A Randomised Phase II Study Investigating Two Doses of Arfolitixorin Compared to Calciumfolinate Together With 5- Fluorouracil on TS Inhibition in Tumour and Adjacent Hepatic Tissue for Patients With Liver Metastases From Colorectal Cancer
试验速览
- 阶段
- 1 期
- 发起方
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- TS inhibition i tumour tissue
研究概览
简要总结
A study that is blinded to the patient and the investigator where the combination of Arfolitixorin + 5-FU is compared to Calciumfolinate + 5-FU. The patients will be randomised and will receive the above described combination as IV bolus injections, peroperatively in conjuction with collection of the first tissue sample.
A low dose (30 mg) and a high dose (120) mg of Arfolitixorin will be used in order to investigate the relation between dose of Arfolitixorin and TS-inhibition.
详细描述
Arfolitixorin ([6R] 5,10-methylenetetrahydrofolate) is a folate based biomodulator designed to replace leucovorin. Arfolitixorin is the key active metabolite of leucovorin (LV) and does in contrast to LV not require enzymatic metabolic activation. In clinical practice, LV is administered in the form of Calciumfolinate. A hypothesis is therefore that patients which are not capable of metabolizing LV could have a better antitumoral effect with Arfolitixorin administration. The antitumoural effect could be measured as inhibition of the enzyme thymidylate synthase, an enzyme essential for DNA synthesis.
Primary objective The primary objective is to compare the properties of Arfolitixorin and Calciumfolinate together with 5-fluorouracil (5-FU) on thymidylate synthase (TS) (i.e. measured as thymidylate synthase inhibition) in tumour and adjacent liver tissue in patients with liver metastases from colorectal cancer receiving a peroperative intravenous administration of Arfolitixorin or Calciumfolinate.
Secondary objectives To study safety in terms of adverse events and laboratory measurements; haematology and clinical chemistry.
To explore differences in pharmacokinetics of folates and folate metabolites in plasma.
To study gene expression in tumour and adjacent hepatic tissue and its correlation to tissue concentration.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
盲法说明
Randomisation will be performed by a sealed envelope system. The randomisation envelopes are kept in a locked cabinet together with the randomisation list Two sets of code envelopes are prepared. The study personnel that will be responsible for study drug administration will have one set for the randomisation of patients and one set will be held by the investigator for emergency code breaking.
The code envelopes are prepared for each patient and contain information about what treatment the patient should receive. The randomisation will be made by the study personnel responsible for the administration of the study drugs at the day of the surgery. The patients will be randomised in consecutive order. The date and time of randomisation should be recorded on the document followed by a signature of the person opening the envelope.
入排标准
- 年龄范围
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •7.3.1 Inclusion criteria
- •Patients must sign an informed consent document.
- •At least two liver metastases secondary to CRC. Patients must have removable metastases amenable to surgery.
- •Performance status of 0 to 2 on the Eastern Cooperative Oncology Group (ECOG). Performance Status scale. (See Protocol Attachment 1.)
- •For women: Must be surgically sterile, postmenopausal, or compliant with a contraceptive regimen during and for 3 months after treatment. Fertile women must have a negative serum or urine pregnancy test (within 7 days before enrolment) and must not be lactating.
- •For men: Must be surgically sterile or compliant with a contraceptive regimen during and for 3 months after treatment.
- •Patient legally competent and able to communicate effectively with the study personnel as judged by the investigator.
- •Patient likely to co-operate during the study.
- •Patients must be at least 18 years of age.
排除标准
- •Concurrent administration of any other anti-tumour therapy minimum 3 weeks before surgery according to clinical practise.
- •Treatment within the last 30 days with a drug/device that has not received regulatory approval for any indication at the time of study entry.
- •Any intake of medication, which could influence folate, and vitamin B12 status, within 30 days of surgery.
- •Serious concomitant systemic disorders (e.g., active infection including HIV, cardiac disease) that in the opinion of the investigator would compromise the patient's ability to complete the study.
- •Second primary malignancy that is clinically detectable at the time of consideration for study enrollment.
- •Patients with a high risk of postoperative liver failure due to advanced liver metastatic load.
- •History of significant neurological or mental disorder, including seizures or dementia.
- •Presence of clinically relevant (i.e., detectable by physical examination) third-space fluid collection (e.g., ascites, pleural effusion) that cannot be controlled by drainage or other procedures prior to study entry.
- •Known hypersensitivity to 5-FU and or Calciumfolinate/Arfolitixorin.
研究组 & 干预措施
Arfolitixorin.
Drug: Arfolitixorin Drug: 5-FU Per operative i.v. bolus injection of Arfolitixorin in combination with 5-FU
干预措施: Arfolitixorin (Drug)
Calciumfolinate.
Drug: Calciumfolinate Drug: 5-FU Per operative i.v. bolus injection of Calciumfolinate in combination with 5-FU
干预措施: Arfolitixorin (Drug)
结局指标
主要结局
TS inhibition i tumour tissue
时间窗: Biopsies will be collected during liver surgery
The primary objective is to compare the TS-inhibtion capacity of the combination Arfolitixorin/5-FU in contrast to Calciumfolinate/5-FU in tumour, adjacent liver parenchyma and plasma in patients with liver metastases from colorectal cancer
TS inhibition in adjacent liver parenchyma
时间窗: Biopsies will be collected during live surgery
The primary objective is to compare the TS-inhibtion capacity of the combination Arfolitixorin/5-FU in contrast to Calciumfolinate/5-FU in adjacent liver in patients with liver metastases from colorectal cancer
TS inhibition in plasma
时间窗: Blood samples will be collected according to a sampling schedule during 24 hours after the bolus injection.
The primary objective is to compare the TS-inhibtion capacity of the combination Arfolitixorin/5-FU in contrast to Calciumfolinate/5-FU in plasma in patients with liver metastases from colorectal cancer
次要结局
未报告次要终点