PK/PD Investigation of Calciumfolinat in Blood, Tumor and Adjacent Mucosa in Patient With Colon Cancer

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

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

Study Overview

• Status: Active, not recruiting
• Conditions: Chemotherapy; Colon Cancer
• Intervention / Treatment: Drug: Leucovorin

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)).

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Sweden
  • Gothenburg, Sweden, 416 85
    • Department of surgery, Östra, Sahlgrenska University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Calciumfolinat 60 mg/m²; Intravenous infusion of Calciumfolinat 60 mg/m²given to patients with colon cancer at the time for the operation of the colon cancer.	Drug: Leucovorin; Other Names: Calciumfolinat is the brandname of Leucovorin
Other: Calciumfolinat 200 mg/m²; Intravenous infusion of Calciumfolinat 200 mg/m² given to patients with colon cancer at the time for the operation of the colon cancer.	Drug: Leucovorin; Other Names: Calciumfolinat is the brandname of Leucovorin
Other: Calciumfolinat 500 mg/ m²; Intravenous infusion of Calciumfolinat 500 mg/ m² given to patients with colon cancer at the time for the operation of the colon cancer.	Drug: Leucovorin; Other Names: Calciumfolinat is the brandname of Leucovorin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
[6R] 5,10-methylene-THF - tumor	Tissue concentration of [6R] 5,10-methylene-THF in the tumor	First day during surgery
[6R] 5,10-methylene-THF - adjacent mucosa	Tissue concentration of [6R] 5,10-methylene-THF in adjacent mucosa	First day during surgery
5-formyl-THF - tumor	Tissue concentration of 5-formyl-THF in the tumor	First day during surgery
5-formyl-THFin - adjacent mucosa	Tissue concentration of 5-formyl-THFin the adjacent mucosa	First day during surgery
5-methyl-THF - tumor	Tissue concentration of 5-methyl-THF in the tumor	First day during surgery
5-methyl-THF - adjacent mucosa	Tissue concentration of 5-methyl-THF in the adjacent mucosa	First day during surgery
THF - tumor	Tissue concentration of THF in the tumor	First day during surgery
THF - adjacent mucosa	Tissue concentration of THF in the adjacent mucosa	First day during surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC [6R] 5,10-methylene-THF	AUC(0-24h) calculated from plasma concentration of [6R] 5,10-methylene-THF	Up to 24 hours
AUC 5-formyl-THF	AUC(0-24h) calculated from plasma concentration of 5-formyl-THF (if data	Up to 24 hours
AUC 5-methyl-THF	AUC(0-24h) calculated from plasma concentration of 5-methyl-THF (if data permits)	Up to 24 hours
AUC THF	AUC(0-24h) calculated from plasma concentration of THF (if data permits)	Up to 24 hours
Correlation AUC - blood and tissue	Correlation between AUC calculated from blood concentration and tissue concentration in the tumor and adjacent mucosa	Up to 24 hours
Gene expression - correlation to tissue concentration of the reduced folates	Gene expression in the tumor and correlation to tissue concentration of the reduced folates	First day during surgery
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	First day during surgery

Collaborators and Investigators

• Sponsor: Vastra Gotaland Region
• Investigators: Principal Investigator: Elinor Bexe Lindskog, MD, PhD, Sahlgrenska University Hospital, Sweden

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2016
• Primary Completion (Actual): May 26, 2020
• Study Completion (Anticipated): December 31, 2022

Study Registration Dates

• First Submitted: October 20, 2016
• First Submitted That Met QC Criteria: November 8, 2016
• First Posted (Estimate): November 9, 2016

Study Record Updates

• Last Update Posted (Actual): June 13, 2022
• Last Update Submitted That Met QC Criteria: June 8, 2022
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Leukovorin
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Colorectal Neoplasms; Colonic Neoplasms; Physiological Effects of Drugs; Protective Agents; Micronutrients; Vitamins; Antidotes; Vitamin B Complex; Leucovorin; Levoleucovorin
• Other Study ID Numbers: 00068128