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    Summary
    EudraCT Number:2007-004535-33
    Sponsor's Protocol Code Number:NCT-200711-02-1003
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2009-03-09
    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 ConcernedGermany - BfArM
    A.2EudraCT number2007-004535-33
    A.3Full title of the trial
    Phase II study on curative resectability of not optimally resectable liver and/or lung metastases from colorectal carcinoma (CRC) under intensified chemotherapy (FLOFOXIRI/Bevacizumab).
    A.3.2Name or abbreviated title of the trial where available
    APRIORI
    A.4.1Sponsor's protocol code numberNCT-200711-02-1003
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversitätsklinikum Heidelberg
    B.1.3.4CountryGermany
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 Oxaliplatin
    D.2.1.1.2Name of the Marketing Authorisation holderWinthrop Arzneimittel GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 INNOxaliplatin
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.3Concentration number5
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 typeantineoplastic medicinal product
    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
    Advanced colorectal carcinoma of UICC stage IV, liver and/or lung metastases only, not optimally resectable
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10010036
    E.1.2Term Colorectal carcinoma
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • To evaluate the proportion of patients who achieve surgically complete resectability (S CR) of metastases after preoperative chemotherapy
    E.2.2Secondary objectives of the trial
    • To evaluate the acute and perioperative toxicity of preoperative chemotherapy.
    • To evaluate the overall survival rate (OS) and progression free survival (PFS)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age ≥18 years
    2. Indication:
    - Histologically confirmed advanced colorectal carcinoma of UICC Stages IV with liver and/or lung only metastases, which are not optimally resectable.
    - Measurable disease according to RECIST criteria.
    - In case of liver metastases: 70% liver replacement and/or > 6 segments tumor involved, and/or involvement of all three hepatic veins, and/or involvement of the right and left portal pedical, and/ or involvement of the vena cava.
    - In case of lung metastases: No tumor with direct infiltration of myocardium, esophageous, spine or intrapericardial large vessels. Preoperative data indicate a significant loss of pulmonary function after pulmonary metastasectomy with severe impairment of quality of life.
    3. ECOG performance status of < 2.
    4. Life expectancy of > 3 months
    5. Laboratory parameters:
    Proteinuria at baseline:
    - Patients with proteinuria <2+ on dip¬stick urinalysis.
    - Patients with 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 h urine collection and must have proteinuria >= 1 g of protein/24 h.
    The required laboratory values at baseline are as follows:
    Hematology:
    º Absolute neutrophil count (ANC) > 1.5 x 109/L
    º Platelet count > 100 x 109/L
    º Haemoglobin > 9 g/dL (may be transfused to maintain or exceed this level)
    º International Normalized Ratio (INR) < 1.5; APTT <1.5 x ULN
    Biochemistry:
    º Total bilirubin < 1.5 x upper limit of normal (UNRL)
    º AST, ALT < 2.5 x UNRL in patients without liver metastases; < 5 x UNRL in patients with liver metastases
    º Serum creatinine <2.0 mg/dL or 177 1. μmol/L
    6. Willingness to give written informed consent, written consent for data protection (legal requirement in Germany: Datenschutzrechtliche Einwilligung) and willingness to participate and to comply with the study.
    E.4Principal exclusion criteria
    1. Past or current history of malignancies other than colorectal carcinoma. Patients with curatively treated basal and squamous cell carcinoma of the skin and/or in-situ carcinoma of the cervix are eligible.
    2. Previous chemotherapy.
    3. Extrahepatic and/or extrapulmonary metastases except of the initially removed lymph node metastases.
    4. History or evidence upon physical examination of CNS disease unless adequately treated (e.g., seizure not controlled with standard medical therapy or history of stroke).
    5.Major surgical procedures, open biopsy, or significant traumatic injury within 28 days prior to study treatment start (wound healing has to be completed), or anticipation of the need for major surgical procedure during the course of the study.
    6. Evidence of bleeding diathesis or coagulopathy
    7. Serious, non-healing wound, ulcer, or bone fracture
    8. Treatment with investigational agents or participation in clinical trials within 30 days before study entry.
    9. Clinically significant (i.e. active) cardiovascular disease, e.g., uncontrolled hypertension, cerebrovascular accidents (≤ 6 months prior to treatment start), myocardial infarction (≤ 6 months prior to treatment start), unstable angina, New York Heart Association (NYHA) grade >= II, congestive heart failure, serious cardiac arrhythmia requiring medication.
    10. Current or recent serious polyneuropathy (grade >= 1 according to NCI CTCAE v3.0 criteria; exception: absence of tendon reflexes).
    11. Hemapoetic diseases.
    12. Known intra-abdominal inflammatory process or serious gastrointestinal ulceration.
    13. Known dihydropyrimidine dehydrogenase (DPD) deficiency.
    14. Thromboembolic events or severe hemorrhage (>= 6 months before treatment start).
    15. Known hypersensitivity to oxaliplatin, the background medication (bevacizumab, FA or 5-FU) or to their compounds, incl. Chinese hamster ovary (CHO) cell proteins or other recombinant human or humanized antibodies.
    16. Known Gilbert-Syndrome
    17. Evidence of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational regimen or patient at high risk from treatment complications
    18. As the following medication(s) can have interactive effects and may interfere with the patient's ability to meet the study requirements, they cannot be administered during the clinical study:
    - Sorivudin or analog compounds.
    - Current or recent (within 10 days of first dose of study treatment) treatment with full-dose oral or parenteral anticoagulants or thrombolytic agents (e.g., marcumar therapy) for therapeutic purposes.
    - Current or recent (within 10 days of first dose of study treatment) chronic use of aspirin (> 325 mg/day) or clopidogrel (> 75 mg/day).
    19. Women, lactating, pregnant or of childbearing potential and fertile men not using a highly effective contraceptive method . [Women of childbearing potential must have a negative pregnancy test (serum ßHCG) within 7 days before the first dose of study drug].
    20. Patients who are confined by order of either judicial or administrative authorities (according to § 40 Abs. 1 S. 3 AMG).
    21. Patients who are incapable to understand the aim, importance and consequences of the study and to give legal informed consent (according to § 40 Abs. 4 and § 41 Abs. 2 and Abs. 3 AMG).
    22. Patients with a history of a psychological illness or condition such as to interfere with the patient's ability to understand the requirements of the study.
    23. Patients who possibly are dependent on the sponsor or investigator.
    24. Patients who have participated in this study before.
    E.5 End points
    E.5.1Primary end point(s)
    Primary efficacy parameter: S-CR, which is defined as histologically confirmed tumor free resection margins (R0-resection).
    Secondary efficacy parameter: Progression free overall survival.

    Safety parameter: Serious adverse events according to ICH (NCI CTCAE) criteria in terms of all chemotherapy related acute and perioperative toxicities as well as peri- and postsurgical complications.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic 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 No
    E.8.1.1Randomised No
    E.8.1.2Open No
    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) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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 concerned4
    E.8.5The trial involves multiple Member States No
    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 Information not present in EudraCT
    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
    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 months7
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception 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 state35
    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 completion of the treatment period of this study, either because of resection of metastases or completion of a maximum of 16 treatment cycles in patients not eligible for resection, patients will be transferred to the routine therapy. The investigator takes responsibility for decision about the subsequent treatment.

    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 Decision2009-05-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-02-18
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2011-03-16
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