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    Summary
    EudraCT Number:2013-000762-11
    Sponsor's Protocol Code Number:62113-55115
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2014-07-08
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2013-000762-11
    A.3Full title of the trial
    A randomized double-blind phase II study evaluating the role of maintenance therapy with cabozantinib in High Grade Undifferentiated Uterine Sarcoma (HGUS) after stabilization or response to doxorubicin +/- ifosfamide following surgery or in metastatic first line treatment
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A randomized double-blind phase II study evaluating the role of maintenance therapy with cabozantinib in High Grade Undifferentiated Uterine Sarcoma (HGUS) after stabilization or response to doxorubicin +/- ifosfamide following surgery or in metastatic first line treatment
    A.4.1Sponsor's protocol code number62113-55115
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01979393
    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 SponsorEuropean Organisation for Research and Treatment of Cancer (EORTC)
    B.1.3.4CountryBelgium
    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 supportExelixis
    B.4.2CountryUnited States
    B.4.1Name of organisation providing supportEuropean Organisation for Research and Treatment of Cancer (EORTC)
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEuropean Organisation for Research and Treatment of Cancer (EORTC)
    B.5.2Functional name of contact pointClinical Operations Department
    B.5.3 Address:
    B.5.3.1Street AddressAvenue E. Mounier 83/11
    B.5.3.2Town/ cityBrussels
    B.5.3.3Post code1200
    B.5.3.4CountryBelgium
    B.5.4Telephone number+3227741062
    B.5.5Fax number+3227741030
    B.5.6E-mailregulatory@eortc.be
    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 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 mg milligram(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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    High Grade Undifferentiated Uterine Sarcoma (HGUS)
    E.1.1.1Medical condition in easily understood language
    Uterine Sarcoma
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level LLT
    E.1.2Classification code 10046821
    E.1.2Term Uterine sarcoma NOS
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The main objective of the trial is to assess, in High Grade Undifferentiated Uterine Sarcoma (HUGS), the activity (PFS at 4 months) of maintenance treatment with cabozantinib when compared with placebo after clinical benefit from standard chemotherapy (doxorubicin +/- ifosfamide) (given as an adjuvant treatment after curative surgery, or for locally advanced or metastatic disease).
    E.2.2Secondary objectives of the trial
    ♦ To assess the efficacy of maintenance treatment with cabozantinib when compared with placebo, using progression-free survival, overall survival, response rate, and duration of response among patients with measurable disease.
    ♦ To describe the safety profile of cabozantinib in patients with HGUS
    ♦ To explore the response rate to chemotherapy in first line treatment for patients with measurable disease
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) At registration
    - Patients who are suitable for treatment with doxorubicin +/- ifosfamide and fall within one of the following patient populations:
    . Locally advanced: newly diagnosed high grade undifferentiated uterine sarcoma with advanced disease (stage III or stage IV) or residual disease after primary surgery
    . Metastatic: diagnosed high grade undifferentiated uterine sarcoma with disease relapse after local treatment for primary tumor
    - 1 formalin fixed paraffin embedded block of tumor tissue (if not available, at least 1 haematoxylin/eosin and 15 unstained slides) is sent after registration of a patient. Histological central review is mandatory to confirm histology and grade.
    - Patients must be at least 18 years old
    - Before patient registration, written informed consent for central collection of tissue block or slides and any other trial-specific procedures must be obtained
    2) At Randomization
    - Central pathological confirmation: Histological evidence of high grade undifferentiated uterine sarcoma
    - Non-progressive patients (CR, PR, SD) at the end of the first line treatment (standard chemotherapy consisting of 4 to 6 cycles of doxorubicin alone or in combination with ifosfamide)
    - Patients able to swallow and retain oral tablets.
    - WHO/ECOG performance status 0-2
    - The subject has organ and marrow function and laboratory values as follows before randomization
    . Absolute neutrophil count (ANC) ≥ 1500/mm3 without colony stimulating factor support for 7 days
    . Platelets ≥ 100,000/mm3
    . Hemoglobin ≥ 9 g/dL
    . Bilirubin ≤ 1.5 × the upper limit of normal. For subjects with known Gilbert’s disease, bilirubin ≤ 3.0 mg/dL
    . Serum albumin ≥ 2.8 g/dl
    . Serum creatinine ≤ 1.5 × the upper limit of normal or creatinine clearance (CrCl) ≥ 50 mL/min. For creatinine clearance estimation, the Cockcroft and Gault equation should be used: CrCl (mL/min) = (140 - age) × wt (kg) / (serum creatinine × 72) × 0.85
    . Alanine aminotransferase and aspartate aminotransferase ≤ 3.0 × the upper limit of normal
    . Lipase < 2.0 × the upper limit of normal and no radiologic or clinical evidence of pancreatitis
    . Urine Dipstick: If Urine Dipstick ≥ 2+, determine Urine Protein to Creatinine Ratio (UPCR) by quantitative analysis; if UPCR ≥ 1, then a 24-hour urine protein must be assessed. Any patient with protein > 150 mg over 24 hours would not be eligible.
    . Serum phosphorus, calcium, magnesium and potassium ≥ lower limit of normal
    . Prothrombin time (PT) or international normalized ratio (INR) ≤ 1.2 × the upper limit of normal
    - Clinically normal cardiac function based on the institutional lower limit of normal (LVEF assessed by MUGA or ECHO), normal 12 lead ECG (no prolongation of corrected QT interval (QTc) > 480 msecs) and no history of any one or more of the following cardiovascular conditions within the past 6 months:
    . Cardiac angioplasty or stenting
    . Myocardial infarction
    . Unstable angina
    . Coronary artery bypass graft surgery
    . Symptomatic peripheral vascular disease
    . Class III or IV congestive heart failure, as defined by the New York Heart Association
    - Women of child bearing potential must have a negative serum/urine pregnancy test within 3 days prior to the first dose of study treatment.
    - Patients of childbearing / reproductive potential should use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 4 months after the last study treatment.
    - Female subjects who are breast feeding should discontinue nursing prior to the first dose of study treatment and until 8 weeks after the last study treatment.
    - Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
    E.4Principal exclusion criteria
    At randomization
    - The following tumor types are NOT eligible: low-grade ESS, leiomyosarcoma (low, intermediate or high grade), carcinosarcoma, adenosarcoma, rhabdomyosarcoma (alveolar or embryonal) and soft tissue PNET of uterus/cervix.
    - concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment
    - patient with poorly controlled hypertension defined at baseline as blood pressure (BP) >150/90
    - patients who have suffered a cerebrovascular accident at any time in the past, patients who have suffered a transient ischemic attack in the past 6 months, patients who have suffered a deep venous thrombosis (DVT) or a pulmonary embolism in the past 6 months
    note: Patients with recent DVT who have been treated with therapeutic anti-coagulating agents and remained stable for at least 6 weeks are eligible.
    - Gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including:
    ♦ Any of the following within 28 days before the first dose of study treatment
    - "known" intra-abdominal tumor/metastases invading GI mucosa
    - active peptic ulcer disease,
    - inflammatory bowel disease (including ulcerative colitis and Crohn’s disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis
    - malabsorption syndrome
    ♦ Any of the following within 6 months before the first dose of study treatment:
    - abdominal or vaginal fistula
    - gastrointestinal perforation
    - bowel obstruction or gastric outlet obstruction
    - intra-abdominal abscess. Note: Complete resolution of an intra-abdominal abscess must be confirmed prior to initiating study treatment (Cabozantinib/placebo) even
    - patients with radiographic evidence of cavitating pulmonary lesion(s).
    - patients with tumor in contact with, invading or encasing any major blood vessels.
    - patients evidence of tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of study treatment (Cabozantinib/placebo).
    - evidence of active bleeding or bleeding diathesis.
    - hemoptysis ≥ 0.5 teaspoon (2.5ml) of red blood within 3 months before the first dose of study treatment. Note: Any patient with a prior history of hemoptysis associated with metastatic disease must have a bronchoscopy to rule out endobronchial lesions. A patient with an endobronchial lesion would be excluded from study.
    - signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment
    - clinically-significant gastrointestinal bleeding within 6 months before the first dose of study treatment
    - prior major surgery or trauma within 6 weeks prior to first dose of study drug and any wound, fracture, or ulcer should be completely healed.
    - concurrent or planned treatment with strong inhibitors or inducers of cytochrome P450 3A4/5 (a one week wash-out period is necessary for patients who are already on these treatments)
    - contraindications to cabozantinib (e.g. no known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to cabozantinib)
    - planned use of chemotherapy, radiation therapy, radionuclide treatment, small molecule TKI or hormonal therapy, and any other investigational agent (Cabozantinib/placebo) during the treatment period.
    E.5 End points
    E.5.1Primary end point(s)
    Progression free survival rate
    E.5.1.1Timepoint(s) of evaluation of this end point
    at 4 months after randomization to cabozantinib or placebo
    E.5.2Secondary end point(s)
    1. Progression free survival rate
    2. Overall survival
    3. response rate and duration of response to cabozantinib
    4. Response rate to doxorubicin-based chemotherapy after registration on trial for the patients with measurable disease
    5. Quality of life (QoL)
    6. Safety of cabozantinib in HGUS
    E.5.2.1Timepoint(s) of evaluation of this end point
    1+2+3+4: prior to registration; prior to randomization; every 8 weeks during the first year of the maintenance period, then every 12 weeks; within 30 days after last dose (if no progression since randomization)
    5. prior to registration; prior to randomization; within 3 days prior to each cycle, every 8 weeks during the first year of the maintenance period, then every 12 weeks; within 30 days after last dose
    6. as of randomization, continuously per event up to 30 days after last dose; for patient who cross-over to cabozantinib after progression: every 4 weeks until further progression
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    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 Yes
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA27
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Belgium
    France
    Germany
    Italy
    Netherlands
    Spain
    United States
    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
    End of study occurs when all of the following criteria have been satisfied:
    -Thirty days after all patients have stopped protocol treatment.
    -The trial is mature for the analysis of the primary endpoint as defined in the protocol, ie. all randomized patients have adequate follow-up to determine their PFS status at 4 months.
    -The database has been fully cleaned and frozen for this analysis.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months0
    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.1.1.1In 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) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 64
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 14
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2014-07-08. Yes
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 63
    F.4.2.2In the whole clinical trial 78
    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)
    After progression:
    - Cabozantinib arm: the treatment will be left to the discretion of the treating physician.
    - Placebo arm: patients may receive cabozantinib.

    Patients discontinuing therapy in the absence of progression should not receive any other cancer treatment before their disease progresses, unless this is clearly not in the interest of the patient.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-08-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-11-10
    P. End of Trial
    P.End of Trial StatusOngoing
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