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    Summary
    EudraCT Number:2009-014725-16
    Sponsor's Protocol Code Number:AIO-SUP-0108
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2009-09-25
    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 - PEI
    A.2EudraCT number2009-014725-16
    A.3Full title of the trial
    Double-blind, placebo-controlled, randomized phase II-study investigating the efficacy of Bevacizumab for symptom control in patients with malignant ascites due to advanced-stage gastrointestinal cancers
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Double-blind, placebo-controlled, randomized phase II-study investigating the efficacy of Bevacizumab for symptom control in patients with malignant ascites due to advanced-stage gastrointestinal cancers
    A.3.2Name or abbreviated title of the trial where available
    AIO-SUP-0108
    A.4.1Sponsor's protocol code numberAIO-SUP-0108
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01200121
    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 SponsorAIO Studien gGmbH
    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 supportAIO Studien gGmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAIO Studien gGmbH
    B.5.2Functional name of contact pointPD Dr. Ullrich Graeven
    B.5.3 Address:
    B.5.3.1Street AddressKuno-Fischer-Straße 8
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code14057
    B.5.3.4CountryGermany
    B.5.4Telephone number00493032293233
    B.5.5Fax number00493032293243
    B.5.6E-mailgmbh@aio-portal.de
    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 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.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntraperitoneal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBevacizumab
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number400
    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 typemonoclonal antibody
    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 placeboConcentrate for solution for infusion
    D.8.4Route of administration of the placeboIntraperitoneal use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    patients with malignant ascites due to advanced-stage gastro-intestinal cancers
    E.1.1.1Medical condition in easily understood language
    patients with malignant ascites due to advanced-stage gastro-intestinal cancers
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10017758
    E.1.2Term Gastric cancer
    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 14.1
    E.1.2Level LLT
    E.1.2Classification code 10015362
    E.1.2Term Esophageal cancer
    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 14.1
    E.1.2Level LLT
    E.1.2Classification code 10056267
    E.1.2Term Gastroesophageal cancer
    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 14.1
    E.1.2Level LLT
    E.1.2Classification code 10049010
    E.1.2Term Carcinoma hepatocellular
    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 14.1
    E.1.2Level LLT
    E.1.2Classification code 10008593
    E.1.2Term Cholangiocarcinoma
    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 14.1
    E.1.2Level PT
    E.1.2Classification code 10061451
    E.1.2Term Colorectal cancer
    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 14.1
    E.1.2Level PT
    E.1.2Classification code 10025538
    E.1.2Term Malignant ascites
    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 14.1
    E.1.2Level LLT
    E.1.2Classification code 10033604
    E.1.2Term Pancreatic cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    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 paracentesis-free survival (ParFS) following intraperitoneal application of Bevacizumab/Placebo
    E.2.2Secondary objectives of the trial
    • To measure the frequency of paracenteses required for symptom control following intraperitoneal application of Bevacizumab/Placebo, by assessing the longest paracen¬tesis-free period within the 12-week main observation period (“best response”)
    • To measure the volume of ascites following intraperitoneal application of Bevacizumab/Placebo
    • To measure the effect of study treatment on the quality of life
    • To assess feasibility and safety of intraperitoneal application of Bevacizumab including pharmakocinetic of Bevacizumab
    • To evaluate the effect of an intraperitoneal application of Bevacizumab/Placebo on serum and ascites VEGF concen¬trations
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age >= 18 years
    2. Written informed consent has been obtained prior to inclu¬sion into the study
    3. Patient is capable and willing to comply with the study
    4. Histologically confirmed esophageal, gastric, pancreatic, cholangiocellular, hepatocellular, or colorectal carcinoma
    5. Cytologically confirmed ascites OR diagnosis of an exsudate (total protein in ascites > 30 g/l) clinically suggestive for malignant ascites OR morphological diagnosis of peritoneal carcinosis by CT , MRT or ultrasound
    6. Ascites clinically judged as not responsive to conventional systemic therapies for primary malignancy
    7. Ascites clinically judged as not responsive to diuretics
    8. At the time of inclusion paracentesis required at least once within past 4 weeks. The first application of study medication must not take place later than 4 weeks after the preceding paracentesis in screening phase.
    9. Before inclusion of the patient into the study, a 4-week screening period will allow for a stringent evaluation of the patient regarding fulfillment of inclusion and exclusion criteria. Importantly, no treatments for malignant ascites other than paracentesis and diuretics are allowed during the 4-week screening period.
    10. ECOG performance score 0-3
    11. Life expectancy > 12 weeks
    12. Laboratory parameters:
    Hematology
    • Neutrophils > 1,500/µl
    • Platelets > 100,000/µl
    • Hemoglobin >= 9 g/dl or 5.59 mmol/l
    Hemastasiology
    • INR <= 1.5 x ULN and aPTT <= 1.5 x ULN within past 7 d
    Clinical chemistry
    • Creatinine clearance > 30 ml/min, serum creatinine < 2.5 x ULN
    • Serum bilirubin < 3.0 x ULN
    • Alkaline phosphatase and transaminases < 3.0 x ULN (in case of liver metastases < 7 x ULN)
    Urinalysis:
    • Patients with < 2+ proteinuria on dipstick urinalysis.
    • Patients with >= 2+ proteinuria on dipstick urinalysis, who demonstrate < 2.0 g of protein/24 h on 24-h urine collection.
    E.4Principal exclusion criteria
    1. Concomitant malignancies other than gastrointestinal cancers (Patients with curatively treated basal and squamous cell carcino¬ma of the skin and / or in-situ carci¬noma of the cervix are eligible).
    2. Bacterial peritonitis as indicated by laboratory results (neutrophil count > 250 / µl ascites) or clinical suspicion
    3. Hemorrhagic ascites (ascites hematocrit > 2%)
    5. Parallel treatment with anti-tumor agents other than the study medication from inclusion into the study until safety follow-up. Chemotherapy may be continued if started before screening phase (– 4 weeks before inclusion). Parallel Treatment with Bevacizumab i.v. is not allowed.
    6. Therapy naïve patients
    7. Parallel treatment of ascites with measures other than paracentesis, diuretics, and the study drugs from 4 weeks before inclusion into the study until safety follow-up.
    8. Patients with extensive metastases of the liver making up > 70% of the total liver mass
    9. Child C cirrhosis of the liver
    10. Occlusion or thrombosis of the portal vein.
    11. Evidence of current and symptomatic central nervous system (CNS) metastases or spinal cord compression.
    12. 12. Clinically significant cardiovascular diseases, e.g., un¬con¬trolled hypertension, uncontrolled arrhythmia, hemoptoe, cardiovascular accident within the last 6 months before treatment start, unstable angina, congestive heart failure (CHF) NYHA grade III/IV, symptomatic coronary heart disease, peripheral arterial disease stage >= II.
    13. History of fistula formation involving an internal organ (e.g. tracheo-oesophagal, bronchopleural, biliary, vagina and bladder)
    14. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study treatment start, or anticipation of the need for major surgical procedure during the course of the study.
    15. Concomitant treatment with intravenous Bevacizumab for primary malignancy from inclusion into study until safety follow-up, Prior treatment with Bevacizumab for primary malignancy is not exclusionary.
    16. Serious non-healing wound, ulcer or bone fracture.
    17. Radiotherapy for purposes other than local control of symptoms.
    18. Evidence of bleeding diathesis or coagulopathy.
    19. Hematopoietic diseases.
    20. Known intra-abdominal inflammatory process or serious gastrointestinal ulceration.
    21. History of chronic intestinal diseases associated with severe diarrhea.
    22. Thrombo-embolic events or severe hemorrhage (<= 6 months before treatment start).
    23. Known hypersensitivity to the test drug Bevacizumab
    24. Evidence of any other disease, metabolic dysfunction, physical examination finding, or laboratory finding giving reasonable suspicion of a disease or condition that contra-indicates the use of an investigational drug or puts the patient at high risk for treatment-related complications.
    25. 25. With the only exception of full dose (INR > 1.5) oral coumarin-derived anticoagulants, the use of full dose anticoagulants is allowed as long as the INR or a PTT is within therapeutic limits (according to the medical standard in the institution) and the patient has been on a stable dose for at least two weeks at the time of randomisation.
    26. Patients who participated within the last 30 days prior to enrolment in a clinical trial and received a non approved investigational drug (e.g. follow up within the trial is not exclusionary).
    27. Patients who have participated in this study before.
    28. 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 beta-HCG) within 7 days before the first dose of study drug].
    29. Patients who are committed to an institution by virtue of an order issued either by the judicial or the administrative authorities (according to § 40 (1) 4 AMG).
    30. Patients who are underage or patients who are incapable to understand the aim, importance and consequences of the study and to give legal informed consent (according to § 40 (4) and § 41 (2) and (3) AMG).
    31. 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.
    32. Patients who possibly are dependent on the sponsor or investigator.
    E.5 End points
    E.5.1Primary end point(s)
    Efficacy:
    • Paracentesis-free survival (ParFS), i.e. the time period between the initial puncture after randomization to the first subsequent paracentesis or other symptomatic treatments for ascites with the exception of diuretics or until death (whichever occurs first)
    E.5.1.1Timepoint(s) of evaluation of this end point
    at the first subsequent paracentesis after the initial puncture
    E.5.2Secondary end point(s)
    best response representing the longest period of time (in days) from one paracentesis until next paracentesis within the treatment period or, if longer, from the last paracentesis performed within the treatment period until first subsequent symptomatic treatment for ascites or, if longer, from the last paracentesis performed within the treatment period until death or, if longer, from the last paracentesis performed within the treatment period until 4 week follow-up.
    Volume of ascites drained by routine paracentesis
    Total volume of ascites as indicated by body weight
    Quality of life as assessed by standardized questionnaires
    Number of patients with CR/PR
    E.5.2.1Timepoint(s) of evaluation of this end point
    at each paracentesis
    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 Yes
    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 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 concerned20
    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 No
    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
    Survival Follow up after EOT will be included, which is anticipated to continuie approximately 6 months after EOT
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    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 years4
    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: 72
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 72
    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 state72
    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 discontinuation or termination of the study, patients will be treated at the discretion of the investigator and according to medical routine. Further treatment modalities include continuing diuresis, salt restriction and repeated para¬centesis. This would also include the possibility of applying the tri-functional antibody catumaxomab or intraperitoneal chemotherapy.
    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 Decision2009-12-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-01-14
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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