PK/PD Investigation of Calciumfolinat in Blood, Tumor and Adjacent Mucosa in Patient With Colon Cancer
Primary Purpose
Colon Cancer, Chemotherapy
Status
Unknown status
Phase
Not Applicable
Locations
Sweden
Study Type
Interventional
Intervention
Leucovorin
Sponsored by
About this trial
This is an interventional basic science trial for Colon Cancer focused on measuring Leukovorin
Eligibility Criteria
Inclusion Criteria:
- Patients must have an operable colon cancer that is determined to colorectal surgery
- Patients must sign an informed consent document
- Patients must be ≥ 18 years of age
- Fertile women must present a negative pregnancy test and use secure contraceptives during and three months after treatment
Exclusion Criteria:
- Neo-adjuvant chemotherapy within the last 30 days
- 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
- Female patients: currently pregnant or breast-feeding
- Patient with epileptic medication, such as fenobarbital, primidon, fenytoin och succinimider
Sites / Locations
- Department of surgery, Östra, Sahlgrenska University Hospital
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Other
Other
Other
Arm Label
Calciumfolinat 60 mg/m²
Calciumfolinat 200 mg/m²
Calciumfolinat 500 mg/ m²
Arm Description
Intravenous infusion of Calciumfolinat 60 mg/m²given to patients with colon cancer at the time for the operation of the colon cancer.
Intravenous infusion of Calciumfolinat 200 mg/m² given to patients with colon cancer at the time for the operation of the colon cancer.
Intravenous infusion of Calciumfolinat 500 mg/ m² given to patients with colon cancer at the time for the operation of the colon cancer.
Outcomes
Primary Outcome Measures
[6R] 5,10-methylene-THF - tumor
Tissue concentration of [6R] 5,10-methylene-THF in the tumor
[6R] 5,10-methylene-THF - adjacent mucosa
Tissue concentration of [6R] 5,10-methylene-THF in adjacent mucosa
5-formyl-THF - tumor
Tissue concentration of 5-formyl-THF in the tumor
5-formyl-THFin - adjacent mucosa
Tissue concentration of 5-formyl-THFin the adjacent mucosa
5-methyl-THF - tumor
Tissue concentration of 5-methyl-THF in the tumor
5-methyl-THF - adjacent mucosa
Tissue concentration of 5-methyl-THF in the adjacent mucosa
THF - tumor
Tissue concentration of THF in the tumor
THF - adjacent mucosa
Tissue concentration of THF in the adjacent mucosa
Secondary Outcome Measures
AUC [6R] 5,10-methylene-THF
AUC(0-24h) calculated from plasma concentration of [6R] 5,10-methylene-THF
AUC 5-formyl-THF
AUC(0-24h) calculated from plasma concentration of 5-formyl-THF (if data
AUC 5-methyl-THF
AUC(0-24h) calculated from plasma concentration of 5-methyl-THF (if data permits)
AUC THF
AUC(0-24h) calculated from plasma concentration of THF (if data permits)
Correlation AUC - blood and tissue
Correlation between AUC calculated from blood concentration and tissue concentration in the tumor and adjacent mucosa
Gene expression - correlation to tissue concentration of the reduced folates
Gene expression in the tumor and correlation to tissue concentration of the reduced folates
Gene expression - correlation adjacent mucosa tissue concentration of the reduced folates
Gene expression in the adjacent mucosa and correlation to tissue concentration of the reduced folates
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02959541
Brief Title
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
2. Study Status
Record Verification Date
September 2021
Overall Recruitment Status
Unknown status
Study Start Date
September 2016 (Actual)
Primary Completion Date
May 26, 2020 (Actual)
Study Completion Date
December 31, 2022 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Vastra Gotaland Region
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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)).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Colon Cancer, Chemotherapy
Keywords
Leukovorin
7. Study Design
Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
48 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Calciumfolinat 60 mg/m²
Arm Type
Other
Arm Description
Intravenous infusion of Calciumfolinat 60 mg/m²given to patients with colon cancer at the time for the operation of the colon cancer.
Arm Title
Calciumfolinat 200 mg/m²
Arm Type
Other
Arm Description
Intravenous infusion of Calciumfolinat 200 mg/m² given to patients with colon cancer at the time for the operation of the colon cancer.
Arm Title
Calciumfolinat 500 mg/ m²
Arm Type
Other
Arm Description
Intravenous infusion of Calciumfolinat 500 mg/ m² given to patients with colon cancer at the time for the operation of the colon cancer.
Intervention Type
Drug
Intervention Name(s)
Leucovorin
Other Intervention Name(s)
Calciumfolinat is the brandname of Leucovorin
Primary Outcome Measure Information:
Title
[6R] 5,10-methylene-THF - tumor
Description
Tissue concentration of [6R] 5,10-methylene-THF in the tumor
Time Frame
First day during surgery
Title
[6R] 5,10-methylene-THF - adjacent mucosa
Description
Tissue concentration of [6R] 5,10-methylene-THF in adjacent mucosa
Time Frame
First day during surgery
Title
5-formyl-THF - tumor
Description
Tissue concentration of 5-formyl-THF in the tumor
Time Frame
First day during surgery
Title
5-formyl-THFin - adjacent mucosa
Description
Tissue concentration of 5-formyl-THFin the adjacent mucosa
Time Frame
First day during surgery
Title
5-methyl-THF - tumor
Description
Tissue concentration of 5-methyl-THF in the tumor
Time Frame
First day during surgery
Title
5-methyl-THF - adjacent mucosa
Description
Tissue concentration of 5-methyl-THF in the adjacent mucosa
Time Frame
First day during surgery
Title
THF - tumor
Description
Tissue concentration of THF in the tumor
Time Frame
First day during surgery
Title
THF - adjacent mucosa
Description
Tissue concentration of THF in the adjacent mucosa
Time Frame
First day during surgery
Secondary Outcome Measure Information:
Title
AUC [6R] 5,10-methylene-THF
Description
AUC(0-24h) calculated from plasma concentration of [6R] 5,10-methylene-THF
Time Frame
Up to 24 hours
Title
AUC 5-formyl-THF
Description
AUC(0-24h) calculated from plasma concentration of 5-formyl-THF (if data
Time Frame
Up to 24 hours
Title
AUC 5-methyl-THF
Description
AUC(0-24h) calculated from plasma concentration of 5-methyl-THF (if data permits)
Time Frame
Up to 24 hours
Title
AUC THF
Description
AUC(0-24h) calculated from plasma concentration of THF (if data permits)
Time Frame
Up to 24 hours
Title
Correlation AUC - blood and tissue
Description
Correlation between AUC calculated from blood concentration and tissue concentration in the tumor and adjacent mucosa
Time Frame
Up to 24 hours
Title
Gene expression - correlation to tissue concentration of the reduced folates
Description
Gene expression in the tumor and correlation to tissue concentration of the reduced folates
Time Frame
First day during surgery
Title
Gene expression - correlation adjacent mucosa tissue concentration of the reduced folates
Description
Gene expression in the adjacent mucosa and correlation to tissue concentration of the reduced folates
Time Frame
First day during surgery
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Patients must have an operable colon cancer that is determined to colorectal surgery
Patients must sign an informed consent document
Patients must be ≥ 18 years of age
Fertile women must present a negative pregnancy test and use secure contraceptives during and three months after treatment
Exclusion Criteria:
Neo-adjuvant chemotherapy within the last 30 days
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
Female patients: currently pregnant or breast-feeding
Patient with epileptic medication, such as fenobarbital, primidon, fenytoin och succinimider
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Elinor Bexe Lindskog, MD, PhD
Organizational Affiliation
Sahlgrenska University Hospital, Sweden
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of surgery, Östra, Sahlgrenska University Hospital
City
Gothenburg
ZIP/Postal Code
416 85
Country
Sweden
12. IPD Sharing Statement
Learn more about this trial
PK/PD Investigation of Calciumfolinat in Blood, Tumor and Adjacent Mucosa in Patient With Colon Cancer
We'll reach out to this number within 24 hrs