Gastrointestinal Cancers, Malignant Ascites
Conditions
Keywords
Symptomatic malignant ascites due to advanced-stage gastrointestinal cancers
Brief summary
Malignant ascites represents a severe clinical problem for physicians and patients being confronted with this common symptom of advanced-stage gastrointestinal cancer. Unfortunately, there is no standardized and evidence-based treatment for malignant ascites and therapies which are commonly being used are only temporarily effective. Newer modes of therapy, such as the application of the tri-functional antibody catumaxomab, are associated with significant side effects and are limited to patients in stages of good overall performance. Therefore, there is still an urgent need for more effective, longer-lasting, and less toxic modes of treatment for peritoneal effusions caused by gastrointestinal cancers. Preclinical data strongly suggest that bevacizumab might be a very effective agent for the treatment of malignant ascites, which is in large part caused by the hyperpermeability-promoting factor VEGF. Emerging clinical results from cancer patients with malignant ascites treated with bevacizumab add further support to this idea. Bevacizumab has been tested in a variety of large clinical trials, has a good toxicity profile, and is effective in a number of human cancers underlying malignant ascites. In the present study, Bevacizumab will be administered as an intraperitoneal infusion at an absolute standardized dosage of 400 mg. This dosage was chosen because it is comparable to the approved standard dosage for intravenous administration which was also used in both studies reporting the successful and safe intraperitoneal administration of Bevacizumab to patients with malignant ascites. Finally, a standardized dosage seems more practical in the particular patient population treated in this study.
Interventions
DRUGBevacizumab
Patients will receive paracentesis as needed for symptom con¬trol. In addition, patients will receive up to 4 intraperitoneal administrations of 400 mg Bevacizumabafter paracentesis has been performed. During the 8-week treatment period, a minimum interval of 14 days will be kept between applications of the study medication.
OTHERPlacebo
Patients will receive paracentesis as needed for symptom con¬trol. In addition, patients will receive up to 4 intraperitoneal administrations of Placebo after paracentesis has been performed. During the 8-week treatment period, a minimum interval of 14 days will be kept between applications of the study medication.
Sponsors
AIO-Studien-gGmbH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 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: 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| paracentesis-free survival (ParFS) | one year | The first primary endpoint will consist of paracentesis-free survival (ParFS) which will be calculated as 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Volume of ascites | 12 weeks | Volume of ascites drained by routine paracentesis (ascites volume minus lavage volumes, if applicable) |
| Quality of life | 12 weeks | Quality of life as assessed by standardized questionnaires |
| Changes in ECOG performance status | baseline and 12 weeks | Calculation: 12 weeks minus baseline |
| Pharmacokinetics of Bevacizumab and VEGF concentrations | 12 weeks | — |
| Best Response (BR) | 12 weeks from 1st application | Best Response representing the longest period of time 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 with the exception of diuretics (before end of the standard 4 week follow-up) or, if longer, from the last paracentesis performed within the treatment period until death (before end of the standard 4 week follow-up) or, if longer, from the last paracentesis performed within the treatment period until 4 week follow-up |
| Proportions of patients with adverse events of special interest | 12 weeks | any grade of gastrointestinal perforation, gastrointestinal fistulas or other internal fistulas, wound-healing disturbances, hemorrhagic events and arterial thrombo-embolic events. |
| All adverse events | 12 weeks | — |
| Changes in laboratory values and vital signs. | baseline, every two weeks up to week 12 | Calculation: Value from later timepoints minus baseline value |
| Proportions of patients with adverse events grades 3, 4, or 5. | 12 weeks | — |
Countries
Germany
Outcome results
None listed