Clinical trial NCT03976973: BromAc for Recurrent Peritoneal Mucinous Tumour or Pseudomyxoma Peritonei
Official title: A Phase 2, Multi-centre Study of BromAc for Recurrent Peritoneal Mucinous Tumour or Pseudomyxoma Peritonei
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Pseudomyxoma Peritonei
Peritoneal Cancer
Mucinous Adenocarcinoma
Mucinous Tumor
Lead sponsor: Mucpharm Pty Ltd
Sponsor class: INDUSTRY
Collaborators: name: Mercy Medical Center
name: Wake Forest University Health Sciences
name: University of Pittsburgh Medical Center
name: Catharina Ziekenhuis Eindhoven
name: Hospital Universitario Reina Sofia de Cordoba
First posted: 2019-06-06
Enrollment: 62
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Pseudomyxoma peritonei (PMP) is an orphan disease, characterized by the progressive accumulation of jelly-like material within the abdomen, which occurs in approximately 2-3 people per million per year. Advanced disease is often the result of tumour perforation and seeding of tumour cells within the peritoneal cavity. Complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CCRS HIPEC) is the current standard of care for PMP.

An Australian pharmaceutical company is developing BromAc for diseases involving mucin. This drug is composed of Bromelain and Acetylcysteine. During pre-clinical development, the sponsor found that BromAc rapidly dissolved and removed tumour mucin, making it a potent mucolytic. BromAc in combination have the ability, as shown in pre-clinical studies, to remove the mucin protective framework expressed by cancer including mucin (MUC) 1, MUC2, MUC4, MUC5AC and MUC16. The sponsor has shown the mechanism of action of BromAc - to break peptide and glycosidic linkages and disulphide bonds in tumour produced and respiratory mucin. BromAc has been safe in preclinical development with a manageable adverse event profile and preliminary efficacy in a phase 1 study.

This current study will examine the efficacy and safety of applying BromAc directly into recurrent mucinous tumour deposits in patients that are found to be unsuitable for repeat curative intent intervention by CCRS HIPEC.

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 3 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.

BromAc has been safe in preclinical development and in a phase 1 study, patients received up to 60mg/2000mg of BromAc daily for a median of 3.4 days. Serious treatment-related adverse events (12%) were manageable. There were no anaphylactic reactions. An objective response to treatment was seen in 81% of patients. There were no drug-related deaths due to treatment-related adverse events. With a median follow up of 18.2 months, progression was seen in 55% at a median of 5.8 months.

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).

The aim of this study is to assess whether the application of BromAc via radiologically placed percutaneous catheters directly into the recurrence dissolves the mucinous tumour, allowing for the dissolved tumour 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 BromAc include improvement of symptoms of the disease, which frequently include pain, vomiting, inability to maintain adequate oral intake and progressive loss of condition.

Eligibility criteria: Inclusion Criteria:

* Aged 18 - 80 years
* Have a mucinous tumour/pseudomyxoma peritonei target lesion with a defined cavity, with the shortest diameter being at least 3 centimeters on radiology, and percutaneously accessible. In the case of a target lesion, tumour located at distant sites (for e.g. pleura) will not exclude a patient from this study and these tumours may be treated, if suitable, under expanded access protocols.
* Are symptomatic or at risk of becoming symptomatic or obstructed imminently, are considered inoperable, at high risk of morbidity, mortality or quality of life decline for repeat surgery, or do not wish to explore repeat surgery
* Are considered suitable for the trial based on a multidisciplinary team meeting case review

Exclusion Criteria:

* Have a non-mucinous tumour (hard caked tumour) that does not have cystic appearance on radiology. Having a hard tumour appearance in one region does not exclude treatment in another area, provided the appearance is mucinous.
* Have suspected fistula 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)
* Have known allergy (anaphylaxis) or allergy to pineapples, papain, bromeliads, sulphur, eggs or Acetylcysteine or any other serious allergy or intolerance to fruits or food products
* Have a coagulation disorder of any kind or are on anticoagulant or anti-platelet therapy that cannot be managed or withheld for the radiology procedure
* Have an infected tumour or ongoing inflammatory process (pus on aspiration at radiology will be a delayed failure) as indicated on baseline blood test
* Eastern Cooperative Oncology Group (ECOG) score \>2
* Have had chemotherapy within the last two weeks, have not had bone marrow recovery from chemotherapy, or had Bevacizumab (Avastin) within the last 4 weeks. A staging baseline scan must be completed prior to considering entry into this study.
* Have previously received BromAc for pseudomyxoma or peritoneal mucinous tumour (see expanded access)
* Have other serious comorbidities where inclusion in the trial will subject the participant to an unacceptable higher risk of adverse events as judged by the investigator
* Pregnant women are excluded from this study because BromAc has unknown but a potential risk for adverse events in nursing infants secondary to treatment of the mother
* Participants with psychiatric illness/social situations that would limit compliance with study requirements
* Are unable to give fully informed and educated consent or are unable to comply with the standard follow up procedures of a clinical trial

Primary outcomes:
measure: Tumour response (objective response rate)
timeFrame: 1 month
Secondary outcomes:
measure: Progression free survival post treatment
timeFrame: 1 month, 3 months, 6 months, 9 months and 12 months
measure: 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)'.
timeFrame: Baseline, then at 1 month, 3 months, 6 months, 9 months and 12 months
measure: 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)
timeFrame: Baseline, then at 1 month, 3 months, 6 months, 9 months and 12 months
measure: Incidence of Treatment-Emergent Adverse Events (Pathology) [Safety and Tolerability]
timeFrame: 1 month
measure: Symptomatic response to treatment
timeFrame: Baseline, 1 week, 1 month, 3 months, 6 months, 9 months and 12 months
measure: Laboratory blood test parameters
timeFrame: Baseline, 1 week, 1 month, 3 months, 6 months, 9 months and 12 months
Other outcomes:
Locations:
Study officials:
affiliation: Mercy Medical Center, USA
name: Armando Sardi, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pittsburgh Medical Center, USA
name: Haroon Choudry, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Wake Forest University Hospital, USA
name: Edward Levine, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital Reina Sofia, Spain
name: Alvaro Arjona Sanchez, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Eindhoven Catharina Hospital, Netherlands
name: Ignace de Hingh, MD
role: PRINCIPAL_INVESTIGATOR
References: