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Trial registered on ANZCTR


Registration number
ACTRN12617001612303
Ethics application status
Approved
Date submitted
4/10/2017
Date registered
8/12/2017
Date last updated
18/01/2019
Date data sharing statement initially provided
18/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Injection of Bromelain and Acetylcysteine in combination into recurrent mucinous tumour or pseudomyxoma peritonei: a phase I/II study
Scientific title
A phase I/II study to evaluate the safety and efficacy of injection of Bromelain and Acetylcysteine in combination into recurrent mucinous tumour or pseudomyxoma peritonei and aspiration of tumour
Secondary ID [1] 293055 0
None
Universal Trial Number (UTN)
U1111-1203-1657
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
pseudomyxoma peritonei 304980 0
recurrent pseudomyxoma peritonei 304981 0
peritoneal disease 304982 0
low grade appendix tumour 304983 0
Condition category
Condition code
Cancer 304306 304306 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study involves 60 patients with mucinous peritoneal tumour, including pseudomyxoma peritonei (PMP), that are not suitable for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) or other potentially beneficial surgery.

The combination drug treatment of Bromelain and Acetylcysteine will be injected directly into the tumour or peritoneal cavity via a drain and allowed to dwell for 24 hours. The tumour will then be drained and a repeat treatment will be considered.

The injection will be performed under radiological guidance by an interventional radiologist though a percutaneously inserted drain. The drain will remain in situ for the treatment period. The aspiration/drainage and repeat drug treatments will be delivered via this drain. The dose of the drug is dependent on the calculated tumour dimensions and volume.

The expectation is that the drug combination will dissolve the tumour, allowing it to be drained. Remaining mucinous tumour that is unable to be drained will be considered for repeat drug treatments.
Intervention code [1] 299296 0
Treatment: Drugs
Intervention code [2] 299442 0
Treatment: Other
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 303572 0
The primary endpoint of this study will be based on tumour reduction following direct injection of combination Bromelain and NAC into the recurrent PMP mucin. An assessment of efficacy will be measured by volume of fluid aspirated from the tumour collection (dissolved tumour). The treatment will be seen effective if >25% of tumour volume is aspirated.
Timepoint [1] 303572 0
The primary timepoint will be achieved on the day of treatment based volume of tumour dissolved where the baseline (prior to injection) volume of tumour will be compared to the post treatment volume of tumour drained, occurring 3-5 hours post injection.
Primary outcome [2] 303742 0
Repeat radiological imaging via a CT scan will be utilised to confirm and provide an accurate and re-measurable response to treatment. The post treatment scans will be compared to the pre-treatment radiology. A radiologist will compare both pre- and post-treatment scans to measure response. The endpoint will be reached if radiological response of tumour to therapy is achieved based on a 25% reduction in tumour volume on 3-dimensional imaging and volumetric analysis.
Timepoint [2] 303742 0
The primary timepoint will be achieved on the day of treatment based on repeat radiology scanning where the baseline (prior to injection) volume of tumour will be compared to the post treatment volume of tumour (following drainage) radiology, occurring 3-5 hours post injection.
Secondary outcome [1] 339429 0
Progression free survival (increase >20%) of the treated area based on repeat CT scanning
Timepoint [1] 339429 0
18 months
Secondary outcome [2] 339430 0
Post intervention symptom scoring using a standardised quality of life questionnaires as a tool to assess symptoms (RAND, SF36, EORTC QLQ-30 core questionnaire, EORTC QLQ-C15-PAL, EORTC QLQ-CR29)
Timepoint [2] 339430 0
18 months
Secondary outcome [3] 339431 0
Side effects including but not limited to effect on coagulation, pain, anaphylaxis/sensitivity/rash, infection.
Timepoint [3] 339431 0
At the time of intervention, during the intervention, day following the intervention, 1 week post intervention, 1 month post intervention
Secondary outcome [4] 339432 0
Phamacokinetics (CL) of Bromelain and NAC in tumour removed via the drain - drug concentration assays will be performed on the tumour aspirated at each aspiration timepoint.
Timepoint [4] 339432 0
Bloods will be collected on the day of the drug treatemnt via an IVC 3 hours following the injection of the drug combination. This will be examined for serum drug concentrations. Bloods will also be taken at 24 hours and 1 week.
Secondary outcome [5] 339434 0
Determine the cost to the healthcare system of the direct injection treatment by collection of patient treatment related data and evaluated with the hospital's Network Manager Performance Unit that is responsible for providing activity performance and costing information and analysis to support performance management of health service. The total cost per patient includes all costs related to the authority of the New South Wales Health System.
Timepoint [5] 339434 0
18 months

Eligibility
Key inclusion criteria
Patients with PMP or mucinous tumour who are not candidates for CRS/HIPEC or other surgery, have soft to intermediate grade tumour and do not meet any exclusion criteria

Patients will be considered for entry into this study if they:

• Are 18 – 80 years old
• Have a mucinous tumour or pseudomyxoma peritonei (target or free intraperitoneal) as identified on prior histology
• Are considered at high risk for repeat surgery, or do not wish to explore repeat surgery and consent to the trial procedures
• Have soft to intermediate grade tumour as identified on prior histology or operation
• Are considered suitable for the trial based on multidisciplinary team meeting review

Tumour should not be hard tumour or caking and have a clear cystic or mucinous appearance as identified on radiology. Having hard tumour in one region does not exclude treatment in another area, provided the appearance is mucinous.

In the case of a target lesion, tumour located elsewhere will not exclude a patient from this study and these tumours may be treated if suitable. The tumour must be safely accessible percutaneously by an interventional radiologist to allow insertion of a catheter or drain
Minimum age
18 Years
Maximum age
80 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria

Patients will be excluded from the study if they:

• Have a non-mucinous tumour recurrence (hard tumour)
• Have suspected fistulisation of the tumour into the gastrointestinal tract, invading or abutting major vessel or other area of concern
• Have an allergy to pineapples, papain or bromeliads, sulphur or Acetylcysteine (skin tests will be performed in any patient where allergy or sensitivity is unknown)
• Have a coagulation disorder of any kind or are on anticoagulant or anti-platelet therapy that can not be managed or withheld for the treatment period
• Are asthmatic
• Have infected tumour (pus on aspiration or indicated on blood test)
• Have other serious comorbidities where inclusion in the trial will subject the patient to a higher risk of adverse events
• Are unable to give fully informed and educated consent or are unable to comply with the standard follow up procedures of a clinical trial
• Considered by the interventional radiologist to not be percutaneously accessible

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
Phase 1 / Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The primary endpoint, dissolution of the mucin collection, will be assessed by the measurement of the volume aspirated following the drug therapy and at repeat radiological imaging. Statistical analyses will be performed using SPSS software for Windows or Mac, version 25 (2018). Independent t-test will be used to compare the differences in patients (as well as case-matched controls) with Cox Regression to compare for re-accumulation free survival, as well control for other confounding factors such as volume of disease and hardness of tumour, which we have previously studied. Treatment effects will be expressed as relative risk with a 95% confidence interval. Other secondary outcome measures will be analyzed using Fisher’s exact or Chi-square test. Continuous variables will also be analyzed by independent t-test. The specific quality of life, symptom and treatment questionnaire will be used to gather information on the impact of the patient’s disease and intervention. Data will be graphed as represented across all time points and analyzed using repeated measures of variance. Patients will be analyzed according to the intervention, regardless of compliance. A p-value of <0.05 will be considered statistically significant in all tests.

Recruitment
Recruitment status
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)
NSW
Recruitment hospital [1] 9154 0
St George Hospital - Kogarah
Recruitment postcode(s) [1] 17667 0
2217 - Kogarah
Recruitment outside Australia
Country [1] 21213 0
Netherlands
State/province [1] 21213 0

Funding & Sponsors
Funding source category [1] 297679 0
Hospital
Name [1] 297679 0
Department of Surgery, St George Hospital
Address [1] 297679 0
Department of Surgery Peritonectomy Unit
St George Hospital
1 Short Street
Kogarah NSW 2217
Country [1] 297679 0
Australia
Funding source category [2] 297682 0
Commercial sector/Industry
Name [2] 297682 0
MUCPharm Pty Ltd
Address [2] 297682 0
13/53 High Street
Malvern VIC 3144
Country [2] 297682 0
Australia
Primary sponsor type
Individual
Name
Professor David Morris
Address
Department of Surgery
Level 3, Pitney Clinical Sciences Building
St George Hospital
Gray Street
Kogarah NSW 2217
Country
Australia
Secondary sponsor category [1] 296700 0
None
Name [1] 296700 0
Address [1] 296700 0
Country [1] 296700 0
Other collaborator category [1] 279758 0
Other
Name [1] 279758 0
Dr Glenn & Partners
Address [1] 279758 0
50 Montgomery Street
Kogarah NSW 2217
Country [1] 279758 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298751 0
Bellberry Ltd
Ethics committee address [1] 298751 0
129 Glen Osmond Road
Eastwood SA 5063
Ethics committee country [1] 298751 0
Australia
Date submitted for ethics approval [1] 298751 0
29/12/2017
Approval date [1] 298751 0
12/02/2018
Ethics approval number [1] 298751 0
2017-07-561

Summary
Brief summary
The aim of this study is to evaluate the effect of Bromelain (Br) and Acetylcysteine (NAC) on mucinous tumour in patients that are unsuitable for repeat surgery.

Who is it for?
You may be eligible to join this study if you are aged between 18 and 80 years and have pseudomyxoma peritonei (PMP) or other mucinous tumour and you are not suitable for surgery.

Study details
All participants in this study will receive the treatment under investigation. This will involve injection of the combination drug treatment Bromelain and Acetylcysteine directly into the tumour via a drain. The drain will be aspirated 24 hours after the injection is administered. Repeat drug treatments will be considered. Efficacy will be assessed by volume aspirated and repeat radiological imaging.

This study will assist with establishing the how well the drug works (efficacy) and its safety when injecting it into mucinous tumours in patients that are unsuitable for surgery.
Trial website
Trial related presentations / publications
1. Morris DL, Valle SJ, Akhter J, Pillai K. Direct Injection of Bromelain and N-acetylcysteine into Recurrent, Inoperable, Pseudomyxoma Peritonei Tumors of the Appendix. National Organization for Rare Disorders (NORD) Breakthrough Summit, October 2017, Washington DC. Poster Presentation.
2. Valle SJ, Liauw W, Lodh S, Power M, Glenn D, Morris DL. Preliminary results of a phase I/II study of bromelain and acetylcysteine in patients with inoperable mucinous tumours involving the peritoneum” (of 397 submissions), 10th International Congress on Peritoneal Surface Malignancies, Paris, France, 9-11 September 2018
Public notes
Pseudomyxoma peritonei (PMP) is an orphan disease, characterised by the progressive accumulation of jelly-like material within the abdomen, which occurs in approximately 1-2 people per million per year. Advanced disease is often the result of tumour perforation and seeding of tumour cells within the peritoneal cavity, leading to this syndrome. Multifocal mucin collections are the main cause of morbidity and mortality. In the past, management of mucinous peritoneal disease involved repeated surgical debulking, with systemic chemotherapy having minimal effect. The combined modality of complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CCRS/HIPEC) has been evaluated extensively and is now standard of care for appendiceal and other mucinous peritoneal tumours.

The intention of CCRS/HIPEC is cure, however this is dependent on the characteristics and extent of tumour involvement, with the main limitation being amount of disease involving the serosa or mesentery of small bowel.

Mucin produced by tumours is known to be highly resistant to chemotherapy as mucin acts as a tumour coating. Many patients with mucinous tumours or PMP, however, can achieve long-term survival through this therapy although in a significant proportion recurrence following CCRS/HIPEC occurs, and repeat interventions for recurrent disease have a negative impact on quality of life, where the risks of the procedure in many cases outweigh the benefits, as well as inflicting a considerable strain on the health system with the costs of multiple CRS procedures.

In an attempt to modify these outcomes, mucin and mucin-producing cells have remained the two main targets in our research. We discovered remarkable synergy between Bromelain (Br) and Acetylcysteine (NAC), and together this new method of medical treatment was able to completely dissolve appendix mucin within hours with considerable effects on MUC1, MUC2 and MUC5AC also observed. We have performed a substantial number of preclinical studies on both bench and animal models mucinous tumours, all of which support the use of this new method of medical treatment in mucinous tumours with safety.

This study will examine in a clinical setting, the efficacy and safety of applying Br/NAC directly into recurrent mucinous tumour deposits or intraperitoneally in patients that are not found to be suitable for repeat curative intent intervention by CCRS/HIPEC. These patients currently have no other treatment option for their disease. The aim of this study is to assess whether the application of Br/NAC via radiologically placed percutaneous catheters directly into the recurrence dissolves the mucinous tumour, allowing for it to be drained. The efficacy of this intervention will be assessed via radiological imaging and clinically with the expectation that this combination treatment will result in dissolution and removal of the tumour. The surrogate endpoints used in this study will be radiological response and volume of mucin aspirated. The projected benefits of direct injection of the Br/NAC include improvement of symptoms of the disease, which frequently include pain, vomiting, inability to maintain adequate oral intake and progressive loss of condition.

Contacts
Principal investigator
Name 78114 0
Prof David Morris
Address 78114 0
Department of Surgery Peritonectomy Unit
Level 3, Pitney Clinical Sciences Building
St George Hospital
Gray Street
Kogarah NSW 2217
Country 78114 0
Australia
Phone 78114 0
+61291132070
Fax 78114 0
+61291133997
Email 78114 0
david.morris@unsw.edu.au
Contact person for public queries
Name 78115 0
Miss Sarah Valle
Address 78115 0
Department of Surgery Peritonectomy Unit
Level 3, Pitney Clinical Sciences Building
St George Hospital
Gray Street
Kogarah NSW 2217
Country 78115 0
Australia
Phone 78115 0
+61291132070
Fax 78115 0
+61291133997
Email 78115 0
sarah.valle@health.nsw.gov.au
Contact person for scientific queries
Name 78116 0
Miss Sarah Valle
Address 78116 0
Department of Surgery Peritonectomy Unit
Level 3, Pitney Clinical Sciences Building
St George Hospital
Gray Street
Kogarah NSW 2217
Country 78116 0
Australia
Phone 78116 0
+61291132070
Fax 78116 0
+61291133997
Email 78116 0
sarah.valle@health.nsw.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Clinical study preliminary and final report of results will be released
What supporting documents are/will be available?
Clinical study report
Summary results
Not applicable