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

Malignant Ascites Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01200121
• Other study ID #: AIO-SUP-0108
• Status: Completed
• Phase: Phase 2
• First received: September 9, 2010
• Last updated: April 10, 2015
• Start date: February 2010
• Est. completion date: December 2014

Study information

• Verified date: April 2015
• Source: AIO-Studien-gGmbH
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Paul-Ehrlich-Institut
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 53
• Est. completion date: December 2014
• Est. primary completion date: August 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Ascites
• Gastrointestinal Cancers
• Gastrointestinal Neoplasms
• Malignant Ascites

Intervention

Drug:
• Bevacizumab
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.

Other:
• Placebo
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.

Locations

Country	Name	City	State
Germany	Charité (Campus Virchow-Klinikum), Med. Klinik mit Schwerpunkt Hämatologie und Onkologie	Berlin
Germany	Vivantes Klinikum Am Urban, Klinik für Innere Medizin	Berlin
Germany	VIVANTES Klinikum Neukölln, Onkologisches Zentrum Vivantes Süd	Berlin
Germany	Vivantes Klinikum Spandau, Klinik für Innere Medizin	Berlin
Germany	Medizinisches Versorgungszentrum, Onkologischer Schwerpunkt	Berlin-Zehlendorf	Berlin
Germany	Klinikum Deggendorf, Medizinische Klinik II	Deggendorf	Bayern
Germany	Kliniken Essen-Mitte, Klinik f. intern. Onkologie u. Hämatologie	Essen	Nordrhein-Westfalen
Germany	Universitätsklinikum Essen, Klinik für Innere Medizin - Tumorforschung	Essen	Nordrhein-Westfalen
Germany	Klinikum der J.W. Goethe-Univerisität Frankfurt, Klinik für Allgemein- und Viszeralchirurgie	Frankfurt	Hessen
Germany	Universitätslinikum der Martin-Luther Universität Halle-Wittenberg, Klinik für Innere Medizin IV	Halle	Sachsen-Anhalt
Germany	MVZ für Innere Medizin in Hamburg-Eppendorf	Hamburg
Germany	Universitätsklinikum Hamburg - Eppendorf, Onkologisches Zentrum	Hamburg
Germany	Klinikum Region Hannover GmbH, Krankenhaus Siloah, Med. Klinik III (Hämatologie & Onkologie)	Hannover	Niedersachsen
Germany	Onkologische Schwerpunktpraxis Hildesheim, Im Medicinum	Hildesheim	Niedersachsen
Germany	Universitätsklinikum Leipzig, Klinik für Gastroenterologie und Rheumatologie	Leipzig	Sachsen
Germany	Klinikum Leverkusen gGmbH, Medizinische Klinik III	Leverkusen	Nordrhein-Westfalen
Germany	Klinikum Ludwigsburg, Klinik für Innere Medizin, Gastroenterologie, Hämato-Onkologie, Diabetologie	Ludwigsburg	Baden-Württemberg
Germany	Johannes Gutenberg Universität, Universitätsklinikum, I. Medizinische Klinik und Poliklinik	Mainz	Rheinland-Pfalz
Germany	Kliniken Maria Hilf GmbH, Krankenhaus St. Franziskus, Hämatologie/Onkologie/Gastroonkologie	Mönchengladbach	Nordrhein-Westfalen
Germany	Friedrich-Ebert-Krankenhaus GmbH, Klinik für Hämatologie, Onkologie/Nephrologie	Neumünster	Schleswig-Holstein
Germany	Internistische Praxis und Tagesklinik	Neustadt (Sachsen)	Sachsen
Germany	Ernst von Bergmann Klinikum, Zentrum für Hämatologie/Onkologie/Strahlenheilkunde	Potsdam	Brandenburg
Germany	Prosper-Hospital, Medizinische Klinik I	Recklinghausen	Nordrhein-Westfalen
Germany	Onkologische Schwerpunktpraxis	Wendlingen	Baden-Württemberg
Germany	Klinikum Wetzlar-Braunfels, Medizinische Klinik II	Wetzlar	Hessen
Germany	Hämatologisch Onkologische Praxis Würselen	Würselen	Nordrhein-Westfalen

Sponsors (1)

Lead Sponsor	Collaborator
AIO-Studien-gGmbH

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	paracentesis-free survival (ParFS)	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)	one year	No
Secondary	Best Response (BR)	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	12 weeks from 1st application	No
Secondary	Volume of ascites	Volume of ascites drained by routine paracentesis (ascites volume minus lavage volumes, if applicable)	12 weeks	No
Secondary	Quality of life	Quality of life as assessed by standardized questionnaires	12 weeks	No
Secondary	Changes in ECOG performance status	Calculation: 12 weeks minus baseline	baseline and 12 weeks	Yes
Secondary	Pharmacokinetics of Bevacizumab and VEGF concentrations		12 weeks	No
Secondary	Proportions of patients with adverse events grades 3, 4, or 5.		12 weeks	Yes
Secondary	Proportions of patients with adverse events of special interest	any grade of gastrointestinal perforation, gastrointestinal fistulas or other internal fistulas, wound-healing disturbances, hemorrhagic events and arterial thrombo-embolic events.	12 weeks	Yes
Secondary	All adverse events		12 weeks	Yes
Secondary	Changes in laboratory values and vital signs.	Calculation: Value from later timepoints minus baseline value	baseline, every two weeks up to week 12	Yes

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