PK/PD Investigation of Modufolin (Arfolitixorin) in Plasma, Tumor and Adjacent Mucosa Adjacent Mucosa in Patients With Colon Cancer

Study Overview
=================
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).

Official Title
-----------------
A Single-Blind, Randomized Phase I/II Study of Pharmacokinetic and Pharmacodynamic Investigation of Modufolin® (60 or 200mg/m2) Compared to Levoleucovorin (60 or 200mg/m2) in Tumor, Adjacent Mucosa and Plasma for Patients With Colon Cancer

Conditions
-----------------
Colonic Neoplasms

Intervention / Treatment
-----------------
* Drug: 6R-MTHF (arfolitixorin) 200 mg/m2
* Drug: Levoleucovorin 200 mg/m2
* Drug: 6R-MTHF (arfolitixorin) 60 mg/m2
* Drug: Levoleucovorin 60 mg/m2


Participation Criteria
=================
Eligibility Criteria
-----------------
Main Inclusion Criteria: 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 Exclusion Criteria: Any concurrent other anti-tumor therapy Any prohibited concomitant medication within 30 days of surgery Pregnancy or breast-feeding. Second primary malignancy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Levoleucovorin 200 mg/m2<br>One i.v. bolus injection of study drug after the patient has been anaesthetized. | Drug: Levoleucovorin 200 mg/m2<br>* i.v. bolus injection<br>* Other names: Isovorin®;|
| Active Comparator: Levoleucovorin 60 mg/m2<br>One i.v. bolus injection of study drug after the patient has been anaesthetized. | Drug: Levoleucovorin 60 mg/m2<br>* i.v. bolus injection<br>* Other names: Isovorin®;|
| Experimental: 6R-MTHF 200 mg/m2<br>One i.v. bolus injection of study drug after the patient has been anaesthetized. | Drug: 6R-MTHF (arfolitixorin) 200 mg/m2<br>* i.v. bolus injection<br>* Other names: arfolitixorin;|
| Experimental: 6R-MTHF 60 mg/m2<br>One i.v. bolus injection of study drug after the patient has been anaesthetized. | Drug: 6R-MTHF (arfolitixorin) 60 mg/m2<br>* i.v. bolus injection<br>* Other names: arfolitixorin;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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 Adjacent Mucosa Tissue | Comparison of concentration of the metabolite [6S]-5-methyl-THF in mucosa adjacent to the tumor after the different treatments. | 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. | 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. | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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. | 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. | 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. | 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. | 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. | 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. | 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). | 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). | 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. | 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. | 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 | Screening visit until end of study, Day 5 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Intestinal Neoplasms, Gastrointestinal Neoplasms, Digestive System Neoplasms, Gastrointestinal Diseases, Therapeutic Uses, Pharmacokinetics, Pharmacodynamics, Colon cancer, 5,10-methylenetetrahydrofolate, Rectal Neoplasms, Colorectal Neoplasms