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

• ClinicalTrials.gov Identifier: NCT01681472
• Recruitment Status: Completed
• First Posted: September 10, 2012
• Results First Posted: July 17, 2015
• Last Update Posted: September 25, 2020
• Sponsor: Isofol Medical AB
• Information provided by (Responsible Party): Isofol Medical AB

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Colonic Neoplasms	Drug: 6R-MTHF (arfolitixorin) 200 mg/m2; Drug: Levoleucovorin 200 mg/m2; Drug: 6R-MTHF (arfolitixorin) 60 mg/m2; Drug: Levoleucovorin 60 mg/m2	Phase 1; Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 32 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Investigator)
• Primary Purpose: Treatment
• 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
• Study Start Date: September 2012
• Actual Primary Completion Date: August 2013
• Actual Study Completion Date: August 2013

Arms and Interventions

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 Name: 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 Name: 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: Modufolin®; ISO-901; [6R] 5,10-methylenetetrahydrofolate; arfolitixorin
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: Modufolin®; ISO-901; [6R] 5,10-methylenetetrahydrofolate; arfolitixorin

Outcome Measures

Primary Outcome Measures :

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 Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

Sweden

Sahlgrenska University Hospital

Gothenburg, Sweden, 461 85

Sponsors and Collaborators

Isofol Medical AB

Investigators

• Principal Investigator: Kristoffer Derwinger, MD PhD; Sahlgrenska University Hospital, Sweden

More Information

• Responsible Party: Isofol Medical AB
• ClinicalTrials.gov Identifier: NCT01681472
• Other Study ID Numbers: ISO-CC-002; 2012-000522-22 ( EudraCT Number )
• First Posted: September 10, 2012
• Results First Posted: July 17, 2015
• Last Update Posted: September 25, 2020
• Last Verified: September 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Isofol Medical AB:

Colon cancer; 5,10-methylenetetrahydrofolate; Rectal Neoplasms; Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Therapeutic Uses; Pharmacokinetics; Pharmacodynamics

Additional relevant MeSH terms:

Neoplasms; Colonic Neoplasms; Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Leucovorin; Tetrahydrofolates; Levoleucovorin; Antidotes; Protective Agents; Physiological Effects of Drugs; Vitamin B Complex; Vitamins; Micronutrients