The purpose of this study is to compare the concentration of four different metabolites in the tumor, in adjacent mucosa and in plasma in patients with colon cancer receiving two different doses of Modufolin (arfolitixorin) and Levoleucovorin (Isovorin®), respectively (60 and 200 mg/m2).
The purpose of this study is to compare the concentration of \[6R\] 5,10-methylene-THF, 5-formyl-THF, 5-methyl-THF and THF in the tumor, in adjacent mucosa and in plasma in patients with colon cancer receiving two different does of Modufolin® and Levoleucovorin (Isovorin®), respectively (60 and 200 mg/m2).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
32
i.v. bolus injection
i.v. bolus injection
i.v. bolus injection
Sahlgrenska University Hospital
Gothenburg, Sweden
Concentration of [6R]-5,10-methylene-THF in Tumor Tissue
Comparison of concentration of the active substance in Modufolin: \[6R\]-5,10-methylene-THF in tumor tissue after the different treatments.
Time frame: Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration
Concentration of [6R]-5,10-methylene-THF in Adjacent Mucosa Tissue
Comparison of concentration of the active substance in Modufolin: \[6R\]-5,10-methylene-THF in mucosa adjacent to the tumor after the different treatments.
Time frame: Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration
Concentration of [6S]-5-THF in Tumor Tissue
Comparison of concentration of the metabolite \[6S\]-5-THF in tumor after the different treatments.
Time frame: Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration
Concentration of [6S]-5-THF in Adjacent Mucosa Tissue
Comparison of concentration of the metabolite \[6S\]-5-THF in mucosa adjacent to the tumor after the different treatments.
Time frame: Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration
Concentration of [6S]-5-methyl-THF in Tumor Tissue
Comparison of concentration of the metabolite \[6S\]-5-methyl-THF in tumor after the different treatments.
Time frame: Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration
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i.v. bolus injection
Concentration of [6S]-5-methyl-THF in Adjacent Mucosa Tissue
Comparison of concentration of the metabolite \[6S\]-5-methyl-THF in mucosa adjacent to the tumor after the different treatments.
Time frame: Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration
Concentration of [6S]-5-formyl-THF in Tumor Tissue
Comparison of concentration of the metabolite \[6S\]-5-formyl-THF in tumor after the different treatments.
Time frame: Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration
Concentration of [6S]-5-formyl-THF in Adjacent Mucosa Tissue
Comparison of concentration of the metabolite \[6S\]-5-formyl-THF in mucosa adjacent to the tumor after the different treatments.
Time frame: Sample taken Day 1 (Day of surgery) at 0 min (before anesthetics) and 5, 10, 20, 40, 60, 90, 120, 180, 240, 360 min after study drug administration, and 24 h after study drug administration
AUC(0-2h) of [6R]-5,10-methylene-THF
Area under the plasma concentration versus time curve from time 0 to 2 hours, for the active substance in Modufolin: \[6R\]-5,10-methylene-THF
Time frame: Samples taken Day 1 (Day of surgery)
AUC(0-2h) of [6S]-5-THF
Area under the plasma concentration versus time curve from time 0 to 2 hours, for the metabolite \[6S\]-5-THF
Time frame: Samples taken Day 1 (Day of surgery)
AUC(0-2h) of [6S]-5-methyl-THF
Area under the plasma concentration versus time curve from time 0 to 2 hours, for the metabolite: \[6S\]-5-methyl-THF
Time frame: Samples taken Day 1 (Day of surgery)
AUC(0-2h) of [6SR]-5-formyl-THF
Area under the plasma concentration versus time curve from time 0 to 2 hours, for the metabolite \[6S\]-5-formyl-THF
Time frame: Samples taken Day 1 (Day of surgery)
AUC(Last) of [6R]-5,10-methylene-THF
Area under the plasma concentration versus time curve, from time 0 to the last time point, for the active substance in Modufolin: \[6R\]-5,10-methylene-THF
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
AUC(Last) of [6S]-5-THF
Area under the plasma concentration versus time curve, from time 0 to the last time point, for the metabolite \[6S\]-5-THF
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
AUC(Last) of [6S]-5-methyl-THF
Area under the plasma concentration versus time curve, from time 0 to the last time point, for the metabolite \[6S\]-5-methyl-THF
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
AUC(Last) of [6S]-5-formyl-THF
Area under the plasma concentration versus time curve, from time 0 to the last time point, for the metabolite \[6S\]-5-formyl-THF
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
Cmax of [6R]-5,10-methylene-THF
Maximum concentration (Cmax) in plasma of the active substance in Modufolin: \[6R\]-5,10-methylene-THF
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
Cmax of [6S]-5-THF in Plasma
Maximum concentration (Cmax) in plasma of the metabolite \[6S\]-5-THF
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
Cmax of [6S]-5-methyl-THF in Plasma
Maximum concentration (Cmax) in plasma of the metabolite \[6S\]-5-methyl-THF
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
Cmax of [6S]-5-formyl-THF in Plasma
Maximum concentration (Cmax) in plasma of the active substance in Modufolin: \[6R\] 5,10- methylene-THF and the metabolites: \[6S\]-5-THF, \[6S\]-5-methyl-THF, and \[6S\]-5-formyl-THF
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
Tmax of [6R]-5,10-methylene-THF
Timepoint (tmax) when Cmax in plasma occurs of the active substance in Modufolin: \[6R\]-5,10-methylene-THF
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
Tmax of [6S]-5-THF
Timepoint (tmax) when Cmax in plasma occurs for the metabolite \[6S\]-5-THF
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
Tmax of [6S]-5-methyl-THF
Timepoint (tmax) when Cmax in plasma occurs for the metabolite \[6S\]-5-methyl-THF
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
Tmax of [6S]-5-formyl-THF
Timepoint (tmax) when Cmax in plasma occurs for the metabolite \[6S\]-5-formyl-THF
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
T(1/2) of [6R]-5,10-methylene-THF
Terminal plasma elimination half-life time for the active substance in Modufolin: \[6R\]-5,10-methylene-THF
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
T(1/2) of [6S]-5-THF
Terminal plasma elimination half-life time for the metabolite \[6S\]-5-THF
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
T(1/2) of [6S]-5-methyl-THF
Terminal plasma elimination half-life time for the metabolite \[6S\]-5-methyl-THF
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
T(1/2) of [6S]-5-formyl-THF
Terminal plasma elimination half-life time for the metabolite \[6S\]-5-formyl-THF
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
T(Last) of [6R]-5,10-methylene-THF
The time-point for the last measurable concentration of the active substance in Modufolin: \[6R\]-5,10-methylene-THF
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
T(Last) of [6S]-5-THF
The time-point for the last measurable concentration for the metabolite \[6S\]-5-TH in plasma
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
T(Last) of [6S]-5-methyl-THF
The time-point for the last measurable concentration for the metabolite \[6S\]-5-methyl-THF in plasma
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
T(Last) of [6S]-5-formyl-THF
The time-point for the last measurable concentration for the metabolite \[6S\]-5-formyl-THF in plasma
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6R]-5,10-methylene-THF
Correlation between the exposure of \[6R\]-5,10-methylene-THF following 2 hours after dosing (AUC\[0-2h\]) and the concentration of \[6R\]-5,10-methylene-THF in the tumor or adjacent mucosa at surgery.
Time frame: Samples taken Day 1 (Day of surgery)
Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-THF
Correlation between the exposure of \[6S\]-5-THF following 2 hours after dosing (AUC\[0-2h\]) and the concentration of \[6S\]-5-THF in the tumor or adjacent mucosa at surgery.
Time frame: Samples taken Day 1 (Day of surgery)
Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-methyl-THF
Correlation between the exposure of \[6S\]-5-methyl-THF following 2 hours after dosing (AUC\[0-2h\]) and the concentration of \[6S\]-5-methyl-THF in the tumor or adjacent mucosa at surgery.
Time frame: Samples taken Day 1 (Day of surgery)
Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-formyl-THF
Correlation between the exposure of \[6S\]-5-formyl-THF following 2 hours after dosing (AUC\[0-2h\]) and the concentration of \[6S\]-5-formyl-THF in the tumor or adjacent mucosa at surgery.
Time frame: Samples taken Day 1 (Day of surgery)
Gene Expression Ratios (Mucosa:Tumor)
Concentration of different genes involved in folate transport and metabolism were analysed in both tumor and adjacent mucosa. The concentration in mucosa was divided by the concentration in tumor. A value above 1 indicate that the gene expression was higher in mucosa than in tumor and a value below 1 that the gene expression was higher in tumor than in mucosa.
Time frame: Sample taken Day 1 (Day of Surgery)
Correlation of Gene Expression in Tumor and Adjacent Mucosa
Concentration of the gene expression was analysed in both tumor and adjacent mucosa. The presence of any correlation between the results (i.e., concentration of the gene expression in tumor versus adjacent mucosa) was evaluated for each treatment. No evaluation was done between treatments.
Time frame: Sample taken Day 1 (Day of Surgery)
Homocystein Concentration
Blood samples for folate biomarker (homocystein) analysis were collected at Screening, Day 2, and Day 5 (End of study visit).
Time frame: Samples taken at Screening visit, Day 2, and End of Study (Day 5)
S-Folate Concentration
Blood samples for folate biomarker (S-folate) analysis were collected at Screening, Day 2 and Day 5 (End of study visit).
Time frame: Samples taken at Screening visit, Day 2 and End of Study (Day 5)
Change in Homocystein Concentration From Screening
Blood samples for folate biomarker (homocystein) analysis were collected at Screening, Day 2 and Day 5 (End of study visit). Changes from screening to later visits were counted. The criteria for assessment categories "normal", "low" and "high" were based on the reference ranges for plasma-Homocystein as follows: "low" \<4,7 mcmol/L; "normal" =\> 4,7 and \<=16 mcmol/L; "high" \>16 mcmol/L. Values were applicable for both male and female adults.
Time frame: Samples taken at Screening visit, Day 2 and End of Study (Day 5)
Change in S-Folate Concentration From Screening
Blood samples for folate biomarker (S-folate) analysis were collected at Screening, Day 2 and Day 5 (End of study visit). Changes from screening to later visits were counted.
Time frame: Samples taken at Screening visit, Day 2 and End of Study (Day 5)
Number of AEs Per Severity
Number of reported AEs per treatment with respect to severity
Time frame: Screening visit until end of study, Day 5