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    Summary
    EudraCT Number:2013-002109-73
    Sponsor's Protocol Code Number:NiCCC2013
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2017-04-06
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2013-002109-73
    A.3Full title of the trial
    A Randomised Phase II Study of Nintedanib (BIBF1120) Compared to Chemotherapy in Patients with Recurrent Clear Cell Carcinoma of the Ovary or Endometrium
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    NiCCC - A Randomised Phase II Study Of Nintedanib (BIBF1120) Compared To Chemotherapy in Patients With Recurrent Clear Cell Carcinoma Of The Ovary Or Endometrium
    A.3.2Name or abbreviated title of the trial where available
    NiCCC Trial (BIBF1120)
    A.4.1Sponsor's protocol code numberNiCCC2013
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN50772895
    A.5.4Other Identifiers
    Name:European Network Gynaecological Oncological TrialsNumber:ENGOT GYN-1
    Name:Sponsor ReferenceNumber:GN12ON259
    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 SponsorGreater 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 supportBoehringer Ingelheim Limited
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportCancer Research UK (Clinical Trials Awards and Advisory Committee)
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBeatson West of Scotland Cancer Centre
    B.5.2Functional name of contact pointDr Rosalind Glasspool
    B.5.3 Address:
    B.5.3.1Street Address1053 Great Western Road
    B.5.3.2Town/ cityGLASGOW
    B.5.3.3Post codeG12 0YN
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01413017106
    B.5.6E-mailros.glasspool@gmail.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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/13/1123
    D.3 Description of the IMP
    D.3.1Product nameNintedanib (BIBF1120)
    D.3.4Pharmaceutical form Capsule, soft
    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 INNNintedanib
    D.3.9.1CAS number 928326-83-4
    D.3.9.3Other descriptive name BIBF 1120, Vargatef
    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 number150
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNintedanib
    D.3.9.1CAS number 928326-83-4
    D.3.9.3Other descriptive name BIBF 1120, Vargatef
    D.3.9.4EV Substance CodeAS2
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 CodeAS3
    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.IMP: 3
    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 namePegylated Liposomal Doxorubicin
    D.3.4Pharmaceutical form Concentrate for solution for 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 INNdoxorubicin hydrochloride
    D.3.9.1CAS number 23214-92-8
    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 number2
    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: 4
    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 nameTopotecan
    D.3.4Pharmaceutical form 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 INNTopotecan hydrochloride
    D.3.9.1CAS number 119413-54-6
    D.3.9.4EV Substance CodeAS5
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTopotecan hydrochloride
    D.3.9.1CAS number 119413-54-6
    D.3.9.4EV Substance CodeAS6
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    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: 5
    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 nameCarboplatin
    D.3.4Pharmaceutical form Concentrate for solution for 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 INNCarboplatin
    D.3.9.1CAS number 61825-94-3
    D.3.9.4EV Substance CodeAS7
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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: 6
    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 INNCarboplatin
    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 CodeAS9
    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.IMP: 7
    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 nameDoxorubicin
    D.3.2Product code Not Applicable
    D.3.4Pharmaceutical form Concentrate for solution for 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 INNDoxorubicin
    D.3.9.1CAS number 25316-40-9
    D.3.9.2Current sponsor codeNot applicable
    D.3.9.3Other descriptive nameNot applicable
    D.3.9.4EV Substance CodeAS10
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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
    Recurrent clear cell carcinoma of the ovary or endometrium
    E.1.1.1Medical condition in easily understood language
    ovarian or endometrial clear cell cancer that has come back or started to grow again
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10009252
    E.1.2Term Clear cell endometrial carcinoma
    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 20.0
    E.1.2Level PT
    E.1.2Classification code 10066697
    E.1.2Term Ovarian cancer recurrent
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this research is to estimate progression-free survival (PFS) in women with relapsed clear cell carcinoma of the ovary treated with Nintedanib, and to compare this with PFS in women treated with chemotherapy.
    E.2.2Secondary objectives of the trial
    The secondary objectives of this research are to estimate or assess the following and compare them between women receiving chemotherapy and women receiving Nintedanib:

    -Estimate overall survival, response rate, disease control rate.
    -Assess toxicity, quality of life,Q-TWIST (quality-adjusted time without symptoms of disease or toxicity of treatment)in women with clear cell carcinoma of the ovary, -Q-TWIST in women with clear cell carcinoma of the endometrium
    -Estimate progression-free survival, overall survival, response rate, disease control rate and to record treatment received post-progression.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Funding has already been secured for 'Nintedanib in Clear cell Carcinoma - a sample collection for translational studies'
    The proposed start date is 15/Oct/2013, and the duration will be 48 months.
    The aim of the sample collection study is to establish a collection of tumour, circulating tumour DNA (ctDNA, circulating endothelial cells (CECs), and plasma samples from patients with relapsed ovarian and endometrial CCC that will allow investigation of prognostic and predictive markers and further the understanding of the biology of CCC.

    Initial investigations will focus on the effect of Nintedanib on markers of angiogenesis; markers of activation of the IL6-STAT3-HIF signalling; the frequency of ARID1A and PIK3CA mutations in primary tumours of patients with relapsed disease; and correlation of these factors with clinical outcome measures. In addition the feasibility of collecting ctDNA, its prognostic value and the spectrum of mutations identified in ctDNA at relapse compared with those in original tissue will be assessed.Circulating endothelial cells (CECs) are found in increased numbers in cancer patients as a result of vascular damage and angiogenesis.No studies on the clinical relevance of CEC counts in ovarian cancer have been published so far. This trial allows us to study the prognostic value of CECs in CCC for the first time.
    E.3Principal inclusion criteria
    1.Progressive or recurrent ovarian clear cell carcinoma, or progressive or recurrent endometrial clear cell carcinoma. The primary diagnosis must be histologically confirmed and central pathological review of the presenting tumour or biopsy of relapsed disease must find at least 50% clear cell carcinoma with no serous differentiation. Progressive disease as defined by RECIST 1.1.
    2.Failure after ≥1 prior platinum containing regimen which may have been given in the adjuvant setting. For patients with ovarian clear cell carcinoma, progression must have occurred within 6 months of their last platinum dose.
    3.ECOG Performance status of ≤2.
    4.Life expectancy of >3 months.
    5.Adequate hepatic, bone marrow coagulation and renal function
    a.Hepatic function: total bilirubin within normal limits; ALT and AST < 2.5 x ULN
    b.Coagulation parameters: INR <2 x ULN and prothrombin time and activated partial thromboplastin time < 1.5 x ULN in the absence of therapeutic anticoagulation
    c.absolute neutrophil count (ANC) ≥ 1.5 x 109/L
    d.platelets ≥ 100 x 109L
    e.haemoglobin ≥ 9.0 g/dL
    f.proteinuria < grade 2 CTCAE (version 4)
    g.Glomerular Filtration Rate ≥40ml/min. (calculated using Cockroft & Gault equation or measured by EDTA clearance)
    6.Female and > 18 years of age.
    7.Signed and dated written informed consent prior to admission to the study in accordance with ICH-GCP guidelines and local legislation.
    8.Willingness and ability to comply with scheduled visits, treatment plans and laboratory tests and other study procedures.
    E.4Principal exclusion criteria
    1.Prior treatment with Nintedanib or other angiogenesis inhibitor/VEGF targeted therapy, except for prior treatment with bevacizumab which is permitted..
    2.Treatment within the last 4 weeks with any investigational drug, radiotherapy, immunotherapy, chemotherapy, hormonal therapy or biological therapy. Palliative radiotherapy may be permitted for symptomatic control of pain from bone metastases in extremities, provided that the radiotherapy does not affect target lesions, and the reason for the radiotherapy does not reflect progressive disease.
    3.Previous treatment with the chemotherapy regimen selected as the control arm by the investigator. (Prior therapy with paclitaxel given on a three weekly regimen is permitted for patients receiving weekly paclitaxel).
    4.Other malignancy diagnosed within 5 years of enrolment except for:
    a.non-melanomatous skin cancer (if adequately treated)
    b.cervical carcinoma in situ (if adequately treated)
    c.carcinoma in situ of the breast (if adequately treated)
    d.For patients with ovarian clear cell cancer, prior or synchronous endometrial cancer (if adequately treated), provided all of the following criteria are met:
    •disease stage FIGO Stage 1a (tumour invades less than one half of myometrium)
    •Grade 1 or 2
    5.Patients with any other severe concurrent disease, which may increase the risk associated with study participation or study drug administration and, in the judgement of the investigator, would make the patient inappropriate for entry into this study, including significant neurologic, psychiatric, infectious, hepatic, renal, or gastrointestinal diseases or laboratory abnormality.
    6.Symptoms or signs of gastrointestinal obstruction requiring parenteral nutrition or hydration or any other gastro-intestinal disorders or abnormalities, including difficulty swallowing, that would interfere with drug absorption.
    7.Serious infections in particular if requiring systemic antibiotic (antimicrobial, antifungal) or antiviral therapy, including known hepatitis B and/or C infection and HIV-infection.
    8.Symptomatic CNS metastasis or leptomeningealcarcinomatosis.
    9.Known, uncontrolled hypersensitivity to the investigational drugs or their excipients.
    10.Significant cardiovascular diseases, including uncontrolled hypertension, clinically relevant cardiac arrhythmia, unstable angina or myocardial infarction within 6 months prior to enrolment, congestive heart failure > NYHA III, severe peripheral vascular disease, clinically significant pericardial effusion.
    11.History of major thromboembolic event defined as:
    •pulmonary embolism (PE) within six months prior to enrolment
    •recurrent pulmonary embolism (history of at least 2 events)
    •history of at least 2 unprovoked (=without a transient reversible risk factor) events of proximal deep venous thrombosis
    •history of a provoked (=with transient or reversible risk factor, such as surgery) thrombosis of proximal deep veins or visceral vessels within 6 months prior to enrolment if not on stable therapeutic anticoagulation.
    12.Prior thrombosis or thromboembolic event in the presence of an inherited coagulopathy (including deficiency of antithrombin, deficiency of protein C or protein S, Factor V Leiden mutation, Prothrombin G20210A mutation).
    13.Known inherited predisposition to bleeding or thrombosis.
    14.History of a cerebral vascular accident, transient ischemic attack or subarachnoid haemorrhage within the past 6 months.
    15.History of clinically significant haemorrhage in the past 6 months.
    16.Major injuries or surgery within the past 28 days prior to start of study treatment with incomplete wound healing and/or planned surgery during the on-treatment study period.
    17.Pregnancy or breastfeeding. Patients with preserved reproductive capacity must have a negative pregnancy test (β-HCG test in urine or serum) prior to commencing study treatment.
    18.Patients with preserved reproductive capacity, unwilling to use a medically acceptable method of contraception for the duration of the trial and for 3 months afterwards.
    19.Radiographic evidence of cavitating or necrotic tumours with invasion of adjacent major blood vessels.
    20.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.
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome measure is to estimate the progression free survival (PFS)as defined by RECIST 1.1 criteria, in women with relapsed clear cell carcinoma of the ovary treated with Nintedanib and compare this to PFS in women treated with chemotherapy. PFS is defined as the duration of time from date of randomisation to date of progression or death, which ever occurs earlier. CA125 progression alone will not be considered as progressive disease.




    E.5.1.1Timepoint(s) of evaluation of this end point
    Disease evaluation will be performed based on tumour imaging. All patients will undergo baseline evaluation tumour assessment with a CT scan or MRI of abdomen and pelvis plus a thoracic CT or CXR imaging within 28 days prior to starting study treatment. The same modality should be used for the duration of the study. From date of randomisation until wk 48 or until progressive disease occurs, patients will undergo imaging every 8 weeks. Patients who have not progressed by wk 48 will have a further scan at wk 72. In patients who do not progress by wk 72, subsequent imaging will be performed only as clinically indicated. Patients that come off treatment for reasons other than progression continue to have imaging scans at the specified time points.
    E.5.2Secondary end point(s)
    To estimate overall survival (OS) in women with relapsed clear cell carcinoma of the ovary treated with Nintedanib and compare this to OS in women treated with chemotherapy.

    To estimate response rate (RR) in women with relapsed clear cell carcinoma of the ovary treated with Nintedanib and compare this to RR in women treated with chemotherapy.

    To estimate disease control rate (DCR = Complete Response, Partial Response and Stable Disease) at 12 weeks in women with relapsed clear cell carcinoma of the ovary treated with Nintedanib and compare this to DCRS in women treated with chemotherapy.

    To assess toxicity in women with relapsed clear cell carcinoma of the ovary and endometrium treated with Nintedanib and compare this to women treated with chemotherapy.

    To assess quality of life in women with relapsed clear cell carcinoma of the ovary and endometrium treated with Nintedanib and compare this to women treated with chemotherapy.

    To assess Q-TWiST (Quality-Adjusted Time Without Symptoms of Disease or Toxicity of Treatment) in women with relapsed clear cell carcinoma of the ovary treated with Nintedanib and and compare this with those treated with chemotherapy.

    To assess Q-TWiST in women with relapsed clear cell carcinoma of the endometrium treated with Nintedanib and those treated with chemotherapy.

    To estimate progression free survival (PFS) in women with relapsed clear cell carcinoma of the endometrium treated with Nintedanib and those treated with chemotherapy.

    To estimate overall survival (OS) in women with relapsed clear cell carcinoma of the endometrium treated with Nintedanib and those treated with chemotherapy.

    To estimate response rate (RR) in women with relapsed clear cell carcinoma of the endometrium treated with Nintedanib and those treated with chemotherapy.

    To estimate disease control rate (DCR = Complete Response, Partial Response and Stable Disease) at 12 weeks in women with relapsed clear cell carcinoma of the endometrium treated with Nintedanib and those treated with chemotherapy.

    To record treatment received post progression.

    E.5.2.1Timepoint(s) of evaluation of this end point
    -Toxicity: day 1 of each cycle of treatment (NCI CTC AE version 4.0).
    -Q-TWiST: This is assessed by combining toxicity and progression data.Progression is assessed using the imaging data (see 23-1).
    -RR and DCR: Assessed from imaging data (see 23-1).
    -Quality of life (QoL): QoL questionnaires will be completed at screening, and day 1 of cycle 2, 4 and 6. For patients on chemotherapy QoL assessments will be performed at the end of treatment visit and every 8 weeks subsequently and for patients on Nintedanib, day 1 of every cycle from cycle 7 onwards. QoL assessments will continue 2 monthly post progression as long as the PI considers it appropriate and the patient continues to consent
    -Patients will be followed up for survival after progression (every 2 months).
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA40
    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 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
    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 Nintedanib.

    For the purposes of the main REC approval, the study end date is deemed to be the date of last data capture.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months5
    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: 84
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 36
    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 No
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 120
    F.4.2.2In the whole clinical trial 120
    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 chemotherapy will receive 24 weeks of treatment (maximum), unless their disease progresses, the patient dies, or the patient discontinues treatment due to toxicity, or patient/clinician decision.
    Patients randomised to receive Nintedanib will receive study treatment until their disease progresses, death or until they discontinue treatment due to toxicity, or patient/clinician decision.
    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 Decision
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-05-08
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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