PK/PD Investigation of Modufolin (Arfolitixorin) in Plasma, Tumor and Adjacent Mucosa Adjacent Mucosa in Patients With Colon Cancer
- Conditions
- Colonic Neoplasms
- Interventions
- Registration Number
- NCT01681472
- Lead Sponsor
- Isofol Medical AB
- Brief Summary
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).
- Detailed Description
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).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 32
- Operable colon cancer amenable to curative surgery.
- Performance status of 0 to 1
- Informed consent form
- Patients must be at least 18 years of age.
Main
- Any concurrent other anti-tumor therapy
- Any prohibited concomitant medication within 30 days of surgery
- Pregnancy or breast-feeding.
- Second primary malignancy
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Levoleucovorin 200 mg/m2 Levoleucovorin 200 mg/m2 One i.v. bolus injection of study drug after the patient has been anaesthetized. Levoleucovorin 60 mg/m2 Levoleucovorin 60 mg/m2 One i.v. bolus injection of study drug after the patient has been anaesthetized. 6R-MTHF 60 mg/m2 6R-MTHF (arfolitixorin) 60 mg/m2 One i.v. bolus injection of study drug after the patient has been anaesthetized. 6R-MTHF 200 mg/m2 6R-MTHF (arfolitixorin) 200 mg/m2 One i.v. bolus injection of study drug after the patient has been anaesthetized.
- Primary Outcome Measures
Name Time Method Concentration of [6R]-5,10-methylene-THF in Tumor Tissue 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 Comparison of concentration of the active substance in Modufolin: \[6R\]-5,10-methylene-THF in tumor tissue after the different treatments.
Concentration of [6S]-5-THF in Adjacent Mucosa Tissue 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 Comparison of concentration of the metabolite \[6S\]-5-THF in mucosa adjacent to the tumor after the different treatments.
Concentration of [6S]-5-formyl-THF in Adjacent Mucosa Tissue 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 Comparison of concentration of the metabolite \[6S\]-5-formyl-THF in mucosa adjacent to the tumor after the different treatments.
Concentration of [6R]-5,10-methylene-THF in Adjacent Mucosa Tissue 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 Comparison of concentration of the active substance in Modufolin: \[6R\]-5,10-methylene-THF in mucosa adjacent to the tumor after the different treatments.
Concentration of [6S]-5-methyl-THF in Tumor Tissue 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 Comparison of concentration of the metabolite \[6S\]-5-methyl-THF in tumor after the different treatments.
Concentration of [6S]-5-formyl-THF in Tumor Tissue 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 Comparison of concentration of the metabolite \[6S\]-5-formyl-THF in tumor after the different treatments.
Concentration of [6S]-5-THF in Tumor Tissue 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 Comparison of concentration of the metabolite \[6S\]-5-THF in tumor after the different treatments.
Concentration of [6S]-5-methyl-THF in Adjacent Mucosa Tissue 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 Comparison of concentration of the metabolite \[6S\]-5-methyl-THF in mucosa adjacent to the tumor after the different treatments.
- Secondary Outcome Measures
Name Time Method Tmax of [6S]-5-methyl-THF Samples taken Day 1 (Day of surgery) and Day 2 Timepoint (tmax) when Cmax in plasma occurs for the metabolite \[6S\]-5-methyl-THF
T(1/2) of [6R]-5,10-methylene-THF Samples taken Day 1 (Day of surgery) and Day 2 Terminal plasma elimination half-life time for the active substance in Modufolin: \[6R\]-5,10-methylene-THF
T(1/2) of [6S]-5-formyl-THF Samples taken Day 1 (Day of surgery) and Day 2 Terminal plasma elimination half-life time for the metabolite \[6S\]-5-formyl-THF
Tmax of [6R]-5,10-methylene-THF Samples taken Day 1 (Day of surgery) and Day 2 Timepoint (tmax) when Cmax in plasma occurs of the active substance in Modufolin: \[6R\]-5,10-methylene-THF
Cmax of [6S]-5-THF in Plasma Samples taken Day 1 (Day of surgery) and Day 2 Maximum concentration (Cmax) in plasma of the metabolite \[6S\]-5-THF
Tmax of [6S]-5-formyl-THF Samples taken Day 1 (Day of surgery) and Day 2 Timepoint (tmax) when Cmax in plasma occurs for the metabolite \[6S\]-5-formyl-THF
Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-methyl-THF Samples taken Day 1 (Day of surgery) 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.
AUC(Last) of [6S]-5-methyl-THF Samples taken Day 1 (Day of surgery) and Day 2 Area under the plasma concentration versus time curve, from time 0 to the last time point, for the metabolite \[6S\]-5-methyl-THF
Cmax of [6R]-5,10-methylene-THF Samples taken Day 1 (Day of surgery) and Day 2 Maximum concentration (Cmax) in plasma of the active substance in Modufolin: \[6R\]-5,10-methylene-THF
Cmax of [6S]-5-methyl-THF in Plasma Samples taken Day 1 (Day of surgery) and Day 2 Maximum concentration (Cmax) in plasma of the metabolite \[6S\]-5-methyl-THF
AUC(Last) of [6R]-5,10-methylene-THF Samples taken Day 1 (Day of surgery) and Day 2 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
T(1/2) of [6S]-5-THF Samples taken Day 1 (Day of surgery) and Day 2 Terminal plasma elimination half-life time for the metabolite \[6S\]-5-THF
Cmax of [6S]-5-formyl-THF in Plasma Samples taken Day 1 (Day of surgery) and Day 2 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
AUC(0-2h) of [6R]-5,10-methylene-THF Samples taken Day 1 (Day of surgery) 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
AUC(0-2h) of [6S]-5-THF Samples taken Day 1 (Day of surgery) Area under the plasma concentration versus time curve from time 0 to 2 hours, for the metabolite \[6S\]-5-THF
AUC(0-2h) of [6S]-5-methyl-THF Samples taken Day 1 (Day of surgery) Area under the plasma concentration versus time curve from time 0 to 2 hours, for the metabolite: \[6S\]-5-methyl-THF
AUC(0-2h) of [6SR]-5-formyl-THF Samples taken Day 1 (Day of surgery) Area under the plasma concentration versus time curve from time 0 to 2 hours, for the metabolite \[6S\]-5-formyl-THF
AUC(Last) of [6S]-5-THF Samples taken Day 1 (Day of surgery) and Day 2 Area under the plasma concentration versus time curve, from time 0 to the last time point, for the metabolite \[6S\]-5-THF
AUC(Last) of [6S]-5-formyl-THF Samples taken Day 1 (Day of surgery) and Day 2 Area under the plasma concentration versus time curve, from time 0 to the last time point, for the metabolite \[6S\]-5-formyl-THF
Tmax of [6S]-5-THF Samples taken Day 1 (Day of surgery) and Day 2 Timepoint (tmax) when Cmax in plasma occurs for the metabolite \[6S\]-5-THF
T(Last) of [6S]-5-methyl-THF Samples taken Day 1 (Day of surgery) and Day 2 The time-point for the last measurable concentration for the metabolite \[6S\]-5-methyl-THF in plasma
T(1/2) of [6S]-5-methyl-THF Samples taken Day 1 (Day of surgery) and Day 2 Terminal plasma elimination half-life time for the metabolite \[6S\]-5-methyl-THF
Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-THF Samples taken Day 1 (Day of surgery) 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.
Correlation of Gene Expression in Tumor and Adjacent Mucosa Sample taken Day 1 (Day of Surgery) 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.
Change in Homocystein Concentration From Screening Samples taken at Screening visit, Day 2 and End of Study (Day 5) 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.Number of AEs Per Severity Screening visit until end of study, Day 5 Number of reported AEs per treatment with respect to severity
Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6R]-5,10-methylene-THF Samples taken Day 1 (Day of surgery) 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.
Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-formyl-THF Samples taken Day 1 (Day of surgery) 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.
Gene Expression Ratios (Mucosa:Tumor) Sample taken Day 1 (Day of Surgery) 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.
T(Last) of [6R]-5,10-methylene-THF Samples taken Day 1 (Day of surgery) and Day 2 The time-point for the last measurable concentration of the active substance in Modufolin: \[6R\]-5,10-methylene-THF
T(Last) of [6S]-5-THF Samples taken Day 1 (Day of surgery) and Day 2 The time-point for the last measurable concentration for the metabolite \[6S\]-5-TH in plasma
T(Last) of [6S]-5-formyl-THF Samples taken Day 1 (Day of surgery) and Day 2 The time-point for the last measurable concentration for the metabolite \[6S\]-5-formyl-THF in plasma
Homocystein Concentration Samples taken at Screening visit, Day 2, and End of Study (Day 5) Blood samples for folate biomarker (homocystein) analysis were collected at Screening, Day 2, and Day 5 (End of study visit).
Change in S-Folate Concentration From Screening Samples taken at Screening visit, Day 2 and End of Study (Day 5) 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.
S-Folate Concentration Samples taken at Screening visit, Day 2 and End of Study (Day 5) Blood samples for folate biomarker (S-folate) analysis were collected at Screening, Day 2 and Day 5 (End of study visit).
Trial Locations
- Locations (1)
Sahlgrenska University Hospital
🇸🇪Gothenburg, Sweden