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    Summary
    EudraCT Number:2010-022209-16
    Sponsor's Protocol Code Number:ICON8
    National Competent Authority:Ireland - HPRA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2011-12-05
    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 ConcernedIreland - HPRA
    A.2EudraCT number2010-022209-16
    A.3Full title of the trial
    ICON8 Trials Programme

    ICON8: An international phase III randomised trial of dose-fractionated chemotherapy compared to standard three-weekly chemotherapy, following immediate primary surgery or as part of delayed primary surgery, for women with newly diagnosed epithelial ovarian, fallopian tube or primary peritoneal cancer, and
    ICON8B: A phase III randomised trial investigating the combination of dose-fractionated chemotherapy and bavcizumab compared to either strategy alone for first-line treatment of women with newly diagnosed high-risk stage III-IV epithelial ovarian, fallopian tube or primary peritoneal cancer
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    ICON8 Trials Programme
    ICON8: Weekly chemotherapy in ovarian cancer, and
    ICON8B: Weekly chemotherapy and bevacizumab in advanced ovarian cancer
    A.3.2Name or abbreviated title of the trial where available
    ICON8 Trials Programme
    A.4.1Sponsor's protocol code numberICON8
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN10356387
    A.5.4Other Identifiers
    Name:ENGOTNumber:ov-13
    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 SponsorUniversity College London
    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 supportMedical Research Council
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCancer Trials Ireland
    B.5.2Functional name of contact pointHead of Clinical Operations
    B.5.3 Address:
    B.5.3.1Street AddressInnovation House, Old Finglas Road, Glasnevin
    B.5.3.2Town/ cityDublin
    B.5.3.3Post codeD11KXN4
    B.5.3.4CountryIreland
    B.5.4Telephone number35316677211
    B.5.6E-mailregulatory@cancertrials.ie
    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 Carboplatin
    D.2.1.2Country which granted the Marketing AuthorisationIreland
    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 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 41575-94-4
    D.3.9.4EV Substance CodeSUB06614MIG
    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: 2
    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 Paclitaxel
    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 namePaclitaxel
    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 INNPACLITAXEL
    D.3.9.1CAS number 33069-62-4
    D.3.9.4EV Substance CodeSUB09583MIG
    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 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 Avastin
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    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 nameBevacizumab
    D.3.2Product code R04876646
    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 INNBEVACIZUMAB
    D.3.9.1CAS number 216974-75-3
    D.3.9.2Current sponsor codeRO4876646
    D.3.9.3Other descriptive namerhuMab, VEGF, anti-VEGF
    D.3.9.4EV Substance CodeSUB16402MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100mg/4ml
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    D.3.11.13.1Other medicinal product typeRecombinant humanised monoclonal antibody
    D.IMP: 4
    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 Avastin
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    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 nameBevacizumab
    D.3.2Product code R04876646
    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 INNBEVACIZUMAB
    D.3.9.1CAS number 216974-75-3
    D.3.9.2Current sponsor codeRO4876646
    D.3.9.3Other descriptive namerhuMab, VEGF, anti-VEGF
    D.3.9.4EV Substance CodeSUB16402MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number400mg/16ml
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    D.3.11.13.1Other medicinal product typeRecombinant humanised monoclonal antibody
    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
    ICON8: Newly diagnosed high risk early stage (FIGO stage IC/IIA, grade 3 or clear cell histology only) or advanced stage (FIGO stage IIB-IV,
    all grades and all histological types) epithelial ovarian, fallopian tube or primary peritoneal carcinoma.
    ICON8B: Patients with newly diagnosed, histologically confirmed high-risk stage III-IV ovarian cancer: FIGO (2013) stage IIIA-C disease with >1cm residual disease following IPS or those planned to undergo primary chemotherapy with or without DPS.
    E.1.1.1Medical condition in easily understood language
    Newly diagnosed ovarian cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10016183
    E.1.2Term Fallopian tube cancer NOS
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10033159
    E.1.2Term Ovarian epithelial cancer NOS
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10052171
    E.1.2Term Peritoneal carcinoma
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the ICON8 Trials Programme are to test:

    1. Whether dose-fractionated chemotherapy is more effective than standard 3-weekly treatment for women with FIGO stage IC-IV ovarian cancer. (ICON8)

    2. Whether the combination of bevacizumab plus dose-fractionated chemotherapy will prolong progression-free survival compared to bevacizumab or dose-fractionation alone for women with high-risk stage III-IV ovarian cancer. If superiority of the combination is not shown, to assess evidence for the non-inferiority of dose-fractionated chemotherapy to standard 3-weekly chemotherapy + bevacizumab. (ICON8B)
    E.2.2Secondary objectives of the trial
    Secondary objectives in the 3rd stage analysis of ICON8:
    1. Assess the impact of each of the dose-fractionated regimens on the safety and toxicity of carboplatin-paclitaxel combination chemotherapy vs the standard treatment schedule.
    2. Assess the impact of dose-fractionated chemotherapy on patients' quality of life, both while receiving chemotherapy and during follow-up.
    3. Evaluate the cost-effectiveness of the dose-fractionated regimens.

    Secondary objectives in the 2nd stage analysis of ICON8B:
    1. Assess the impact on the safety & toxicity of dose fractionated carboplatin-paclitaxel + bevaciumab regimens vs the standard treatment schedule & dose-fractionated chemotherapy alone.
    2. Assess the impact of dose-fractionated chemotherapy + bevacizumab on patients' quality of life, both while receiving protocol defined treatment and during follow-up.
    3. Evaluate the cost-effectiveness of the dose-fractionated regimens.
    4. Prolonged overall survival.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Translational Research Substudy of ICON8 (TRICON8) and ICON8B (TRICON8B). Details of the substudy can be found in the ICON8 trials programme protocol. The aim of the TRICON8 programme is to establish a large, comprehensive biobank comprising tumour tissue, blood and serial plasma with associated clinical data which will be an invaluable resource for high-quality translational research in ovarian cancer.
    E.3Principal inclusion criteria
    ICON8 Inclusion Criteria:

    1. Females aged 18 years and above
    2. Signed informed consent and ability to comply with the protocol
    3. Histologically confirmed, with core biopsy from a disease site as minimum requirement (cytology alone is insufficient for diagnosis):
    • Epithelial ovarian carcinoma
    • Primary peritoneal carcinoma of Müllerian histological type
    • Fallopian tube carcinoma
    • Ovarian carcinosarcoma (malignant mixed Müllerian tumour (MMMT) of the ovary)
    4. FIGO stage IC or above, which may be based on clinical and radiological assessment in patients who have not undergone immediate primary surgery
    5. Confirmed high-risk histological subtype for patients with FIGO stage IC/IIA disease, namely
    • High grade serous carcinoma
    • Clear cell carcinoma
    • Other histological subtype considered poorly differentiated/grade 3
    6. ECOG Performance Status (PS) 0-2
    7. Life expectancy > 12 weeks
    8. Adequate bone marrow function
    • Absolute Neutrophil Count >1.5 x 10^9/l
    • Platelets (Plt) >100 x 10^9/l
    • Haemoglobin (Hb) > 9g/dl (can be post transfusion)
    9. Adequate liver function (within 28 days prior to randomisation)
    • Serum bilirubin ≤ 1.5 x ULN
    • Serum transaminases ≤ 3 x ULN in the absence of parenchymal liver metastases or ≤ 5 x ULN in the presence of parenchymal liver metastases
    10. Adequate renal function as defined by:
    • Directly measured GFR (Glomerular Filtration Rate) ≥ 30 ml/min, or
    • Calculated creatinine clearance ≥ 60 ml/min
    NB. If the calculated creatinine clearance is <60 ml/min the GFR should be directly measured using either a 24 hour urine collection or an isotopic evaluation
    11. Able to start chemotherapy within 8 weeks after immediate primary surgery (where applicable)
    ICON8B Inclusion Criteria:
    1. Females aged 18 years or above
    2. Signed informed consent and ability to comply with the protocol
    3. Histologically confirmed, with core biopsy from a disease site as minimum requirement (cytology alone is insufficient for diagnosis):
    • Epithelial ovarian carcinoma
    • Primary peritoneal carcinoma of Müllerian histological type
    • Fallopian tube carcinoma
    • Ovarian carcinosarcoma (malignant mixed Müllerian tumour (MMMT) of the ovary)
    4. High –risk disease defined as
    • FIGO (2013) Stage IIA1(ii), IIA2 with positive retroperitoneal lymph nodes >10mm in diameter, IIIB or IIIC disease
    i. With >1cm residual disease following IPS or
    ii. Planned to undergo primary chemotherapy with or without DPS
    • FIGO Stage IV disease:
    i. With any volume of residual disease following IPS or
    ii. Planned to undergo primary chemotherapy with or without DPS
    5. ECOG Performance Status (PS) 0-2
    6. Life expectancy >12 weeks
    7. Adequate bone marrow function;
    • Absolute Neutrophil Count (ANC) ≥ 1.5 x 10^9/l
    • Platelets (Plt) ≥100 x 10^9/l
    • Haemoglobin (Hb) ≥9g/dl (can be post transfusion)
    8. Adequate liver function;
    • Serum bilirubin (BR) ≤1.5 x ULN
    • Serum transaminases ≤3 x ULN in the absence of parenchymal liver metastases or ≤5 x ULN in the presence of parenchymal liver metastases
    9. Adequate renal function as defined by:
    • Directly measured GFR (Glomerular Filtration Rate) ≥30 ml/min, or
    • Calculated creatinine clearance ≥60ml/min
    NB. If the calculated creatinine clearance is <60 ml/min the GFR should be directly measured using either a 24 hour urine collection or an isotopic evaluation
    10. Adequate coagulation profile:
    • International normalised ratio (INR) ≤1.5
    • Activated prothrombin time (APTT) ≤1.5 x ULN
    11. Able to start chemotherapy within 8 weeks after IPS (where applicable)
    E.4Principal exclusion criteria
    ICON8 Exclusion Criteria;
    1. Non-epithelial ovarian cancer
    2. Peritoneal cancer that is not of Müllerian origin, including mucinous histology
    3. Borderline tumours (tumours of low malignant potential)
    4. Prior systemic anti-cancer therapy for ovarian cancer (for example chemotherapy, monoclonal antibody therapy, tyrosine kinase inhibitor therapy or hormonal therapy)
    5. Previous malignancies within 5 years prior to randomisation apart from;
    • Adequately treated carcinoma in-situ of the cervix, breast ductal carcinoma in-situ, non-melanomatous skin cancer; or
    • Previous/synchronous early-stage endometrial cancer defined as stage IA (FIGO 2009) grade 1 or 2 endometrioid cancers with no lymphovascular space invasion
    6. Pre-existing sensory or motor neuropathy grade ≥2
    7. Evidence of any other disease/metabolic dysfunction that in the opinion of the investigator would put the subject at high-risk of treatment-related complications or prevent compliance with the trial protocol
    8. Planned intraperitoneal cytotoxic chemotherapy
    9. Planned maintenance treatment with systemic anti-cancer therapy following completion of protocol treatment and prior to protocol defined progression
    10. Any previous radiotherapy to the abdomen or pelvis
    11. Sexually active women of childbearing potential not willing to use adequate contraception (eg. oral contraceptives, intrauterine device or barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) for the study duration and at least six months afterwards
    12. Pregnant or lactating women who are currently breastfeeding
    13. Treatment with any other investigational agent prior to protocol defined progression
    14. Known hypersensitivity to carboplatin, paclitaxel or their excipients (including cremophor)
    15. History or clinical suspicion of brain metastases or spinal cord compression. CT/MRI of the brain is mandatory in the case of suspected brain metastases. Spinal MRI is mandatory in the case of suspected spinal cord compression. Patients with brain or meningeal metastases are not eligible.
    Additional Exclusion Criteria for ICON8B:
    1. Proteinuria at baseline:
    • >1gm protein/24h by a 24-hour urine collection
    NB. Proteinuria should be initially assessed by urine dipstick. If urine protein is ≥2+ on urine dipstick, a 24-hour urine protein collection must be performed.
    2. Significant co-existing or previous medical conditions that are contra-indications to treatment with bevacizumab, including;
    a. Cerebrovascular disease, including transient ischaemic attacks (TIAs), cerebrovascular accident (CVA; i.e. stroke) and intracranial bleeds (i.e. intra-cerebral haemorrhage, sub-arachnoid haemorrhage or sub-dural haemorrhage) within 6 months before trial entry
    b. Cardiovascular disease as follows:
    i. Uncontrolled hypertension, defined as sustained BP>150/100mgHg while receiving anti-hypertensive medication
    ii. Myocardial infarction or unstable angina within 6 months prior to randomisation
    iii. New York Heart Association (NYHA) grade ≥2 congestive heart failure
    iv. Poorly controlled cardiac arrhythmia despite medication
    NB. Patients with rate-controlled atrial fibrillation are eligible
    v. Peripheral vascular disease grade ≥3, i.e. symptomatic and interfering with activities of daily living requiring repair or revision
    c. History or evidence of bleeding diathesis or coagulopathy (in patients not on therapeutic anti-coagulant medication)
    d. Recent history of proven active peptic ulcer disease, diverticulitis or inflammatory bowel disease (Crohns’ Disease and ulcerative colitis)
    e. Previous gastrointestinal perforation
    3. Chronic daily use of high-dose aspirin, >325mg/day, within 10 days prior to study entry
    4. Surgery (including open biopsy) or significant traumatic injury within 28 days prior to anticipated date of first dose of bevacizumab
    NB. If IPS was performed within 28 days of planned start of treatment, patients are eligible but bevacizumab must be omitted from cycle 1.
    5. Serious non-healing wound, worse than CTCAE Wound Complication or Wound Dehiscence grade 1
    6. Active ulcer or bone fracture
    7. Anticipated to require extensive dental work during protocol treatment
    8. Clinical symptoms of radiological evidence of bowel obstruction (including sub-acute obstruction) or extensive rectosigmoid involvement on imaging related to ovarian cancer
    9. Evidence of intra-abdominal free air not explained by paracentesis or recent surgical procedure
    10. Symptomatic abdominal fistulae

    E.5 End points
    E.5.1Primary end point(s)
    The ICON8 analyses will have 3 stages. The outcome measures for each stage are as follows:
    Stage 1: Feasibility and safety
    Stage 2: 9 month progression-free survival rate
    Stage 3: Progression-free survival and overall survival (dual primary outcome measures)

    The ICON8B analyses will compare the three randomised arms on the following outcome measures:
    -Progression-free survival (PFS)
    E.5.1.1Timepoint(s) of evaluation of this end point
    ICON8:
    1. In stage 1, feasibility and safety will be assessed in approximately the first 150 women entering the trial and additionally in approximately the first 150 women who enter the trial with a plan to undergo delayed primary surgery during chemotherapy.
    2. In stage 2, 9 month PFS rate will be assessed in approximately the first 186 women to enter the trial.
    3. In stage 3, PFS and OS will be assessed in terms of whether the dose fractionated regimens result in prolonged progression free survival and overall survival.

    ICON8B:
    1. In stage 1, safety of bevacizumab in combination with DPS will be assessed.
    2. In stage 2, PFS and OS will be assessed.
    E.5.2Secondary end point(s)
    The ICON8B analyses will compare the three randomised arms on the following outcome measures:
    -Overall survival (OS)
    E.5.2.1Timepoint(s) of evaluation of this end point
    An Independend Data Monitoring Committee (IDMC) will review data, unblinded by treatment group, on patients in the trial. The IDMC will meet at least annually during the accrual period and around the time that the planned first and second stage analyses are performed.
    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 Yes
    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 Yes
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Quality of Life
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 trial3
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA57
    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
    Australia
    Korea, Republic of
    Mexico
    New Zealand
    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
    The trial will be considered closed for regulatory purposes after data on overall survival are sufficiently mature for the
    primary publication. This is to ensure that the standard of follow up and data collection conforms to the trial protocol
    until the primary outcome measures are reported. Further observational follow up of all patients enrolled in the trial
    may continue indefinitely. This will initially be via hospitals and clinics, but in the longer term may exploit national
    registers.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years10
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years10
    E.8.9.2In all countries concerned by the trial months8
    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.1.1.1In 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: 1170
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1170
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 2200
    F.4.2.2In the whole clinical trial 2655
    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)
    The course of chemotherapy within the ICON8 trial lasts for 18 weeks only, in ICON8B patients receiving bevacizumab will have treatment for 54 weeks. All patients will have completed protocol treatment before the end of the trial and will go on to have expected standard follow-up and further treatments for ovarian cancer as needed. Further treatment will be determined by their treating clinicans.
    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 Decision2012-01-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-12-06
    P. End of Trial
    P.End of Trial StatusOngoing
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