A Phase 2, Multi-centre Study of BromAc for Recurrent Peritoneal Mucinous Tumour or Pseudomyxoma Peritonei
试验速览
- 阶段
- 2 期
- 入组人数
- 62
- 主要终点
- Tumour response (objective response rate)
研究概览
简要总结
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.
详细描述
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Intervention
Participants with inoperable pseudomyxoma peritonei or peritoneal mucinous tumour that meet the entry criteria and consent to the intervention will receive intratumoural treatment/s with the combination drug BromAc. The drug product will be injected directly into the tumour via a radiologically placed drain
干预措施: Bromelain (Drug)
Intervention
Participants with inoperable pseudomyxoma peritonei or peritoneal mucinous tumour that meet the entry criteria and consent to the intervention will receive intratumoural treatment/s with the combination drug BromAc. The drug product will be injected directly into the tumour via a radiologically placed drain
干预措施: Acetylcysteine (Drug)
Intervention
Participants with inoperable pseudomyxoma peritonei or peritoneal mucinous tumour that meet the entry criteria and consent to the intervention will receive intratumoural treatment/s with the combination drug BromAc. The drug product will be injected directly into the tumour via a radiologically placed drain
干预措施: Interventional radiology insertion of drain (Procedure)
结局指标
主要结局
Tumour response (objective response rate)
时间窗: 1 month
Tumour changes following BromAc combination treatment compared to baseline. Efficacy will be measured by RECIST v1.1 with the volume of fluid aspirated from the drain (dissolved tumour). The treatment will be seen effective if \>30% 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. Given the difficulty of assessing soft tumour (cystic/mucinous) response by RECIST, a surrogate assessment of efficacy will be measured (if unable to assess based on RECIST v1.1 criteria) by tumour changes following BromAc combination treatment.
次要结局
- Incidence of Treatment-Emergent Adverse Events (Pathology) [Safety and Tolerability](1 month)
- Progression free survival post treatment(1 month, 3 months, 6 months, 9 months and 12 months)
- 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)'.(Baseline, then at 1 month, 3 months, 6 months, 9 months and 12 months)
- Laboratory blood test parameters(Baseline, 1 week, 1 month, 3 months, 6 months, 9 months and 12 months)
- Symptomatic response to treatment(Baseline, 1 week, 1 month, 3 months, 6 months, 9 months and 12 months)
- 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)(Baseline, then at 1 month, 3 months, 6 months, 9 months and 12 months)