Clinical trial NCT02959541: PK/PD Investigation of Calciumfolinat in Blood, Tumor and Adjacent Mucosa in Patient With Colon Cancer
Official title: An Open Randomized Single Site Pharmacokinetic and Pharmacodynamic Study, of Calciumfolinat 60 mg/m², 200 mg/m² or 500 mg/ m² in Blood, Tumor and Adjacent Mucosa From Patients With Colon Cancer
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Colon Cancer
Chemotherapy
Keywords: Leukovorin
Lead sponsor: Vastra Gotaland Region
Sponsor class: OTHER_GOV
First posted: 2016-11-09
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: This is an open randomized single site Pharmacokinetic and Pharmacodynamic study,of Calciumfolinat 60 mg/m², 200 mg/m² or 500 mg/ m² in blood, tumor and adjacent mucosa from patients with colon cancer

Detailed description: Cytotoxic treatment of patients with colorectal cancer (CRC) includes most various different drugs but 5-fluorouracil (5-FU) is the cornerstone in most regimens. Leucovorin (LV) is frequently used as a part of a standard treatment regime for advanced CRC in combination with 5-FU. In numerous randomized clinical trials the addition of LV to 5-FU has been shown to significantly improve the antitumor activity and to prolong the survival of patients receiving adjuvant chemotherapy or treatment for advanced disease as to compared to treatment with 5-FU as single drug therapy.

In most European countries 5-FU is given as an infusion during 46 hours in combination with a two hour infusion of LV. This regime is called the deGramont schedule. In the Nordic countries, 5-FU and LV are often given as bolus injections according to the regime called Nordic FLV. Leucovorin is a prodrug which has to be metabolized to methylenetetrahydrofolate (mTHF) in order to increase inhibition of the target enzyme thymidylate synthase (TS). Due to the low concentrations of the reduced folate forms intracellular there is a lack of knowledge of the pharmacodynamics of LV when used as an infusion. When the 5-FU/LV used today was introduced it was technically not possible to measure the different metabolites of the reduced folates in blood and tissue. In the literature there is only one published reference measuring the blood concentration after a two hour infusion of LV. However, it has recently been possible to separate and quantitate the different folates using sensitive Liquid Chromatography/Masspectrometry (LC/MS) methods. Furthermore it has been stated that differences in enzyme activity for genes involved in the transport and metabolism of folates may be responsible for the large inter individual differences in folate tissue concentrations.

This study is designed to gain an understanding of how a single intravenous infusion of LV affects the folate concentration in blood, tumor and adjacent mucosa tissue. By using the LC/MS method which was recently developed and it is now possible to quantitate the different metabolites of LV in small tissue samples as well as in blood. It is further now possible to measure by quantitative Polymerase Chain Reaction techniques (PCR) the most important genes involved in the folate transport and metabolism ((SHMT1), SerineHydroxyMethylTransferase1 and (ABCC3) ATP-binding cassette, sub-family C, (CFTR/MRP), member 3)).

Eligibility criteria: Inclusion Criteria:

1. Patients must have an operable colon cancer that is determined to colorectal surgery
2. Patients must sign an informed consent document
3. Patients must be ≥ 18 years of age
4. Fertile women must present a negative pregnancy test and use secure contraceptives during and three months after treatment

Exclusion Criteria:

1. Neo-adjuvant chemotherapy within the last 30 days
2. 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
3. Female patients: currently pregnant or breast-feeding
4. Patient with epileptic medication, such as fenobarbital, primidon, fenytoin och succinimider

Primary outcomes:
measure: [6R] 5,10-methylene-THF - tumor
timeFrame: First day during surgery
measure: [6R] 5,10-methylene-THF - adjacent mucosa
timeFrame: First day during surgery
measure: 5-formyl-THF - tumor
timeFrame: First day during surgery
measure: 5-formyl-THFin - adjacent mucosa
timeFrame: First day during surgery
measure: 5-methyl-THF - tumor
timeFrame: First day during surgery
measure: 5-methyl-THF - adjacent mucosa
timeFrame: First day during surgery
measure: THF - tumor
timeFrame: First day during surgery
measure: THF - adjacent mucosa
timeFrame: First day during surgery
Secondary outcomes:
measure: AUC [6R] 5,10-methylene-THF
timeFrame: Up to 24 hours
measure: AUC 5-formyl-THF
timeFrame: Up to 24 hours
measure: AUC 5-methyl-THF
timeFrame: Up to 24 hours
measure: AUC THF
timeFrame: Up to 24 hours
measure: Correlation AUC - blood and tissue
timeFrame: Up to 24 hours
measure: Gene expression - correlation to tissue concentration of the reduced folates
timeFrame: First day during surgery
measure: Gene expression - correlation adjacent mucosa tissue concentration of the reduced folates
timeFrame: First day during surgery
Other outcomes:
Locations:
city: Gothenburg
country: Sweden
facility: Department of surgery, Östra, Sahlgrenska University Hospital
Study officials:
affiliation: Sahlgrenska University Hospital
name: Elinor Bexe Lindskog, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: