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

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

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).

Study Overview

• Status: Completed
• Conditions: Colonic Neoplasms
• Intervention / Treatment: Drug: Levoleucovorin 200 mg/m2; Drug: Levoleucovorin 60 mg/m2; Drug: 6R-MTHF (arfolitixorin) 200 mg/m2; Drug: 6R-MTHF (arfolitixorin) 60 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).

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Sweden
  • Gothenburg, Sweden, 461 85
    • 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

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Levoleucovorin 200 mg/m2; One i.v. bolus injection of study drug after the patient has been anaesthetized.	Drug: Levoleucovorin 200 mg/m2; i.v. bolus injection; Other Names: Isovorin®
Active Comparator: Levoleucovorin 60 mg/m2; One i.v. bolus injection of study drug after the patient has been anaesthetized.	Drug: Levoleucovorin 60 mg/m2; i.v. bolus injection; Other Names: Isovorin®
Experimental: 6R-MTHF 200 mg/m2; One i.v. bolus injection of study drug after the patient has been anaesthetized.	Drug: 6R-MTHF (arfolitixorin) 200 mg/m2; i.v. bolus injection; Other Names: ISO-901; arfolitixorin; [6R] 5,10-methylenetetrahydrofolate; Modufolin®
Experimental: 6R-MTHF 60 mg/m2; One i.v. bolus injection of study drug after the patient has been anaesthetized.	Drug: 6R-MTHF (arfolitixorin) 60 mg/m2; i.v. bolus injection; Other Names: ISO-901; arfolitixorin; [6R] 5,10-methylenetetrahydrofolate; Modufolin®

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

Collaborators and Investigators

• Sponsor: Isofol Medical AB
• Investigators: Principal Investigator: Kristoffer Derwinger, MD PhD, Sahlgrenska University Hospital, Sweden

Study record dates

Study Major Dates

• Study Start: September 1, 2012
• Primary Completion (Actual): August 1, 2013
• Study Completion (Actual): August 1, 2013

Study Registration Dates

• First Submitted: September 5, 2012
• First Submitted That Met QC Criteria: September 7, 2012
• First Posted (Estimate): September 10, 2012

Study Record Updates

• Last Update Posted (Actual): September 25, 2020
• Last Update Submitted That Met QC Criteria: September 7, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Gastrointestinal Diseases; Pharmacodynamics; Colorectal Neoplasms; Colon cancer; Therapeutic Uses; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Rectal Neoplasms; 5,10-methylenetetrahydrofolate
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Colorectal Neoplasms; Neoplasms; Colonic Neoplasms; Physiological Effects of Drugs; Protective Agents; Micronutrients; Vitamins; Antidotes; Vitamin B Complex; Leucovorin; Levoleucovorin; Tetrahydrofolates
• Other Study ID Numbers: ISO-CC-002; 2012-000522-22 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No