Bevacizumab as a Palliative Treatment for Patients With Symptomatic Malignant Ascites Due to Advanced-stage Gastrointestinal Cancers

Inclusion criteria

• Age >= 18 years
• Written informed consent has been obtained prior to inclu¬sion into the study
• Patient is capable and willing to comply with the study
• Histologically confirmed esophageal, gastric, pancreatic, cholangiocellular, hepatocellular, or colorectal carcinoma
• 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
• Ascites clinically judged as not responsive to conventional systemic therapies for primary malignancy
• Ascites clinically judged as not responsive to diuretics
• At the time of inclusion paracentesis required at least twice within past 4 weeks.
• 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.
• ECOG performance score 0-3
• Life expectancy > 12 weeks
• 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 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 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

Exclusion criteria

• 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).
• Bacterial peritonitis as indicated by laboratory results (neutrophil count > 250 / µl ascites) or clinical suspicion
• Hemorrhagic ascites (ascites hematocrit > 2%)
• Transudative ascites (total protein in ascites < 30 g/l)
• 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.
• Therapy naïve patients
• 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.
• Patients with extensive metastases of the liver making up > 70% of the total liver mass
• Child C cirrhosis of the liver
• Occlusion or thrombosis of the portal vein.
• Evidence of current and symptomatic central nervous system (CNS) metas¬ta¬ses or spinal cord compression.
• 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.
• History of fistula formation involving an internal organ (e.g. tracheo-oesophagal, bronchopleural, biliary, vagina and bladder)
• 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.
• 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.
• Serious non-healing wound, ulcer or bone fracture.
• Radiotherapy for purposes other than local control of symp¬toms.
• Evidence of bleeding diathesis or coagulopathy.
• Hematopoietic diseases.
• Known intra-abdominal inflammatory process or serious gastrointestinal ulceration.
• History of chronic intestinal diseases associated with severe diarrhea.
• Thrombo-embolic events or severe hemorrhage (<= 6 months before treatment start).
• Known hypersensitivity to the test drug Bevacizumab
• 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.
• 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.
• 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).
• Patients who have participated in this study before.
• 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 drug].
• 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).
• 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).
• 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.
• Patients who possibly are dependent on the sponsor or investigator.