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
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
7. Ascites clinically judged as not responsive to diuretics
8. At the time of inclusion paracentesis required at least twice within past 4 weeks.
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:
- 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 dClinical 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
- 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
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 eli¬gible).
2. Bacterial peritonitis as indicated by laboratory results (neutrophil count > 250 / µl
ascites) or clinical suspicion
3. Hemorrhagic ascites (ascites hematocrit > 2%)
4. Transudative ascites (total protein in ascites < 30 g/l)
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 para¬centesis, 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
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) metas¬ta¬ses or
spinal cord compression.
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 trau¬matic 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 symp¬toms.
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, physi¬cal 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 compli¬cations.
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 ß HCG) within 7 days before the first dose of study
29. Patients who are committed to an institution by virtue of an order issued either by
the judicial or the administra¬tive 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 con¬di¬tion such as to
interfere with the patient's ability to un¬der¬stand the requirements of the study.
32. Patients who possibly are dependent on the sponsor or investigator.