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

Colonic Neoplasms Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01681472
• Other study ID #: ISO-CC-002
• Secondary ID: 2012-000522-22
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: September 2012
• Est. completion date: August 2013

Study information

• Verified date: September 2020
• Source: Isofol Medical AB
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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 information / eligibility

• Status: Completed
• Enrollment: 32
• Est. completion date: August 2013
• Est. primary completion date: August 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Colonic Neoplasms
• Neoplasms

Intervention

Drug:
• 6R-MTHF (arfolitixorin) 200 mg/m2
i.v. bolus injection
• Levoleucovorin 200 mg/m2
i.v. bolus injection
• 6R-MTHF (arfolitixorin) 60 mg/m2
i.v. bolus injection
• Levoleucovorin 60 mg/m2
i.v. bolus injection

Locations

Country	Name	City	State
Sweden	Sahlgrenska University Hospital	Gothenburg

Sponsors (1)

Lead Sponsor	Collaborator
Isofol Medical AB

Country where clinical trial is conducted

Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Number of AEs Per Severity	Number of reported AEs per treatment with respect to severity	Screening visit until end of study, Day 5