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Injection of Bromelain and Acetylcysteine in Combination Into Recurrent Mucinous Tumour or Pseudomyxoma Peritonei

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ClinicalTrials.gov Identifier: NCT03976973
Recruitment Status : Not yet recruiting
First Posted : June 6, 2019
Last Update Posted : March 9, 2020
Sponsor:
Collaborators:
Mercy Medical Center
Wake Forest University Health Sciences
St George Hospital, Australia
Memorial Sloan Kettering Cancer Center
Catharina Ziekenhuis Eindhoven
Hospices Civils de Lyon
Information provided by (Responsible Party):
David Morris, Mucpharm Pty Ltd

Tracking Information
First Submitted Date  ICMJE May 24, 2019
First Posted Date  ICMJE June 6, 2019
Last Update Posted Date March 9, 2020
Estimated Study Start Date  ICMJE May 2020
Estimated Primary Completion Date May 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 3, 2020)
  • Tumour response [ Time Frame: 1 month ]
    Tumour changes following BromAc combination treatment. Efficacy will be measured by the volume of fluid aspirated from the drain (dissolved tumour). The treatment will be seen effective if >25% of tumour volume is aspirated or there is a >30% reduction on CT scan post treatment at 1 month compared to the pre-treatment scan.
  • Incidence of Treatment-Emergent Adverse Events (Pathology) [Safety and Tolerability] [ Time Frame: 1 month ]
    Reported as any untoward medical occurrence or worsening of a pre-existing medical condition in a participant administered BromAc, and judged possibly, probably, or definitely related to treatment
Original Primary Outcome Measures  ICMJE
 (submitted: June 4, 2019)
  • Tumour response [ Time Frame: 1 month ]
    Tumour changes following Bromelain and NAC combination treatment. Efficacy will be measured by the volume of fluid aspirated from the drain (dissolved tumour). The treatment will be seen effective if >25% of tumour volume is aspirated or there is a >20% reduction in dimensions on CT scan post treatment at 1 month compared to the pre-treatment scan.
  • Incidence of Treatment-Emergent Adverse Events (Pathology) [Safety and Tolerability] [ Time Frame: 1 month ]
    Reported as any untoward medical occurrence or worsening of a pre-existing medical condition in a participant administered bromelain and NAC, and judged possibly, probably, or definitely related to treatment
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 5, 2020)
  • Progression free survival post treatment [ Time Frame: 1, 3, 6, 9 and 12 months ]
    Time to progression of the treated area based on repeat CT scanning where RECIST v1.1 will be used where possible. The follow up scan will be compared to the 1 month post treatment scan where dimensions and volume will be calculated by an experienced radiologist.
  • Impact of treatment on Quality of Life over time in patients evaluated by the core questionnaire 'European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer (EORTC-QLQ-C30)'. [ Time Frame: Baseline, then at 1 month, 3 months, 9 months and 12 months ]
    The EORTC-QLQ-C30 (European Organisation for Research and Treatment of Cancer - Quality of Life Questionnaire Core - C30) is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / Quality of Life (QoL) scale, and six single items. The global health status / Quality of Life scale has scores from 1 (very poor) to 7 (excellent) and the others from 1 (not at all) to 4 (very much) where 4 is the worst score. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. Thus a high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems.
  • Impact of treatment on Quality of Life in colorectal cancer over time by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Colorectal Cancers (EORTC-QLQ-CR29) [ Time Frame: Baseline, then at 1 month, 3 months, 9 months and 12 months ]
    The symptom scores (Fatigue, Nausea and vomiting, Pain …), with scores from 1 (not at all) to 4 (very much), where 4 is the worst score, will be evaluated by the use of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Colorectal Cancer (EORTC-QLQ-CR29). The trend of each category of outcome measures given by the EORTC-QLQ-CR29 in four groups of patients: tumour on the right and transverse part of the colon; tumour on the left part of the colon; rectal tumour; metastatic colorectal cancer.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 4, 2019)
  • Progression free survival post treatment [ Time Frame: 1, 3, 6, 9 and 12 months ]
    Time to progression of the treated area based on repeat CT scanning where RECIST v1.1 will be used where possible. The follow up scan will be compared to the 1 month post treatment scan where dimensions and volume will be calculated by an experienced radiologist.
  • Quality of life score and impact of treatment on quality of life in palliative cancer patients [ Time Frame: Baseline, then at 1 month, 3 months, 9 months and 12 months ]
    Standardised quality of life (QLQ) questionnaire European Organisation for Research and Treatment of Cancer (EORTC) core questionnaire EORTC QLQ-C15-PAL for quality of life measurement in palliative cancer patients. Does the treatment with BrNAC improve quality of life? Scale range is 1 to 4; 1 (not at all) being no improvement in quality of life to the maximal rating of 4 (improvement in quality of life).
  • Impact of treatment on Quality of Life in colorectal type diseases - assess the most accurate trend of the Global Health Status (Quality of Life evolution) over time in mucinous cancer patients evaluated by the EORTC-QLQ-C30 questionnaire. [ Time Frame: Baseline, then at 1 month, 3 months, 9 months and 12 months ]
    The EORTC-QLQ-C30 (European Organisation for Research and Treatment of Cancer - Quality of Life Questionnaire - C30) is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / Quality of Life (QoL) scale, and six single items. The global health status / Quality of Life scale runs from 1 (very poor) to 7 (excellent) and the others from 1 (not at all) to 4 (very much). All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. Thus: a high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems.
  • Impact of treatment on Quality of Life in colorectal type diseases - assess the trend of over time in mucinous cancer (colorectal type) patients by the European Organisation for Research and Treatment of Cancer (EORTC) EORTC-QLQ-CR29 questionnaire [ Time Frame: Baseline, then at 1 month, 3 months, 9 months and 12 months ]
    The symptom scores (Fatigue, Nausea and vomiting, Pain …), running from 1 (not at all) to 4 (very much), will be evaluated by the use of the European Organisation for Research and Treatment of Cancer EORTC-QLQ-CR29 questionnaire. The trend of each category of PROMS given by the EORTC-QLQ-CR29 in four groups of patients: tumour on the right and transverse part of the colon; tumour on the left part of the colon; rectal tumour; metastatic colorectal cancer.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Injection of Bromelain and Acetylcysteine in Combination Into Recurrent Mucinous Tumour or Pseudomyxoma Peritonei
Official Title  ICMJE Injection of Bromelain and Acetylcysteine in Combination Into Recurrent Mucinous Tumour or Pseudomyxoma Peritonei
Brief Summary

This study involves 100 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 (BromAc) will be administered directly into the tumour or peritoneal cavity via percutaneous drain and allowed to dwell for 24 hours. The tumour will then be drained and a repeat treatment will be considered.

An interventional radiologist will insert a percutaneous 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 outlined in the protocol.

The expectation is that the drug combination will dissolve the tumour, allowing it to be removed. Remaining mucinous tumour that is unable to be drained will be considered for repeat drug treatments.

Detailed Description

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) is considered standard of care for peritoneal spread of appendiceal tumours and a treatment option for 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 are increasingly complex and may have a negative impact on quality of life, where the risks of the procedure in many cases outweigh the benefits.

In an attempt to modify these outcomes, mucin and mucin-producing cells have remained the two main targets of the investigator's research. The principal investigator discovered remarkable synergy between Bromelain (Brom) and Acetylcysteine (Ac), and together this new method of medical treatment was able to completely dissolve appendix mucin within hours with considerable effects on gastrointestinal cancer muffins known as MUC1 and MUC5AC. The investigators have since performed a substantial number of preclinical studies in both bench and animal models of human mucinous tumours including adenocarcinomas and signet ring tumours, which support the use of this method of treatment with efficacy and safety.

This potential treatment for pseudomyxoma peritonei/appendix mucinous tumours received orphan designation from the (Food and Drug Administration (FDA) (DRU-2018-6644) European Medicines Agency (EMA) (EMA/3/18/2107, EMA/3/18/2113). A phase I study at the Peritonectomy Unit at St George Hospital in Sydney, Australia has treated 31 patients with mucinous tumours with a manageable safety profile and an improvement in presenting symptoms was reported in over 65% of patients.

This study will extend to examine in a larger cohort, the safety and efficacy of applying BromAc directly into recurrent mucinous tumour deposits or intraperitoneally in patients that are not suitable for repeat intervention by CCRS/HIPEC or debulking surgery. These patients currently have no other treatment option for their disease.

The aim of this study is to assess whether the application of BromAc via radiologically placed percutaneous catheters directly into the tumour in an extended study remains safe and dissolves the mucinous tumour, with the hypothesis being that the tumour may be drained.

A pre-treatment computed tomography (CT) scan less than 6 weeks old is required for assessment of the tumour and calculation of the size (dimensions) and volume (of a sphere if spherical) of tumour to be treated (RECIST v1.1 if measurable). Blood tests including full blood count (FBC), electrolytes urea creatinine (EUC), liver function tests (LFT), c-reactive protein (CRP) and coagulation screen (INR, APTT, PTT, Fibrinogen, CEA, CA19-9 and CA125) will be performed. Multidisciplinary team assessment of suitability will be performed and the participant will be educated and consented if all criteria are met.

Under radiological guidance, a needle-wire-dilator approach will be taken to access the target tumour or free intraperitoneally, then a large pigtail drain (10fg) is guided into the tumour cavity, or free intraperitoneally (14fg) under standard procedures. The drain will be aspirated to ensure that tumour material cannot be removed prior to the drug treatment as a baseline measurement. The drug is then injected through the drain, administered over a period of at least 5 minutes. The drain is then clamped/capped. The participant is monitored for 3 hours post procedure with clinical observations and blood testing performed at specific intervals (30 min, 1 hr, 2 hr, 3 hr (bloods)).

The participant is seen the following day (approx. 24 hours post) and the drain is aspirated. Fluid aspirated is collected and measured. The participant is assessed for any symptoms and repeat treatment is dependent on clinical condition. If re-treated, the above drug delivery procedure is repeated with a further 24 hour dwell time, followed by aspiration. A maximum of two drug treatments are given in a 48 hour period.

The efficacy of this intervention will be assessed on post intervention radiological imaging and volume aspirated.The projected benefits of direct injection of the BromAc include improvement of symptoms of the disease, which frequently include pain, vomiting, inability to maintain adequate oral intake and progressive loss of condition.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Pseudomyxoma Peritonei
  • Peritoneal Cancer
  • Mucinous Adenocarcinoma
  • Mucinous Tumor
Intervention  ICMJE
  • Drug: Bromelain, Stem
    Intratumoural injections of Bromelain 15-45mg (concentration 600ug/ml) or intraperitoneal injections of Bromelain 60mg will be administered via a radiologically placed drain in combination with Acetylcysteine in 0.9% sodium chloride (normal saline).
    Other Name: Bromelain
  • Drug: Acetylcysteine
    Intratumoural injections of Acetylcysteine 1g or intraperitoneal injections of Acetylcysteine 2g will be administered via a radiologically drain in combination with Bromelain in 0.9% sodium chloride (normal saline).
    Other Names:
    • N-acetylcysteine
    • Acetadote
  • Procedure: Interventional radiology insertion of drain
    Under radiological guidance (CT), a needle, wire, dilator will be placed directly into the tumour then a large pigtail drain (i.e. 10Fg) will be placed into the tumour by an experienced, interventional radiologist, under standard procedures.
  • Diagnostic Test: Pathology: blood testing during intervention
    Blood tests are taken 3 hours after each drug intervention then 24 hours following the last drug intervention to assess for short-term systemic side effects and measure pharmacokinetics of bromelain and acetylcysteine.
  • Other: Routine follow up
    Patients will have outpatient reviews at 1 week and 1, 3, 6, 9 and 12 months post drug intervention. Blood tests will be performed at 1 week and 1, 3, 6, 9 and 12 months after the drug intervention to assess for short and long term systemic side effects. At 1, 3, 6, 9 and 12 months post drug intervention, a CT-scan is part of the study protocol to assess for response and progression of disease.
Study Arms  ICMJE Experimental: Intervention
Patients with inoperable pseudomyxoma peritonei or peritoneal mucinous tumour that meet the entry criteria and consent to the intervention will receive intratumoural or intraperitoneal treatment/s with the combination experimental drug treatment BromAc. The drug will be injected directly into the tumour or free intraperitoneally via a percutaneously radiologically placed drain.
Interventions:
  • Drug: Bromelain, Stem
  • Drug: Acetylcysteine
  • Procedure: Interventional radiology insertion of drain
  • Diagnostic Test: Pathology: blood testing during intervention
  • Other: Routine follow up
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: March 3, 2020)
100
Original Estimated Enrollment  ICMJE
 (submitted: June 4, 2019)
60
Estimated Study Completion Date  ICMJE November 2021
Estimated Primary Completion Date May 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Mucinous tumour or pseudomyxoma peritonei (target lesion or free intraperitoneal) as identified on prior histology or radiology
  • Considered at high risk for repeat surgery, or do not wish to explore repeat surgery and consent to the trial procedures
  • Considered suitable for the trial based on multidisciplinary team meeting review

Exclusion Criteria:

  • Non-mucinous tumour recurrences (hard tumour)
  • Suspected fistulation of the tumour into the gastrointestinal tract, invading or abutting major vessel or other area of concern (fistulation into bladder or vaginal cuff is not an exclusion for treatment)
  • Known allergy (anaphylaxis) to pineapples, papain, bromeliads, sulphur, eggs or Acetylcysteine
  • Coagulation disorders of any kind or are on anticoagulant or anti-platelet therapy that cannot be managed or withheld for the treatment period
  • Signs of an infected tumour (pus on aspiration or indicated on blood test)
  • Eastern Cooperative Oncology Group (ECOG) score >2
  • Other serious co-morbidities where inclusion in the trial will subject the patient to a higher risk of adverse events
  • Unable to provide 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 have a tumour that is not percutaneously accessible
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: David L Morris, MD, PhD +61291132070 david.morris@unsw.edu.au
Contact: Sarah J Valle, BN +61291132070 sarah.valle@mucpharm.com
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03976973
Other Study ID Numbers  ICMJE BRACIS-2
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party David Morris, Mucpharm Pty Ltd
Study Sponsor  ICMJE David Morris
Collaborators  ICMJE
  • Mercy Medical Center
  • Wake Forest University Health Sciences
  • St George Hospital, Australia
  • Memorial Sloan Kettering Cancer Center
  • Catharina Ziekenhuis Eindhoven
  • Hospices Civils de Lyon
Investigators  ICMJE
Principal Investigator: David L Morris, MD, PhD St George Hospital
PRS Account Mucpharm Pty Ltd
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP