Clinical trial NCT01200121: Bevacizumab as a Palliative Treatment for Patients With Symptomatic Malignant Ascites Due to Advanced-stage Gastrointestinal Cancers
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Malignant Ascites
Gastrointestinal Cancers
Keywords: Symptomatic malignant ascites due to advanced-stage gastrointestinal cancers
Lead sponsor: AIO-Studien-gGmbH
Sponsor class: OTHER
First posted: 2010-09-13
Enrollment: 53
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

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 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 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) 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 . \[Women of childbearing potential must have a negative pregnancy test (serum ß HCG) within 7 days before the first dose of study drug\].
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.

Primary outcomes:
measure: paracentesis-free survival (ParFS)
timeFrame: one year
Secondary outcomes:
measure: Best Response (BR)
timeFrame: 12 weeks from 1st application
measure: Volume of ascites
timeFrame: 12 weeks
measure: Quality of life
timeFrame: 12 weeks
measure: Changes in ECOG performance status
timeFrame: baseline and 12 weeks
measure: Pharmacokinetics of Bevacizumab and VEGF concentrations
timeFrame: 12 weeks
measure: Proportions of patients with adverse events grades 3, 4, or 5.
timeFrame: 12 weeks
measure: Proportions of patients with adverse events of special interest
timeFrame: 12 weeks
measure: All adverse events
timeFrame: 12 weeks
measure: Changes in laboratory values and vital signs.
timeFrame: baseline, every two weeks up to week 12
Other outcomes:
Locations:
city: Ludwigsburg
country: Germany
facility: Klinikum Ludwigsburg, Klinik für Innere Medizin, Gastroenterologie, Hämato-Onkologie, Diabetologie
state: Baden-Württemberg
city: Wendlingen
country: Germany
facility: Onkologische Schwerpunktpraxis
state: Baden-Württemberg
city: Deggendorf
country: Germany
facility: Klinikum Deggendorf, Medizinische Klinik II
state: Bayern
city: Berlin-Zehlendorf
country: Germany
facility: Medizinisches Versorgungszentrum, Onkologischer Schwerpunkt
state: Berlin
city: Potsdam
country: Germany
facility: Ernst von Bergmann Klinikum, Zentrum für Hämatologie/Onkologie/Strahlenheilkunde
state: Brandenburg
city: Frankfurt
country: Germany
facility: Klinikum der J.W. Goethe-Univerisität Frankfurt, Klinik für Allgemein- und Viszeralchirurgie
state: Hessen
city: Wetzlar
country: Germany
facility: Klinikum Wetzlar-Braunfels, Medizinische Klinik II
state: Hessen
city: Hannover
country: Germany
facility: Klinikum Region Hannover GmbH, Krankenhaus Siloah, Med. Klinik III (Hämatologie & Onkologie)
state: Niedersachsen
city: Hildesheim
country: Germany
facility: Onkologische Schwerpunktpraxis Hildesheim, Im Medicinum
state: Niedersachsen
city: Essen
country: Germany
facility: Kliniken Essen-Mitte, Klinik f. intern. Onkologie u. Hämatologie
state: Nordrhein-Westfalen
city: Essen
country: Germany
facility: Universitätsklinikum Essen, Klinik für Innere Medizin - Tumorforschung
state: Nordrhein-Westfalen
city: Leverkusen
country: Germany
facility: Klinikum Leverkusen gGmbH, Medizinische Klinik III
state: Nordrhein-Westfalen
city: Mönchengladbach
country: Germany
facility: Kliniken Maria Hilf GmbH, Krankenhaus St. Franziskus, Hämatologie/Onkologie/Gastroonkologie
state: Nordrhein-Westfalen
city: Recklinghausen
country: Germany
facility: Prosper-Hospital, Medizinische Klinik I
state: Nordrhein-Westfalen
city: Würselen
country: Germany
facility: Hämatologisch Onkologische Praxis Würselen
state: Nordrhein-Westfalen
city: Mainz
country: Germany
facility: Johannes Gutenberg Universität, Universitätsklinikum, I. Medizinische Klinik und Poliklinik
state: Rheinland-Pfalz
city: Halle
country: Germany
facility: Universitätslinikum der Martin-Luther Universität Halle-Wittenberg, Klinik für Innere Medizin IV
state: Sachsen-Anhalt
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig, Klinik für Gastroenterologie und Rheumatologie
state: Sachsen
city: Neustadt (Sachsen)
country: Germany
facility: Internistische Praxis und Tagesklinik
state: Sachsen
city: Neumünster
country: Germany
facility: Friedrich-Ebert-Krankenhaus GmbH, Klinik für Hämatologie, Onkologie/Nephrologie
state: Schleswig-Holstein
city: Berlin
country: Germany
facility: Vivantes Klinikum Am Urban, Klinik für Innere Medizin
city: Berlin
country: Germany
facility: VIVANTES Klinikum Neukölln, Onkologisches Zentrum Vivantes Süd
city: Berlin
country: Germany
facility: Charité (Campus Virchow-Klinikum), Med. Klinik mit Schwerpunkt Hämatologie und Onkologie
city: Berlin
country: Germany
facility: Vivantes Klinikum Spandau, Klinik für Innere Medizin
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg - Eppendorf, Onkologisches Zentrum
city: Hamburg
country: Germany
facility: MVZ für Innere Medizin in Hamburg-Eppendorf
Study officials:
affiliation: Universitätslinikum der Martin-Luther Universität Halle-Wittenberg
name: Karin Jordan, Dr. med.
role: PRINCIPAL_INVESTIGATOR
References: