Targeted Therapy With Imatinib for Treatment of Poor Prognosis Mesenchymal-type Resectable Colon Cancer: a Proof-of-concept Study in the Preoperative Window Period.
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- UMC Utrecht
- 入组人数
- 5
- 试验地点
- 3
- 主要终点
- Effects of treatment on the mesenchymal gene expression profile
研究概览
简要总结
In this proof-of-concept trial the investigators will study the effects of imatinib treatment on the biology of mesenchymal-type colon cancers.
详细描述
Tumor biopsies from patients with newly diagnosed colon cancer will be pre-screened with an RT-qPCR test to identify tumors of the mesenchymal subtype. Patients with mesenchymal-type tumors that meet the in- and exclusion criteria will be treated with imatinib during the "window period" that normally precedes surgery. Immediately following tumor resection, biopsies will be taken from the surgical specimen. Gene and protein expression of the pre- and post-treatments biopsies will be compared to assess the effects of imatinib therapy on PDGFR- and cKIT-signalling and on the mesenchymal gene expression profile.
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
- •Male or female aged ≥18 years
- •Histologically proven adenocarcinoma of the colon;
- •Completed cancer staging with CT-abdomen and CT-thorax/X-thorax according to hospital's standard of care;
- •Confirmed eligibility for surgery with curative intent as deemed by the hospital's multidisciplinary board (MDB) review;
- •An intratumoural gene expression profile of PDGFR-α, PDGFR-β, PDGF-C and KIT, indicative of the mesenchymal phenotype, according to our diagnostic RT-qPCR test (i.e. more than 50% chance of having the mesenchymal phenotype);
- •Minimum of four properly stored pre-treatment biopsies for gene expression analysis/ELISA;
- •WHO performance status 0 or 1;
- •Adequate haematology status and organ function, defined as:
- •Normal creatinine clearance (≥60 ml/min (MRDR))
- •ALAT within 2.5x upper limit of normal (ULN)
- •PT-INR < 1.5
- •Leukocytes > 1,5*10^9/L; Hb > 6.0 mmol/L; platelets > 100*10^9/L
- •Willingness and ability to comply with scheduled visits, treatment plans and laboratory tests;
- •Written informed consent.
排除标准
- •The presence of synchronous distant metastases;
- •Current hospital standard of care dictates that subject should undergo any neoadjuvant therapy;
- •Concurrent participation in another clinical trial using any medicinal product, or participation in such a trial in the period of three months prior to the current trial;
- •Women who are pregnant, plan to become pregnant or are lactating during the study or for up to 30 days after the last dose of imatinib;
- •Known HIV or Hepatitis B/C infection;
- •Known symptomatic congestive heart failure;
- •Co-morbidity requiring concomitant treatment with drugs that act as strong inducers of CYP3A4 or with drugs with a narrow therapeutic range influenced by imatinib
研究组 & 干预措施
Intervention
Subjects will be treated with the medicinal product imatinib, which will be administered orally in tablets of 400mg, once per day, during two weeks prior to tumor resection.
干预措施: Imatinib (Drug)
结局指标
主要结局
Effects of treatment on the mesenchymal gene expression profile
时间窗: period from diagnostic colonoscopy until surgical resection (~5 weeks)
To assess the extent of change in the mesenchymal phenotype, gene expression arrays will be generated from pre- and post-treatment tissue samples and the expression of genes associated with the poor-prognosis mesenchymal subtype will be compared.
次要结局
- Extent of targeted inhibition of PDGFR and KIT phosphorylation in cancer cells(period from diagnostic colonoscopy until surgical resection (~5 weeks))
- Correlation between plasma imatinib trough levels on day 14 and intratumoural concentration of imatinib in the resection specimen(at time of surgery)
- Change in plasma levels of circulating tumor DNA(period between diagnostic colonoscopy until surgical resection (~5 weeks))
- Number of participants with treatment-related adverse events as assessed by CTCAEv4.02(from start of treatment until 2 weeks after last dose imatinib)
- Change in plasma CEA-concentrations(period between diagnostic colonoscopy until surgical resection (~5 weeks))
- Effects of imatinib on the ability of cancer cells to form in vitro 3D cell cultures (organoids)(at time of surgery)
- Correlation between the extent of PDGFR and cKIT inhibition and systemic and intratumoural imatinib and CGP74588 concentration(at time of surgery)
研究者
Prof dr I.H.M. Borel Rinkes
Chief Surgical Specialities
UMC Utrecht