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Trial registered on ANZCTR


Registration number
ACTRN12611000134921
Ethics application status
Not yet submitted
Date submitted
28/01/2011
Date registered
4/02/2011
Date last updated
11/01/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Pilot Study of Intraperitoneal Bevacizumab for the Palliation of Malignant Ascites
Scientific title
A 10 patient pilot study of bevacizumab (100-300mg) delivered by intraperitoneal infusion, to prevent or delay the recurrence of malignant ascites
Secondary ID [1] 253500 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malignant Ascites 261047 0
Condition category
Condition code
Cancer 259189 259189 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A 10 patient pilot study of bevacizumab administered by intraperitoneal infusion to delay or prevent the recurrence of malignant ascites.

Participants will be patients of the Department of Oncology and Palliative Care at Mater Heath Services, South Brisbane, Queensland, Australia.

Eligible patients are those receiving paracentesis for the management of symptomatic malignant ascites.

Potentially eligible patients will be screened by research staff. Those that are eligible will be provided with all trial information and asked to provide written consent. Research staff will ensure that the patient understands the off-label use of bevacizumab and the potential toxicities.

Therapeutic abdominal paracentesis using a Cardinal Health thoracocentesis/paracentesis catheter (REF:TPK1001) will be undertaken at the site of maximal fluid collection as identified by abdominal ultrasound. Ascitic fluid will be drained to dryness, or until there is less than 200ml/hr output from the drain. Maximum fluid removal at one time will be 5 litres, after this the drain will be clamped for two hours before further fluid is removed. Intravenous fluids will only be administered if clinically indicated.

Prior to removal of the catheter, bevacizumab will be administered into the peritoneal cavity via an Alaris pump over 1 hour. The intraperitoneal catheter will be removed at the end of the infusion and a small transparent drainage bag placed over the drain site.

The first five patients will receive a dose of 200mg intraperitoneal bevacizumab following paracentesis. Interim analysis of safety and preliminary efficacy will be performed after five patients. Treatment will be considered potentially efficacious if the median time to repeat paracentesis is greater than 14 days in >3 of these patients.

If the 200mg treatment is considered potentially efficacious at interim analysis and there are no serious adverse events effects thought directly attributable to intraperitoneal bevacizumab, a further five patients will receive 100mg intraperitoneal bevacizumab following paracentesis.

If the 200mg treatment does not extend the time to repeat paracentesis to greater than 14 days, and in the absence of adverse effects, the next five patients will receive a dose of 300mg intraperitoneal bevacizumab following paracentesis.

Subsequent administration of intraperitoneal bevacizumab will not be performed if ascites reaccumulates.
Intervention code [1] 257933 0
Treatment: Drugs
Comparator / control treatment
Published data suggests that the average time to repeat paracentesis in malignant ascites is 10-13 days (1-3). Our treatment will be considered potentially efficacious if the median time to repeat paracentesis is greater than 14 days.

References:
1. Husain, A., A. Bezjak, and A. Easson, Malignant ascites symptom cluster in patients referred for paracentesis. Ann Surg Oncol, 2010. 17(2): p. 461-9.
2. Ross, G.J., et al., Sonographically guided paracentesis for palliation of symptomatic malignant ascites. AJR Am J Roentgenol, 1989. 153(6): p. 1309-11.
3. Heiss, M.M., et al., The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: Results of a prospective randomized phase II/III trial. Int J Cancer, 2010. 127(9): p. 2209-21.
Control group
Historical

Outcomes
Primary outcome [1] 262039 0
Efficacy: Paracentesis-free survival.
Treatment at each dose will be considered potentially efficacious if the median time to repeat paracentesis is greater than 14 days in at least 3 of 5 patients.
Clinical need for repeat paracentesis will be based on patient symptoms, clinical examination and abdominal circumference.
Timepoint [1] 262039 0
Weekly assessments until patient death or clinical need for repeat paracentesis.
Secondary outcome [1] 273018 0
Toxicity: Adverse events judged possibly or probably related to intraperitoneal bevacizumab infusion.

Toxicity assessment will include a questionnaire asking about symptoms of: abdominal pain/discomfort, limb swelling or pain, chest pain/dyspnoea, bleeding, headache/neurological symptoms, other.
Patients will also have pulse, blood pressure, temperature and oxygen saturations measured.
Timepoint [1] 273018 0
At baseline, every 4 hours for 24 hours after bevacizumab infusion, then weekly assessments until patient death or clinical need for repeat paracentesis.
Patients will also be asked to report symptoms immediately if they develp in between formal assessments.

Eligibility
Key inclusion criteria
Participants must: be at least 18 years of age, have ascites in the setting of documented intra-abdominal malignant disease, have symptoms related to ascites that necessitate paracentesis for symptom control, be English speaking or have an interpreter available, be able to understand and comply with all trial requirements and the implications of off-label use of intraperitoneal bevacizumab, have exhausted all systemic chemotherapy options OR be unfit to receive systemic chemotherapy OR have declined systemic chemotherapy
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients will be excluded in the case of: ascites due to non-malignant cause, concurrent treatment with systemic chemotherapy that has a realistic chance of controlling the ascites, concurrent treatment with intravenous bevacizumab, life expectancy of less than 2 weeks, a history of bowel perforation or fistula, symptoms or signs suggestive of bacterial peritonitis, child c cirrhosis, uncontrolled hypertension, surgery within 28 days of treatment, evidence of coagulopathy, symptoms suggestive of bowel obstruction

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)

Funding & Sponsors
Funding source category [1] 258401 0
Hospital
Name [1] 258401 0
Palliative Care Research Fund
Address [1] 258401 0
Department of Palliative and Supportive Care Services
Mater Adult Hospital
550 Stanley Street
South Brisbane
QLD 4101
Country [1] 258401 0
Australia
Primary sponsor type
Hospital
Name
Palliative Care Research Fund
Address
Department of Palliative and Supportive Care Services
Mater Adult Hospital
550 Stanley Street
South Brisbane
QLD 4101
Country
Australia
Secondary sponsor category [1] 257549 0
None
Name [1] 257549 0
Address [1] 257549 0
Country [1] 257549 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 260375 0
Ethics committee address [1] 260375 0
Ethics committee country [1] 260375 0
Date submitted for ethics approval [1] 260375 0
08/02/2011
Approval date [1] 260375 0
Ethics approval number [1] 260375 0

Summary
Brief summary
Malignant ascites is a frequent complication of advanced cancer. It is most commonly associated with adenocarcinoma of the ovary, breast, colon, stomach and pancreas.

Ascites has a significant impact on quality of life. Increasing abdominal pressure causes distressing symptoms such as abdominal discomfort, early satiety, nausea and vomiting, dyspnoea, impaired mobility and lethargy. In severe cases vomiting and bowel obstruction may occur.

Approximately half of patients with malignant ascites present with ascites at the time of cancer diagnosis. For the other 50% of patients, ascites is a sign of progressive disease or treatment failure. Median survival for all tumour types after the diagnosis of malignant ascites is 20-25 weeks. If ascites is present at diagnosis systemic cancer therapy can provide early palliation, particularly for those with chemotherapy-sensitive tumours. However in end stage disease tumours are often refractory to cytotoxic chemotherapy and other management options must be considered.

Current guidelines advocate repeat paracentesis, indwelling catheter placement or peritoneovenous shunting for symptom control in malignant ascites. However all of these treatments have significant limitations. Repeat paracentesis is most commonly performed, however this provides only short-term relief, necessitating repeat trips to hospital for further intervention. The average time to repeat paracentesis for patients with malignant ascites is 10-13 days. There is no evidence to support how long the drain should remain in place, whether the drain should be clamped to regulate output, whether intravenous fluids should be administered or whether vital signs should be regularly recorded. The alternatives to repeat paracentesis are less than ideal. In-dwelling catheters risk infection and dislodgement. Peritoneovenous shunting is an invasive procedure and is associated with potentially fatal complications.

Vascular endothelial growth factor (VEGF) is a glycoprotein secreted by tumour cells. VEGF stimulates tumour angiogenesis and increases vascular permeability via interaction with tyrosine kinase receptors on the endothelium of both normal and tumour-induced blood vessels. Malignant pleural and ascitic fluid demonstrates markedly elevated VEGF concentrations, up to 60 fold higher than in matched serum.

The role of VEGF on vascular permeability is thought to be central to the pathogenesis of malignant ascites. Preclinical studies have demonstrated the efficacy and safety of intraperitoneal inhibition of VEGF as therapy to prevent accumulation of ascites.

Bevacizumab is a recombinant humanised monoclonal antibody that binds and inhibits the biological activity of VEGF. Intraperitoneal administration of bevacizumab may be the route of choice when the goal of treatment is to palliate malignant ascites. These patients are routinely managed with repeat paracentesis and intraperitoneal bevacizumab administration can be performed during this procedure. Intraperitoneal administration also has the benefit of directing therapy in to the peritoneal cavity where high VEGF concentrations promote fluid secretion.

One pilot study and two case studies have reported the safety and efficacy of intraperitoneal administration of bevacizumab for the treatment of malignant ascites.

Systemic administration of bevacizumab is usually well tolerated but has been associated with an increased risk increased risk of bowel perforation. This rare but serious complication occurs in 1-2% of patients. Risk factors have not been well defined but may include bowel implants, large tumour burden, prior radiotherapy, recent surgery and bowel obstruction. The mechanism of bevacizumab-associated bowel perforation is likely to be related to the anti-VEGF effects on bowel perfusion and/or tumour regression. Gastrointestinal perforation has not been described following intraperitoneal administration of bevacizumab.

Other side effects of systemic treatment with bevacizumab include hypertension (3-14.8% Grade III/IV), venous and arterial thromboembolic events (0-3%), bleeding, proteinuria, delay in wound healing, and fistula formation.

Our pilot study will evaluate the safety and efficacy of intraperitoneal administration of bevacizumab to prevent the recurrence of malignant ascites. Given the significant cost of bevacizumab, the aim of the study is to find lowest effective dose. As the published data suggests an average time to repeat paracentesis in malignant ascites is 10-13 days, our treatment would be considered potentially efficacious if the median time to repeat paracentesis is greater than 14 days.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 32144 0
Address 32144 0
Country 32144 0
Phone 32144 0
Fax 32144 0
Email 32144 0
Contact person for public queries
Name 15391 0
Prof Janet Hardy
Address 15391 0
Department of Palliative and Supportive Care
Mater Adult Hospital
550 Stanley Street
South Brisbane
QLD 4101
Country 15391 0
Australia
Phone 15391 0
+61 7 3163 3884
Fax 15391 0
+61 7 3163 8856
Email 15391 0
Angela.O'Shea@mater.org.au
Contact person for scientific queries
Name 6319 0
Prof Janet Hardy
Address 6319 0
Department of Palliative and Supportive Care
Mater Adult Hospital
550 Stanley Street
South Brisbane
QLD 4101
Country 6319 0
Australia
Phone 6319 0
+61 7 3163 3884
Fax 6319 0
+61 7 3163 3884
Email 6319 0
Angela.O'Shea@mater.org.au

No information has been provided regarding IPD availability
Summary results
No Results