Modelle 001, TS-inhibition in Colorectal Liver Metastases Comparing Arfolitixorin and Calciumfolinate

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

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.

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.

To investigate the relation between the levels of deoxyuridine (dU) in plasma with the amount of TS inhibition in tumour tissue, in order to evaluate dU as a surrogate marker for TS-inhibition.

Study population:

Thirty adult patients with colorectal cancer and liver metastases, indicated for surgical removal will be randomised.

Inclusion Criteria:

• 7.3.1 Inclusion criteria

  1. Patients must sign an informed consent document.

  2. At least two liver metastases secondary to CRC. Patients must have removable metastases amenable to surgery.

  3. Performance status of 0 to 2 on the Eastern Cooperative Oncology Group (ECOG). Performance Status scale. (See Protocol Attachment 1.)

  4. 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.

  5. For men: Must be surgically sterile or compliant with a contraceptive regimen during and for 3 months after treatment.

  6. Patient legally competent and able to communicate effectively with the study personnel as judged by the investigator.

  7. Patient likely to co-operate during the study.

  8. Patients must be at least 18 years of age.

     Exclusion Criteria:1.

     Concurrent administration of any other anti-tumour therapy minimum 3 weeks before surgery according to clinical practise.

  2. 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.

  3. Any intake of medication, which could influence folate, and vitamin B12 status, within 30 days of surgery.

  4. 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.

  5. Second primary malignancy that is clinically detectable at the time of consideration for study enrollment.

  6. Patients with a high risk of postoperative liver failure due to advanced liver metastatic load.

  7. Pregnancy. 8. History of significant neurological or mental disorder, including seizures or dementia.

  9. 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.

  10. Known hypersensitivity to 5-FU and or Calciumfolinate/Arfolitixorin.