Proof-of-concept Study of Ibrutinib in c-MYC and HER2 Amplified Oesophagogastric Carcinoma
试验速览
- 阶段
- 2 期
- 入组人数
- 17
- 试验地点
- 1
- 主要终点
- Objective response rate in patients with c-MYC and HER2 amplified advanced pre-treated oesophagogastric carcinomas treated with ibrutinib
研究概览
简要总结
Some cancers of the oesophagus and stomach express excessive copies of either the cMYC (Myelocytomatosis oncogene) gene, the HER2 (Human epidermal growth factor receptor 2) gene or both. These genes may potentially contribute to the growth and spread of cancer.Ibrutinib is a drug that is already used in the treatment of certain cancers of the immune system.
There is preclinical evidence that it shows activity against gastric and stomach cancer cells over-expressing cMYC and HER2 genes.
The iMYC study will assess the activity of ibrutinib in cancers of the oesophagus and stomach which over-express these genes and which have previously been treated with standard chemotherapies.
Any anti-cancer activity seen will be measured and correlated with metabolic changes on FDG (18F-2-fluoro-2-deoxy-D-glucose fluorodeoxyglucose) - PET (positron emission tomography) scan, changes in DNA and circulating tumour cells in the blood, and molecular changes in the cancer itself through the use of optional repeat tumour biopsies. If an effect is seen it could provide justification for further research in this group of patients.
Patients will be eligible if they have advanced cancer of the oesophagus or stomach and have been treated with at least one line of prior therapy. The study will be conducted at the Royal Marsden Hospital at its Sutton and Chelsea sites.
It will involve an initial group of up to 17 patients. Screening, recruitment and follow up will last for 3 years in total.
Patients wishing to take part must consent to having their cancer biopsied to test for cMYC and HER2 amplification, as well as a number of imaging and blood tests. There are optional further tumour biopsies whilst on study.
Patients will be treated with ibrutinib until progression of their disease or unacceptable toxicity.
详细描述
This is an open-label, single-arm phase II study. Patients will receive standard dose single-agent ibrutinib delivered orally at a dose of 560mg once daily continuously on a 4 weekly cycle until disease progression or unacceptable toxicity occurs.
Single arm, open label means that both researchers and participants know the treatment which is being administered, and all participants in the trial will receive the study drug ibrutinib.
A Phase 2 study was chosen as more information about the efficacy and toxicity of this drug in this specific group of patients is needed prior to considering a larger phase 3 study.
Eligible patients are those with advanced unresectable or metastatic oesophagogastric adenocarcinoma or squamous cell carcinoma who have been treated with at least 1 prior chemotherapy for advanced or metastatic disease. In the case of HER2 positive tumours, previous treatment with chemotherapy with or without a HER2 targeted agent is allowed.
There will be a two step enrollment process:
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Provision of signed and dated, written informed consent prior to any study specific procedures.
- •Female or male aged 18 years or older.
- •Histologically proven metastatic or locally advanced inoperable squamous or adeno carcinoma of the oesophagus,stomach or oesophago-gastric junction.
- •Documented progression after at least 1 prior line of chemotherapy for advanced disease. For HER2 positive tumours documented progression after at least 1 line of chemotherapy with or without HER2 directed therapy.
- •c-MYC or HER2 gene amplification as defined in trial protocol
- •Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the study. If female patients are taking hormonal contraceptives to prevent pregnancy then this should be combined with a barrier method of contraception. Men must agree to not donate sperm during and after the study. For both males and females restrictions apply for 3 month after the last dose of study drug. See protocol for highly effective methods of birth control.
- •Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [b-hCG]) or urine pregnancy test at screening. Women who are pregnant or breastfeeding are ineligible for this study.
- •Mandatory provision of archival or fresh tumour biopsy for confirmation of c-MYC or HER2 gene amplification.
- •World Health Organisation (ECOG) performance status 0-2, minimum life expectancy of 12 weeks from proposed first dose date, no deterioration within 2 weeks of screening and first dose.
- •Adequate organ and haematological function as evidenced by the following laboratory values within 14 days before enrolment:
- •absolute neutrophil count (ANC) ≥1,500/mm3μL platelets ≥100,000/mm3μL (independent of transfusion support) alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 x upper limit of normal (ULN) total bilirubin ≤1.5 x ULN unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin serum creatinine ≤2 x ULN or estimated creatinine clearance (CCr) ≥30 mL/min/1.73m2
- •At least one measurable target lesion, as per RECIST criteria 1.1
排除标准
- •Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
- •Concurrent treatment within 4 weeks of study entry with any other chemotherapy, anticancer immunotherapy or experimental therapy
- •No available histology for c-MYC or HER-2 amplification testing
- •Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification
- •Patients with ECG abnormalities considered by the investigator to be clinically significant, or repeated baseline prolongation of the rate-corrected QT interval (QTc)
- •Any actively bleeding gastrooesophageal tumour
- •History of stroke or intracranial haemorrhage within 6 months prior to enrolment
- •Symptomatic brain metastases
- •Known history of human immunodeficiency virus (HIV) or active Hepatitis C Virus or active Hepatitis B Virus infection or any uncontrolled active systemic infection requiring intravenous (IV) antibiotics.
- •Ongoing anticoagulation with a vitamin K antagonist
- •Requiring use of strong P450 (CYP) 3A4 inhibitors
- •Major surgery within 4 weeks of enrolment
- •Vaccinated with live, attenuated vaccines within 4 weeks of enrolment
- •Any pre-existing medical condition of sufficient severity to prevent full compliance with the study
研究组 & 干预措施
ibrutinib
ibrutinib delivered orally at a dose of 560mg once daily continuously on a 4 weekly cycle until disease progression or unacceptable toxicity occurs.
干预措施: ibrutinib (Drug)
结局指标
主要结局
Objective response rate in patients with c-MYC and HER2 amplified advanced pre-treated oesophagogastric carcinomas treated with ibrutinib
时间窗: 3 years
Primary end point of objective overall radiological response rate, defined as confirmed complete response and partial response on CT or MRI imaging (assessed according to RECIST 1.1).
次要结局
- Disease control rate at 8 weeks(8 weeks)
- Patient reported outcome- health related quality of life (HRQoL) as assessed by EORTC Quality of Life questionnaire QLQ-C30(3 years)
- Patient reported outcome- health related quality of life (HRQoL) as assessed by EORTC Quality of Life questionnaire STO22(3 years)
- Progression free survival(3 years)
- Overall survival(3 years)
- Safety and tolerability of ibrutinib treatment in advanced oesophagogastric cancer(3 years)
- Correlate metabolic changes on FDG-PET scan with changes in gene expression, circulating tumour cells and CT response(3 years)