollment are not eligible
    • Patients with any medical or surgical conditions that would interfere with gastrointestinal absorption of this oral agent are not eligible
    • Patients who have an uncontrolled infection are not eligible
    • Patients who have received a prior solid organ transplantation are not eligible
    • 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)
    Maximum tolerated dose (MTD) and/or recommended phase 2 dose of cabozantinib S-malate, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
    E.5.1.1Timepoint(s) of evaluation of this end point
    28 days
    E.5.2Secondary end point(s)
    1. Pharmacokinetic (PK) parameters of cabozantinib S-malate including systemic exposure and drug clearance
    2. Disease response assessed according to Response Evaluation Criteria in Solid Tumors
    3. Overall survival (OS)
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. PK parameters - Course 1, day 1 (pre-dose and 4 hours post dose), course 1 day 21 (+/- 2 days) (pre-dose, 2, 4, 8 and 24 hours post dose), course 3 day 1 (pre-dose)
    2 & 3 - Up to 5 years
    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 No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    First administration in paediatric and adolesent population
    E.7.2Therapeutic exploratory (Phase II) No
    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
    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 years6
    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: 35
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 17
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 18
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 6
    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 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.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 41
    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)
    None
    G. Investigator Networks to be involved in the Trial
    H.4 Third Country in which the Trial was first authorised
    H.4.1Third Country in which the trial was first authorised: United States
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