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Completed

NCT Number: NCT01681472

PK/PD Investigation of Modufolin (Arfolitixorin) in Plasma, Tumor and Adjacent Mucosa Adjacent Mucosa in 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).

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Key information

Conditions

Colonic Neoplasms Colonic Diseases Colorectal Neoplasms Digestive System Diseases Digestive System Neoplasms Gastrointestinal Diseases Gastrointestinal Neoplasms Intestinal Diseases Intestinal Neoplasms Neoplasms Neoplasms by Site Rectal Diseases Rectal Neoplasms

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

Sahlgrenska University Hospital

Gothenburg, 461 85, Sweden

About this study

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).

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

6R-MTHF (arfolitixorin) 200 mg/m2

Drug

i.v. bolus injection

Other names: Modufolin®, ISO-901, [6R] 5,10-methylenetetrahydrofolate, arfolitixorin

Levoleucovorin 200 mg/m2

Drug

i.v. bolus injection

Other names: Isovorin®

6R-MTHF (arfolitixorin) 60 mg/m2

Drug

i.v. bolus injection

Other names: Modufolin®, ISO-901, [6R] 5,10-methylenetetrahydrofolate, arfolitixorin

Levoleucovorin 60 mg/m2

Drug

i.v. bolus injection

Other names: Isovorin®

Primary outcomes

  1. Concentration of [6R]-5,10-methylene-THF in Tumor Tissue

    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

    Comparison of concentration of the active substance in Modufolin: [6R]-5,10-methylene-THF in tumor tissue after the different treatments.

  2. Concentration of [6R]-5,10-methylene-THF in Adjacent Mucosa Tissue

    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

    Comparison of concentration of the active substance in Modufolin: [6R]-5,10-methylene-THF in mucosa adjacent to the tumor after the different treatments.

  3. Concentration of [6S]-5-THF in Tumor Tissue

    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

    Comparison of concentration of the metabolite [6S]-5-THF in tumor after the different treatments.

  4. Concentration of [6S]-5-THF in Adjacent Mucosa Tissue

    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

    Comparison of concentration of the metabolite [6S]-5-THF in mucosa adjacent to the tumor after the different treatments.

  5. Concentration of [6S]-5-methyl-THF in Tumor Tissue

    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

    Comparison of concentration of the metabolite [6S]-5-methyl-THF in tumor after the different treatments.

  6. Concentration of [6S]-5-methyl-THF in Adjacent Mucosa Tissue

    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

    Comparison of concentration of the metabolite [6S]-5-methyl-THF in mucosa adjacent to the tumor after the different treatments.

  7. Concentration of [6S]-5-formyl-THF in Tumor Tissue

    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

    Comparison of concentration of the metabolite [6S]-5-formyl-THF in tumor after the different treatments.

  8. Concentration of [6S]-5-formyl-THF in Adjacent Mucosa Tissue

    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

    Comparison of concentration of the metabolite [6S]-5-formyl-THF in mucosa adjacent to the tumor after the different treatments.

Secondary outcomes

  1. AUC(0-2h) of [6R]-5,10-methylene-THF

    Time frame: 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

  2. AUC(0-2h) of [6S]-5-THF

    Time frame: 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

  3. AUC(0-2h) of [6S]-5-methyl-THF

    Time frame: 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

  4. AUC(0-2h) of [6SR]-5-formyl-THF

    Time frame: 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

  5. AUC(Last) of [6R]-5,10-methylene-THF

    Time frame: 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

  6. AUC(Last) of [6S]-5-THF

    Time frame: 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

  7. AUC(Last) of [6S]-5-methyl-THF

    Time frame: 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

  8. AUC(Last) of [6S]-5-formyl-THF

    Time frame: 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

  9. Cmax of [6R]-5,10-methylene-THF

    Time frame: 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

  10. Cmax of [6S]-5-THF in Plasma

    Time frame: Samples taken Day 1 (Day of surgery) and Day 2

    Maximum concentration (Cmax) in plasma of the metabolite [6S]-5-THF

  11. Cmax of [6S]-5-methyl-THF in Plasma

    Time frame: Samples taken Day 1 (Day of surgery) and Day 2

    Maximum concentration (Cmax) in plasma of the metabolite [6S]-5-methyl-THF

  12. Cmax of [6S]-5-formyl-THF in Plasma

    Time frame: 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

  13. Tmax of [6R]-5,10-methylene-THF

    Time frame: 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

  14. Tmax of [6S]-5-THF

    Time frame: Samples taken Day 1 (Day of surgery) and Day 2

    Timepoint (tmax) when Cmax in plasma occurs for the metabolite [6S]-5-THF

  15. Tmax of [6S]-5-methyl-THF

    Time frame: Samples taken Day 1 (Day of surgery) and Day 2

    Timepoint (tmax) when Cmax in plasma occurs for the metabolite [6S]-5-methyl-THF

  16. Tmax of [6S]-5-formyl-THF

    Time frame: Samples taken Day 1 (Day of surgery) and Day 2

    Timepoint (tmax) when Cmax in plasma occurs for the metabolite [6S]-5-formyl-THF

  17. T(1/2) of [6R]-5,10-methylene-THF

    Time frame: 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

  18. T(1/2) of [6S]-5-THF

    Time frame: Samples taken Day 1 (Day of surgery) and Day 2

    Terminal plasma elimination half-life time for the metabolite [6S]-5-THF

  19. T(1/2) of [6S]-5-methyl-THF

    Time frame: Samples taken Day 1 (Day of surgery) and Day 2

    Terminal plasma elimination half-life time for the metabolite [6S]-5-methyl-THF

  20. T(1/2) of [6S]-5-formyl-THF

    Time frame: Samples taken Day 1 (Day of surgery) and Day 2

    Terminal plasma elimination half-life time for the metabolite [6S]-5-formyl-THF

  21. T(Last) of [6R]-5,10-methylene-THF

    Time frame: 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

  22. T(Last) of [6S]-5-THF

    Time frame: 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

  23. T(Last) of [6S]-5-methyl-THF

    Time frame: 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

  24. T(Last) of [6S]-5-formyl-THF

    Time frame: 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

  25. Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6R]-5,10-methylene-THF

    Time frame: 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.

  26. Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-THF

    Time frame: 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.

  27. Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-methyl-THF

    Time frame: 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.

  28. Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-formyl-THF

    Time frame: 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.

  29. Gene Expression Ratios (Mucosa:Tumor)

    Time frame: 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.

  30. Correlation of Gene Expression in Tumor and Adjacent Mucosa

    Time frame: 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.

  31. Homocystein Concentration

    Time frame: 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).

  32. S-Folate Concentration

    Time frame: 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).

  33. Change in Homocystein Concentration From Screening

    Time frame: 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.

  34. Change in S-Folate Concentration From Screening

    Time frame: 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.

  35. Number of AEs Per Severity

    Time frame: Screening visit until end of study, Day 5

    Number of reported AEs per treatment with respect to severity

Sponsors and collaborators

Lead sponsor

Isofol Medical AB

Industry

Registry information

Official study 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

Important dates

Study start
2012
Primary completion
2013
Study completion
2013
First posted
Sep 10, 2012
Registry last updated
Sep 25, 2020

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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