Colonic Neoplasms
Conditions
Keywords
Colon cancer, 5,10-methylenetetrahydrofolate, Rectal Neoplasms, Colorectal Neoplasms, Intestinal Neoplasms, Gastrointestinal Neoplasms, Digestive System Neoplasms, Gastrointestinal Diseases, Therapeutic Uses, Pharmacokinetics, Pharmacodynamics
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).
Interventions
DRUG6R-MTHF (arfolitixorin) 200 mg/m2
i.v. bolus injection
DRUGLevoleucovorin 200 mg/m2
i.v. bolus injection
DRUG6R-MTHF (arfolitixorin) 60 mg/m2
i.v. bolus injection
DRUGLevoleucovorin 60 mg/m2
i.v. bolus injection
Sponsors
Isofol Medical AB
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Concentration of [6R]-5,10-methylene-THF in Tumor Tissue | 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. |
| Concentration of [6R]-5,10-methylene-THF in Adjacent Mucosa Tissue | 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. |
| Concentration of [6S]-5-THF in Tumor Tissue | 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. |
| Concentration of [6S]-5-THF in Adjacent Mucosa Tissue | 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. |
| Concentration of [6S]-5-methyl-THF in Tumor Tissue | 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. |
| Concentration of [6S]-5-methyl-THF in Adjacent Mucosa Tissue | 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. |
| Concentration of [6S]-5-formyl-THF in Tumor Tissue | 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. |
| Concentration of [6S]-5-formyl-THF in Adjacent Mucosa Tissue | 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
| Measure | Time frame | Description |
|---|---|---|
| Cmax of [6R]-5,10-methylene-THF | 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 |
| Cmax of [6S]-5-THF in Plasma | Samples taken Day 1 (Day of surgery) and Day 2 | Maximum concentration (Cmax) in plasma of the metabolite \[6S\]-5-THF |
| Cmax of [6S]-5-methyl-THF in Plasma | Samples taken Day 1 (Day of surgery) and Day 2 | Maximum concentration (Cmax) in plasma of the metabolite \[6S\]-5-methyl-THF |
| Cmax of [6S]-5-formyl-THF in Plasma | 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 |
| Tmax of [6R]-5,10-methylene-THF | 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 |
| Tmax of [6S]-5-THF | Samples taken Day 1 (Day of surgery) and Day 2 | Timepoint (tmax) when Cmax in plasma occurs for the metabolite \[6S\]-5-THF |
| Tmax of [6S]-5-methyl-THF | Samples taken Day 1 (Day of surgery) and Day 2 | Timepoint (tmax) when Cmax in plasma occurs for the metabolite \[6S\]-5-methyl-THF |
| Tmax of [6S]-5-formyl-THF | Samples taken Day 1 (Day of surgery) and Day 2 | Timepoint (tmax) when Cmax in plasma occurs for the metabolite \[6S\]-5-formyl-THF |
| T(1/2) of [6R]-5,10-methylene-THF | 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 |
| T(1/2) of [6S]-5-THF | Samples taken Day 1 (Day of surgery) and Day 2 | Terminal plasma elimination half-life time for the metabolite \[6S\]-5-THF |
| T(1/2) of [6S]-5-methyl-THF | Samples taken Day 1 (Day of surgery) and Day 2 | Terminal plasma elimination half-life time for the metabolite \[6S\]-5-methyl-THF |
| T(1/2) of [6S]-5-formyl-THF | Samples taken Day 1 (Day of surgery) and Day 2 | Terminal plasma elimination half-life time for the metabolite \[6S\]-5-formyl-THF |
| T(Last) of [6R]-5,10-methylene-THF | 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 |
| T(Last) of [6S]-5-THF | 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 |
| T(Last) of [6S]-5-methyl-THF | 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 |
| T(Last) of [6S]-5-formyl-THF | 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 |
| Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6R]-5,10-methylene-THF | 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. |
| Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-THF | 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. |
| AUC(0-2h) of [6R]-5,10-methylene-THF | 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 |
| Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-formyl-THF | 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. |
| Gene Expression Ratios (Mucosa:Tumor) | 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. |
| Correlation of Gene Expression in Tumor and Adjacent Mucosa | 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. |
| Homocystein Concentration | 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). |
| S-Folate Concentration | 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). |
| Change in Homocystein Concentration From Screening | 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. |
| Change in S-Folate Concentration From Screening | 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. |
| Number of AEs Per Severity | Screening visit until end of study, Day 5 | Number of reported AEs per treatment with respect to severity |
| Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-methyl-THF | 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. |
| AUC(0-2h) of [6S]-5-THF | 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 |
| AUC(0-2h) of [6S]-5-methyl-THF | 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 |
| AUC(0-2h) of [6SR]-5-formyl-THF | 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 |
| AUC(Last) of [6R]-5,10-methylene-THF | 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 |
| AUC(Last) of [6S]-5-THF | 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 |
| AUC(Last) of [6S]-5-methyl-THF | 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 |
| AUC(Last) of [6S]-5-formyl-THF | 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 |
Countries
Sweden
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Levoleucovorin 200 mg/m2 Levoleucovorin: i.v. bolus injection | 8 |
| Levoleucovorin 60 mg/m2 Levoleucovorin: i.v. bolus injection | 8 |
| Modufolin 200 mg/m2 \[6R\] 5,10-methylenetetrahydrofolate: i.v. bolus injection | 8 |
| Modufolin 60 mg/m2 \[6R\] 5,10-methylenetetrahydrofolate: i.v. bolus injection | 8 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Levoleucovorin 60 mg/m2 | Modufolin 200 mg/m2 | Levoleucovorin 200 mg/m2 | Modufolin 60 mg/m2 | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 6 Participants | 8 Participants | 6 Participants | 25 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 2 Participants | 0 Participants | 2 Participants | 7 Participants |
| Age, Continuous | 66.71 years STANDARD_DEVIATION 16.89 | 72 years STANDARD_DEVIATION 15 | 80.5 years STANDARD_DEVIATION 9.15 | 71.75 years STANDARD_DEVIATION 11.25 | 72.74 years STANDARD_DEVIATION 13.07 |
| Region of Enrollment Sweden | 8 Participants | 8 Participants | 8 Participants | 8 Participants | 32 Participants |
| Sex: Female, Male Female | 5 Participants | 3 Participants | 4 Participants | 4 Participants | 16 Participants |
| Sex: Female, Male Male | 3 Participants | 5 Participants | 4 Participants | 4 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 8 | 2 / 7 | 4 / 8 | 5 / 8 |
| serious Total, serious adverse events | 0 / 8 | 1 / 7 | 2 / 8 | 2 / 8 |
Outcome results
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.
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
Population: Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | Concentration of [6R]-5,10-methylene-THF in Adjacent Mucosa Tissue | 1333 pmol/g | Standard Deviation 852 |
| Levoleucovorin 60 mg/m2 | Concentration of [6R]-5,10-methylene-THF in Adjacent Mucosa Tissue | 626 pmol/g | Standard Deviation 439 |
| Modufolin 200 mg/m2 | Concentration of [6R]-5,10-methylene-THF in Adjacent Mucosa Tissue | 5099 pmol/g | Standard Deviation 3927 |
| Modufolin 60 mg/m2 | Concentration of [6R]-5,10-methylene-THF in Adjacent Mucosa Tissue | 3481 pmol/g | Standard Deviation 3926 |
Comparison: The exploratory evaluation of \[6R\]-5,10-methylene-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.148Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6R\]-5,10-methylene-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0034Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6R\]-5,10-methylene-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0177Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6R\]-5,10-methylene-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: <0.0001Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6R\]-5,10-methylene-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0019Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6R\]-5,10-methylene-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0118Wilcoxon (Mann-Whitney)
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.
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
Population: Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | Concentration of [6R]-5,10-methylene-THF in Tumor Tissue | 1871 pmol/g | Standard Deviation 1159 |
| Levoleucovorin 60 mg/m2 | Concentration of [6R]-5,10-methylene-THF in Tumor Tissue | 959 pmol/g | Standard Deviation 417 |
| Modufolin 200 mg/m2 | Concentration of [6R]-5,10-methylene-THF in Tumor Tissue | 4725 pmol/g | Standard Deviation 2210 |
| Modufolin 60 mg/m2 | Concentration of [6R]-5,10-methylene-THF in Tumor Tissue | 2393 pmol/g | Standard Deviation 1920 |
Comparison: The exploratory evaluation of \[6R\]-5,10-methylene-THF concentration in tumor tissue was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0323Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6R\]-5,10-methylene-THF concentration in tumor tissue was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.1336Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6R\]-5,10-methylene-THF concentration in tumor tissue was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.8622Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6R\]-5,10-methylene-THF concentration in tumor tissue was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0024Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6R\]-5,10-methylene-THF concentration in tumor tissue was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0074Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6R\]-5,10-methylene-THF concentration in tumor tissue was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.1752Wilcoxon (Mann-Whitney)
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.
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
Population: Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | Concentration of [6S]-5-formyl-THF in Adjacent Mucosa Tissue | 5456 pmol/g | Standard Deviation 3963 |
| Levoleucovorin 60 mg/m2 | Concentration of [6S]-5-formyl-THF in Adjacent Mucosa Tissue | 1403 pmol/g | Standard Deviation 640 |
| Modufolin 200 mg/m2 | Concentration of [6S]-5-formyl-THF in Adjacent Mucosa Tissue | 82 pmol/g | Standard Deviation 77 |
| Modufolin 60 mg/m2 | Concentration of [6S]-5-formyl-THF in Adjacent Mucosa Tissue | 42 pmol/g | Standard Deviation 18 |
Comparison: The exploratory evaluation of \[6S\]-5-formyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.024Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6S\]-5-formyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0058Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6S\]-5-formyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0015Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6S\]-5-formyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: <0.0001Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6S\]-5-formyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0014Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6S\]-5-formyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0338Wilcoxon (Mann-Whitney)
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.
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
Population: Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | Concentration of [6S]-5-formyl-THF in Tumor Tissue | 3611 pmol/g | Standard Deviation 3899 |
| Levoleucovorin 60 mg/m2 | Concentration of [6S]-5-formyl-THF in Tumor Tissue | 512 pmol/g | Standard Deviation 259 |
| Modufolin 200 mg/m2 | Concentration of [6S]-5-formyl-THF in Tumor Tissue | 100 pmol/g | Standard Deviation 47 |
| Modufolin 60 mg/m2 | Concentration of [6S]-5-formyl-THF in Tumor Tissue | 57 pmol/g | Standard Deviation 48 |
Comparison: The exploratory evaluation of \[6S\]-5-formyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0728Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6S\]-5-formyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0034Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6S\]-5-formyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0015Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6S\]-5-formyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0024Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6S\]-5-formyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0009Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6S\]-5-formyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0055Wilcoxon (Mann-Whitney)
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.
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
Population: Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | Concentration of [6S]-5-methyl-THF in Adjacent Mucosa Tissue | 3667 pmol/g | Standard Deviation 2043 |
| Levoleucovorin 60 mg/m2 | Concentration of [6S]-5-methyl-THF in Adjacent Mucosa Tissue | 1216 pmol/g | Standard Deviation 455 |
| Modufolin 200 mg/m2 | Concentration of [6S]-5-methyl-THF in Adjacent Mucosa Tissue | 2494 pmol/g | Standard Deviation 765 |
| Modufolin 60 mg/m2 | Concentration of [6S]-5-methyl-THF in Adjacent Mucosa Tissue | 2066 pmol/g | Standard Deviation 1517 |
Comparison: The exploratory evaluation of \[6S\]-5-methyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0728Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6S\]-5-methyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.2246Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6S\]-5-methyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0428Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6S\]-5-methyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0003Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6S\]-5-methyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.4309Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6S\]-5-methyl-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0055Wilcoxon (Mann-Whitney)
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.
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
Population: Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | Concentration of [6S]-5-methyl-THF in Tumor Tissue | 3574 pmol/g | Standard Deviation 2415 |
| Levoleucovorin 60 mg/m2 | Concentration of [6S]-5-methyl-THF in Tumor Tissue | 1904 pmol/g | Standard Deviation 918 |
| Modufolin 200 mg/m2 | Concentration of [6S]-5-methyl-THF in Tumor Tissue | 4396 pmol/g | Standard Deviation 1858 |
| Modufolin 60 mg/m2 | Concentration of [6S]-5-methyl-THF in Tumor Tissue | 1882 pmol/g | Standard Deviation 1204 |
Comparison: The exploratory evaluation of \[6S\]-5-methyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0092Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6S\]-5-methyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.8303Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6S\]-5-methyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.1182Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6S\]-5-methyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0081Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6S\]-5-methyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.3184Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6S\]-5-methyl-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.1752Wilcoxon (Mann-Whitney)
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.
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
Population: Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | Concentration of [6S]-5-THF in Adjacent Mucosa Tissue | 1333 pmol/g | Standard Deviation 852 |
| Levoleucovorin 60 mg/m2 | Concentration of [6S]-5-THF in Adjacent Mucosa Tissue | 626 pmol/g | Standard Deviation 439 |
| Modufolin 200 mg/m2 | Concentration of [6S]-5-THF in Adjacent Mucosa Tissue | 5099 pmol/g | Standard Deviation 3927 |
| Modufolin 60 mg/m2 | Concentration of [6S]-5-THF in Adjacent Mucosa Tissue | 3481 pmol/g | Standard Deviation 3926 |
Comparison: The exploratory evaluation of \[6S\]-5-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.2716Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6S\]-5-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0124Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6S\]-5-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0728Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6S\]-5-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: <0.0001Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6S\]-5-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0039Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6S\]-5-THF concentration in mucosa adjacent to the tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0454Wilcoxon (Mann-Whitney)
Primary
Concentration of [6S]-5-THF in Tumor Tissue
Comparison of concentration of the metabolite \[6S\]-5-THF in tumor after the different treatments.
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
Population: Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | Concentration of [6S]-5-THF in Tumor Tissue | 1329 pmol/g | Standard Deviation 720 |
| Levoleucovorin 60 mg/m2 | Concentration of [6S]-5-THF in Tumor Tissue | 933 pmol/g | Standard Deviation 598 |
| Modufolin 200 mg/m2 | Concentration of [6S]-5-THF in Tumor Tissue | 4175 pmol/g | Standard Deviation 3127 |
| Modufolin 60 mg/m2 | Concentration of [6S]-5-THF in Tumor Tissue | 2219 pmol/g | Standard Deviation 1995 |
Comparison: The exploratory evaluation of \[6S\]-5-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.1182Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6S\]-5-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0538Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6S\]-5-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.5244Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6S\]-5-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0081Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6S\]-5-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0313Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of \[6S\]-5-THF concentration in tumor was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.4777Wilcoxon (Mann-Whitney)
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
Time frame: Samples taken Day 1 (Day of surgery)
Population: Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | AUC(0-2h) of [6R]-5,10-methylene-THF | 326.40261 mcg*h/L | Standard Deviation 61.98416 |
| Levoleucovorin 60 mg/m2 | AUC(0-2h) of [6R]-5,10-methylene-THF | 239.90076 mcg*h/L | Standard Deviation 0 |
| Modufolin 200 mg/m2 | AUC(0-2h) of [6R]-5,10-methylene-THF | 7734.09113 mcg*h/L | Standard Deviation 1557.76552 |
| Modufolin 60 mg/m2 | AUC(0-2h) of [6R]-5,10-methylene-THF | 0 mcg*h/L | Standard Deviation 0 |
Comparison: The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0015Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
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
Time frame: Samples taken Day 1 (Day of surgery)
Population: Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | AUC(0-2h) of [6S]-5-methyl-THF | 2336.24432 mcg*h/L | Standard Deviation 829.18634 |
| Levoleucovorin 60 mg/m2 | AUC(0-2h) of [6S]-5-methyl-THF | 1258.60184 mcg*h/L | Standard Deviation 247.51353 |
| Modufolin 200 mg/m2 | AUC(0-2h) of [6S]-5-methyl-THF | 2277.89290 mcg*h/L | Standard Deviation 1132.95603 |
| Modufolin 60 mg/m2 | AUC(0-2h) of [6S]-5-methyl-THF | 997.74091 mcg*h/L | Standard Deviation 413.68052 |
Comparison: The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0728Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.2246Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0166Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.1752Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.9581Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0118Wilcoxon (Mann-Whitney)
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
Time frame: Samples taken Day 1 (Day of surgery)
Population: Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | AUC(0-2h) of [6S]-5-THF | 827.1083 mcg*h/L | Standard Deviation 178.23243 |
| Levoleucovorin 60 mg/m2 | AUC(0-2h) of [6S]-5-THF | 640.0489 mcg*h/L | Standard Deviation 0 |
| Modufolin 200 mg/m2 | AUC(0-2h) of [6S]-5-THF | 19408.1712 mcg*h/L | Standard Deviation 3000.64794 |
| Modufolin 60 mg/m2 | AUC(0-2h) of [6S]-5-THF | 5639.2700 mcg*h/L | Standard Deviation 885.82223 |
Comparison: The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0015Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0015Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0009Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
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
Time frame: Samples taken Day 1 (Day of surgery)
Population: Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | AUC(0-2h) of [6SR]-5-formyl-THF | 29911.9184 mcg*h/L | Standard Deviation 6924.78031 |
| Levoleucovorin 60 mg/m2 | AUC(0-2h) of [6SR]-5-formyl-THF | 7595.4599 mcg*h/L | Standard Deviation 764.2765 |
| Modufolin 200 mg/m2 | AUC(0-2h) of [6SR]-5-formyl-THF | 0 mcg*h/L | Standard Deviation 0 |
| Modufolin 60 mg/m2 | AUC(0-2h) of [6SR]-5-formyl-THF | 0 mcg*h/L | Standard Deviation 0 |
Comparison: The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(0-2h) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0024Wilcoxon (Mann-Whitney)
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
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
Population: Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | AUC(Last) of [6R]-5,10-methylene-THF | 462.10746 mcg*h/L | Standard Deviation 221.85761 |
| Levoleucovorin 60 mg/m2 | AUC(Last) of [6R]-5,10-methylene-THF | 239.90076 mcg*h/L | Standard Deviation 0 |
| Modufolin 200 mg/m2 | AUC(Last) of [6R]-5,10-methylene-THF | 7910.61038 mcg*h/L | Standard Deviation 1623.243 |
| Modufolin 60 mg/m2 | AUC(Last) of [6R]-5,10-methylene-THF | 2272.78010 mcg*h/L | Standard Deviation 448.01407 |
Comparison: The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0015Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0022Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0015Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
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
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
Population: Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | AUC(Last) of [6S]-5-formyl-THF | 43429.1885 mcg*h/L | Standard Deviation 12411.2844 |
| Levoleucovorin 60 mg/m2 | AUC(Last) of [6S]-5-formyl-THF | 9637.0308 mcg*h/L | Standard Deviation 1637.2118 |
| Modufolin 200 mg/m2 | AUC(Last) of [6S]-5-formyl-THF | 75.6174 mcg*h/L | Standard Deviation 69.2176 |
| Modufolin 60 mg/m2 | AUC(Last) of [6S]-5-formyl-THF | 50.1858 mcg*h/L | Standard Deviation 0 |
Comparison: The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0142Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0085Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0024Wilcoxon (Mann-Whitney)
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
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
Population: Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | AUC(Last) of [6S]-5-methyl-THF | 32206.2771 mcg*h/L | Standard Deviation 9121.1818 |
| Levoleucovorin 60 mg/m2 | AUC(Last) of [6S]-5-methyl-THF | 7689.0921 mcg*h/L | Standard Deviation 5164.6098 |
| Modufolin 200 mg/m2 | AUC(Last) of [6S]-5-methyl-THF | 21737.2428 mcg*h/L | Standard Deviation 21757.1545 |
| Modufolin 60 mg/m2 | AUC(Last) of [6S]-5-methyl-THF | 5495.1924 mcg*h/L | Standard Deviation 6110.0065 |
Comparison: The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.024Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.1336Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0015Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.2725Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.1893Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0024Wilcoxon (Mann-Whitney)
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
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
Population: Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | AUC(Last) of [6S]-5-THF | 2231.1443 mcg*h/L | Standard Deviation 1051.0665 |
| Levoleucovorin 60 mg/m2 | AUC(Last) of [6S]-5-THF | 640.0489 mcg*h/L | Standard Deviation 0 |
| Modufolin 200 mg/m2 | AUC(Last) of [6S]-5-THF | 28466.5389 mcg*h/L | Standard Deviation 5303.28705 |
| Modufolin 60 mg/m2 | AUC(Last) of [6S]-5-THF | 6766.9104 mcg*h/L | Standard Deviation 1484.91243 |
Comparison: The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0015Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0015Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0009Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of AUC(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
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.
Time frame: Samples taken at Screening visit, Day 2 and End of Study (Day 5)
Population: The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | Change in Homocystein Concentration From Screening | Normal at Screen and Normal at Day 2 | 5 Participants |
| Levoleucovorin 200 mg/m2 | Change in Homocystein Concentration From Screening | Shift from High at Screen and Normal at Day 5 | 2 Participants |
| Levoleucovorin 200 mg/m2 | Change in Homocystein Concentration From Screening | Shift from Normal at Screen to Low at Day 5 | 0 Participants |
| Levoleucovorin 200 mg/m2 | Change in Homocystein Concentration From Screening | Shift from Normal at Screen to Low at Day 2 | 0 Participants |
| Levoleucovorin 200 mg/m2 | Change in Homocystein Concentration From Screening | Missing data Screen to Day 5 | 0 Participants |
| Levoleucovorin 200 mg/m2 | Change in Homocystein Concentration From Screening | Shift from High at Screen to Normal at Day 2 | 2 Participants |
| Levoleucovorin 200 mg/m2 | Change in Homocystein Concentration From Screening | Normal at Screen and Normal at Day 5 | 5 Participants |
| Levoleucovorin 60 mg/m2 | Change in Homocystein Concentration From Screening | Shift from High at Screen and Normal at Day 5 | 3 Participants |
| Levoleucovorin 60 mg/m2 | Change in Homocystein Concentration From Screening | Normal at Screen and Normal at Day 5 | 5 Participants |
| Levoleucovorin 60 mg/m2 | Change in Homocystein Concentration From Screening | Shift from High at Screen to Normal at Day 2 | 3 Participants |
| Levoleucovorin 60 mg/m2 | Change in Homocystein Concentration From Screening | Shift from Normal at Screen to Low at Day 5 | 0 Participants |
| Levoleucovorin 60 mg/m2 | Change in Homocystein Concentration From Screening | Missing data Screen to Day 5 | 0 Participants |
| Levoleucovorin 60 mg/m2 | Change in Homocystein Concentration From Screening | Shift from Normal at Screen to Low at Day 2 | 1 Participants |
| Levoleucovorin 60 mg/m2 | Change in Homocystein Concentration From Screening | Normal at Screen and Normal at Day 2 | 4 Participants |
| Modufolin 200 mg/m2 | Change in Homocystein Concentration From Screening | Normal at Screen and Normal at Day 5 | 4 Participants |
| Modufolin 200 mg/m2 | Change in Homocystein Concentration From Screening | Normal at Screen and Normal at Day 2 | 4 Participants |
| Modufolin 200 mg/m2 | Change in Homocystein Concentration From Screening | Shift from Normal at Screen to Low at Day 2 | 2 Participants |
| Modufolin 200 mg/m2 | Change in Homocystein Concentration From Screening | Shift from High at Screen to Normal at Day 2 | 0 Participants |
| Modufolin 200 mg/m2 | Change in Homocystein Concentration From Screening | Shift from Normal at Screen to Low at Day 5 | 1 Participants |
| Modufolin 200 mg/m2 | Change in Homocystein Concentration From Screening | Shift from High at Screen and Normal at Day 5 | 0 Participants |
| Modufolin 200 mg/m2 | Change in Homocystein Concentration From Screening | Missing data Screen to Day 5 | 1 Participants |
| Modufolin 60 mg/m2 | Change in Homocystein Concentration From Screening | Shift from High at Screen to Normal at Day 2 | 2 Participants |
| Modufolin 60 mg/m2 | Change in Homocystein Concentration From Screening | Missing data Screen to Day 5 | 0 Participants |
| Modufolin 60 mg/m2 | Change in Homocystein Concentration From Screening | Shift from High at Screen and Normal at Day 5 | 2 Participants |
| Modufolin 60 mg/m2 | Change in Homocystein Concentration From Screening | Shift from Normal at Screen to Low at Day 2 | 2 Participants |
| Modufolin 60 mg/m2 | Change in Homocystein Concentration From Screening | Normal at Screen and Normal at Day 2 | 4 Participants |
| Modufolin 60 mg/m2 | Change in Homocystein Concentration From Screening | Shift from Normal at Screen to Low at Day 5 | 0 Participants |
| Modufolin 60 mg/m2 | Change in Homocystein Concentration From Screening | Normal at Screen and Normal at Day 5 | 6 Participants |
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.
Time frame: Samples taken at Screening visit, Day 2 and End of Study (Day 5)
Population: The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | Change in S-Folate Concentration From Screening | Shift from Normal at Screen to High at Day 5 | 4 Participants |
| Levoleucovorin 200 mg/m2 | Change in S-Folate Concentration From Screening | Missing data Screen to Day 2 | 0 Participants |
| Levoleucovorin 200 mg/m2 | Change in S-Folate Concentration From Screening | Missing data Screen to Day 5 | 0 Participants |
| Levoleucovorin 200 mg/m2 | Change in S-Folate Concentration From Screening | Normal at Screening and Normal at Day 5 | 3 Participants |
| Levoleucovorin 200 mg/m2 | Change in S-Folate Concentration From Screening | Shift from Normal at Screen to High at Day 2 | 7 Participants |
| Levoleucovorin 60 mg/m2 | Change in S-Folate Concentration From Screening | Normal at Screening and Normal at Day 5 | 1 Participants |
| Levoleucovorin 60 mg/m2 | Change in S-Folate Concentration From Screening | Shift from Normal at Screen to High at Day 5 | 6 Participants |
| Levoleucovorin 60 mg/m2 | Change in S-Folate Concentration From Screening | Missing data Screen to Day 5 | 1 Participants |
| Levoleucovorin 60 mg/m2 | Change in S-Folate Concentration From Screening | Missing data Screen to Day 2 | 0 Participants |
| Levoleucovorin 60 mg/m2 | Change in S-Folate Concentration From Screening | Shift from Normal at Screen to High at Day 2 | 8 Participants |
| Modufolin 200 mg/m2 | Change in S-Folate Concentration From Screening | Normal at Screening and Normal at Day 5 | 1 Participants |
| Modufolin 200 mg/m2 | Change in S-Folate Concentration From Screening | Shift from Normal at Screen to High at Day 2 | 5 Participants |
| Modufolin 200 mg/m2 | Change in S-Folate Concentration From Screening | Missing data Screen to Day 2 | 1 Participants |
| Modufolin 200 mg/m2 | Change in S-Folate Concentration From Screening | Shift from Normal at Screen to High at Day 5 | 4 Participants |
| Modufolin 200 mg/m2 | Change in S-Folate Concentration From Screening | Missing data Screen to Day 5 | 1 Participants |
| Modufolin 60 mg/m2 | Change in S-Folate Concentration From Screening | Shift from Normal at Screen to High at Day 5 | 8 Participants |
| Modufolin 60 mg/m2 | Change in S-Folate Concentration From Screening | Missing data Screen to Day 2 | 0 Participants |
| Modufolin 60 mg/m2 | Change in S-Folate Concentration From Screening | Shift from Normal at Screen to High at Day 2 | 8 Participants |
| Modufolin 60 mg/m2 | Change in S-Folate Concentration From Screening | Normal at Screening and Normal at Day 5 | 0 Participants |
| Modufolin 60 mg/m2 | Change in S-Folate Concentration From Screening | Missing data Screen to Day 5 | 0 Participants |
Secondary
Cmax of [6R]-5,10-methylene-THF
Maximum concentration (Cmax) in plasma of the active substance in Modufolin: \[6R\]-5,10-methylene-THF
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
Population: Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | Cmax of [6R]-5,10-methylene-THF | 195.0000 µg/L | Standard Deviation 40.76763 |
| Levoleucovorin 60 mg/m2 | Cmax of [6R]-5,10-methylene-THF | 123.0000 µg/L | Standard Deviation 0 |
| Modufolin 200 mg/m2 | Cmax of [6R]-5,10-methylene-THF | 22087.5000 µg/L | Standard Deviation 5635.45853 |
| Modufolin 60 mg/m2 | Cmax of [6R]-5,10-methylene-THF | 6452.8571 µg/L | Standard Deviation 559.18477 |
Comparison: The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0014Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0021Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0014Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
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
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
Population: Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | Cmax of [6S]-5-formyl-THF in Plasma | 32962.5000 µg/L | Standard Deviation 8594.17369 |
| Levoleucovorin 60 mg/m2 | Cmax of [6S]-5-formyl-THF in Plasma | 10168.3333 µg/L | Standard Deviation 2271.47896 |
| Modufolin 200 mg/m2 | Cmax of [6S]-5-formyl-THF in Plasma | 252.7500 µg/L | Standard Deviation 141.51178 |
| Modufolin 60 mg/m2 | Cmax of [6S]-5-formyl-THF in Plasma | 261.0000 µg/L | Standard Deviation 0 |
Comparison: The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0142Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0085Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0024Wilcoxon (Mann-Whitney)
Secondary
Cmax of [6S]-5-methyl-THF in Plasma
Maximum concentration (Cmax) in plasma of the metabolite \[6S\]-5-methyl-THF
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
Population: Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | Cmax of [6S]-5-methyl-THF in Plasma | 2786.25000 µg/L | Standard Deviation 822.6253 |
| Levoleucovorin 60 mg/m2 | Cmax of [6S]-5-methyl-THF in Plasma | 1078.00000 µg/L | Standard Deviation 275.26206 |
| Modufolin 200 mg/m2 | Cmax of [6S]-5-methyl-THF in Plasma | 2020.50000 µg/L | Standard Deviation 1142.25116 |
| Modufolin 60 mg/m2 | Cmax of [6S]-5-methyl-THF in Plasma | 800.42857 µg/L | Standard Deviation 396.41849 |
Comparison: The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.024Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.1336Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0015Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.1551Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.1563Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0024Wilcoxon (Mann-Whitney)
Secondary
Cmax of [6S]-5-THF in Plasma
Maximum concentration (Cmax) in plasma of the metabolite \[6S\]-5-THF
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
Population: Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | Cmax of [6S]-5-THF in Plasma | 577.6250 µg/L | Standard Deviation 190.74436 |
| Levoleucovorin 60 mg/m2 | Cmax of [6S]-5-THF in Plasma | 335.0000 µg/L | Standard Deviation 0 |
| Modufolin 200 mg/m2 | Cmax of [6S]-5-THF in Plasma | 13372.5000 µg/L | Standard Deviation 2108.15932 |
| Modufolin 60 mg/m2 | Cmax of [6S]-5-THF in Plasma | 5015.7143 µg/L | Standard Deviation 427.35064 |
Comparison: The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0015Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0015Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0009Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of Cmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
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.
Time frame: Samples taken Day 1 (Day of surgery)
Population: The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6R]-5,10-methylene-THF | AUC(0-2h) vs. conc in tumor | 0.54039 correlation coefficient |
| Levoleucovorin 200 mg/m2 | Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6R]-5,10-methylene-THF | AUC(0-2h) vs. conc in adjacent mucosa | 0.68223 correlation coefficient |
| Levoleucovorin 60 mg/m2 | Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6R]-5,10-methylene-THF | AUC(0-2h) vs. conc in tumor | NA correlation coefficient |
| Levoleucovorin 60 mg/m2 | Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6R]-5,10-methylene-THF | AUC(0-2h) vs. conc in adjacent mucosa | NA correlation coefficient |
| Modufolin 200 mg/m2 | Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6R]-5,10-methylene-THF | AUC(0-2h) vs. conc in tumor | -0.21666 correlation coefficient |
| Modufolin 200 mg/m2 | Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6R]-5,10-methylene-THF | AUC(0-2h) vs. conc in adjacent mucosa | 0.27618 correlation coefficient |
Comparison: AUC(0-2h) vs. concentration in tumorp-value: 0.6063Pearson Correlation
Comparison: AUC(0-2h) vs. concentration in tumorp-value: 0.2105Pearson Correlation
Comparison: AUC(0-2h) vs. concentration in adjacent mucosap-value: 0.5079Pearson Correlation
Comparison: AUC(0-2h) vs. concentration in adjacent mucosap-value: 0.0913Pearson Correlation
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.
Time frame: Samples taken Day 1 (Day of surgery)
Population: The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-formyl-THF | AUC(0-2h) vs. conc in tumor | 0.68778 correlation coefficient |
| Levoleucovorin 200 mg/m2 | Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-formyl-THF | AUC(0-2h) vs. conc in adjacent mucosa | 0.23512 correlation coefficient |
| Levoleucovorin 60 mg/m2 | Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-formyl-THF | AUC(0-2h) vs. conc in tumor | 0.11512 correlation coefficient |
| Levoleucovorin 60 mg/m2 | Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-formyl-THF | AUC(0-2h) vs. conc in adjacent mucosa | 0.02576 correlation coefficient |
Comparison: AUC(0-2h) vs. concentration in adjacent mucosap-value: 0.5751Pearson Correlation
Comparison: AUC(0-2h) vs. concentration in adjacent mucosap-value: 0.9672Pearson Correlation
Comparison: AUC(0-2h) vs. conc in tumorp-value: 0.0594Pearson Correlation
Comparison: AUC(0-2h) vs. conc in tumorp-value: 0.8281Pearson Correlation
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.
Time frame: Samples taken Day 1 (Day of surgery)
Population: The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-methyl-THF | AUC(0-2h) vs. conc in tumor | 0.73743 correlation coefficient |
| Levoleucovorin 200 mg/m2 | Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-methyl-THF | AUC(0-2h) vs. conc in adjacent mucosa | 0.76502 correlation coefficient |
| Levoleucovorin 60 mg/m2 | Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-methyl-THF | AUC(0-2h) vs. conc in adjacent mucosa | 0.34496 correlation coefficient |
| Levoleucovorin 60 mg/m2 | Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-methyl-THF | AUC(0-2h) vs. conc in tumor | 0.44757 correlation coefficient |
| Modufolin 200 mg/m2 | Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-methyl-THF | AUC(0-2h) vs. conc in tumor | 0.03292 correlation coefficient |
| Modufolin 200 mg/m2 | Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-methyl-THF | AUC(0-2h) vs. conc in adjacent mucosa | -0.66295 correlation coefficient |
| Modufolin 60 mg/m2 | Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-methyl-THF | AUC(0-2h) vs. conc in tumor | 0.09033 correlation coefficient |
| Modufolin 60 mg/m2 | Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-methyl-THF | AUC(0-2h) vs. conc in adjacent mucosa | 0.36854 correlation coefficient |
Comparison: AUC(0-2h) vs. conc in tumorp-value: 0.0586Pearson Correlation
Comparison: AUC(0-2h) vs. conc in tumorp-value: 0.2661Pearson Correlation
Comparison: AUC(0-2h) vs. conc in tumorp-value: 0.9506Pearson Correlation
Comparison: AUC(0-2h) vs. conc in tumorp-value: 0.8315Pearson Correlation
Comparison: AUC(0-2h) vs. conc in adjacent mucosap-value: 0.0451Pearson Correlation
Comparison: AUC(0-2h) vs. concentration in adjacent mucosap-value: 0.4027Pearson Correlation
Comparison: AUC(0-2h) vs. concentration in adjacent mucosap-value: 0.1513Pearson Correlation
Comparison: AUC(0-2h) vs. concentration in adjacent mucosap-value: 0.369Pearson Correlation
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.
Time frame: Samples taken Day 1 (Day of surgery)
Population: The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-THF | AUC(0-2h) vs. conc in tumor | -0.02188 correlation coefficient |
| Levoleucovorin 200 mg/m2 | Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-THF | AUC(0-2h) vs. conc in adjacent mucosa | 0.07937 correlation coefficient |
| Levoleucovorin 60 mg/m2 | Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-THF | AUC(0-2h) vs. conc in adjacent mucosa | NA correlation coefficient |
| Levoleucovorin 60 mg/m2 | Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-THF | AUC(0-2h) vs. conc in tumor | NA correlation coefficient |
| Modufolin 200 mg/m2 | Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-THF | AUC(0-2h) vs. conc in tumor | 0.27018 correlation coefficient |
| Modufolin 200 mg/m2 | Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-THF | AUC(0-2h) vs. conc in adjacent mucosa | 0.34905 correlation coefficient |
| Modufolin 60 mg/m2 | Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-THF | AUC(0-2h) vs. conc in tumor | 0.38298 correlation coefficient |
| Modufolin 60 mg/m2 | Correlation Between Plasma and Tissue Concentration (Tumor and Mucosa) for [6S]-5-THF | AUC(0-2h) vs. conc in adjacent mucosa | 0.45404 correlation coefficient |
Comparison: AUC(0-2h) vs. concentration in tumorp-value: 0.3964Pearson Correlation
Comparison: AUC(0-2h) vs. concentration in tumorp-value: 0.5175Pearson Correlation
Comparison: AUC(0-2h) vs. concentration in tumorp-value: 0.959Pearson Correlation
Comparison: AUC(0-2h) vs. concentration in adjacent mucosap-value: 0.3061Pearson Correlation
Comparison: AUC(0-2h) vs. concentration in adjacent mucosap-value: 0.3967Pearson Correlation
Comparison: AUC(0-2h) vs. concentration in adjacent mucosap-value: 0.8518Pearson Correlation
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.
Time frame: Sample taken Day 1 (Day of Surgery)
Population: The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | FPGS | 0.17664 Normalized concentration |
| Levoleucovorin 200 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | MTHFS | 0.95840 Normalized concentration |
| Levoleucovorin 200 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | MTHFD1L | 0.74459 Normalized concentration |
| Levoleucovorin 200 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | ABCC1 | 0.74757 Normalized concentration |
| Levoleucovorin 200 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | RFC-1 | 0.64565 Normalized concentration |
| Levoleucovorin 200 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | ABCC3 | 0.00322 Normalized concentration |
| Levoleucovorin 200 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | SHMT1 | 0.59183 Normalized concentration |
| Levoleucovorin 200 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | PCFT | 0.11497 Normalized concentration |
| Levoleucovorin 200 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | SHMT2 | 0.55508 Normalized concentration |
| Levoleucovorin 200 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | GGH | 0.78928 Normalized concentration |
| Levoleucovorin 200 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | AMT | -0.47193 Normalized concentration |
| Levoleucovorin 60 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | GGH | -0.09737 Normalized concentration |
| Levoleucovorin 60 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | SHMT1 | 0.05531 Normalized concentration |
| Levoleucovorin 60 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | ABCC1 | 0.14436 Normalized concentration |
| Levoleucovorin 60 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | AMT | -0.70730 Normalized concentration |
| Levoleucovorin 60 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | MTHFD1L | 0.20955 Normalized concentration |
| Levoleucovorin 60 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | FPGS | -0.64743 Normalized concentration |
| Levoleucovorin 60 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | MTHFS | 0.58419 Normalized concentration |
| Levoleucovorin 60 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | RFC-1 | -0.02450 Normalized concentration |
| Levoleucovorin 60 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | SHMT2 | -0.71666 Normalized concentration |
| Levoleucovorin 60 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | ABCC3 | 0.77700 Normalized concentration |
| Levoleucovorin 60 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | PCFT | 0.89976 Normalized concentration |
| Modufolin 200 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | SHMT2 | 0.86266 Normalized concentration |
| Modufolin 200 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | AMT | 0.75404 Normalized concentration |
| Modufolin 200 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | PCFT | 0.58502 Normalized concentration |
| Modufolin 200 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | FPGS | 0.88682 Normalized concentration |
| Modufolin 200 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | MTHFS | 0.43194 Normalized concentration |
| Modufolin 200 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | ABCC3 | -0.25891 Normalized concentration |
| Modufolin 200 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | GGH | 0.46883 Normalized concentration |
| Modufolin 200 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | ABCC1 | -0.16724 Normalized concentration |
| Modufolin 200 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | MTHFD1L | 0.37160 Normalized concentration |
| Modufolin 200 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | SHMT1 | 0.67853 Normalized concentration |
| Modufolin 200 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | RFC-1 | 0.23312 Normalized concentration |
| Modufolin 60 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | GGH | 0.93711 Normalized concentration |
| Modufolin 60 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | RFC-1 | 0.31800 Normalized concentration |
| Modufolin 60 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | SHMT1 | 0.50966 Normalized concentration |
| Modufolin 60 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | ABCC3 | -0.38987 Normalized concentration |
| Modufolin 60 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | MTHFS | 0.94364 Normalized concentration |
| Modufolin 60 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | FPGS | 0.97624 Normalized concentration |
| Modufolin 60 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | SHMT2 | 0.81040 Normalized concentration |
| Modufolin 60 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | PCFT | 0.88128 Normalized concentration |
| Modufolin 60 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | AMT | 0.42972 Normalized concentration |
| Modufolin 60 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | MTHFD1L | 0.32113 Normalized concentration |
| Modufolin 60 mg/m2 | Correlation of Gene Expression in Tumor and Adjacent Mucosa | ABCC1 | 0.82963 Normalized concentration |
Comparison: Correlation for ABCC1 gene expressionp-value: 0.6922Pearson Correlation
Comparison: Correlation for ABCC1 gene expressionp-value: 0.785Pearson Correlation
Comparison: Correlation for ABCC1 gene expressionp-value: 0.033Pearson Correlation
Comparison: Correlation for MTHFD1L gene expressionp-value: 0.4825Pearson Correlation
Comparison: Correlation for AMT gene expressionp-value: 0.3359Pearson Correlation
Comparison: Correlation for AMT gene expressionp-value: 0.0307Pearson Correlation
Comparison: Correlation for AMT gene expressionp-value: 0.116Pearson Correlation
Comparison: Correlation for AMT gene expressionp-value: 0.2377Pearson Correlation
Comparison: Correlation for PCFT gene expressionp-value: 0.0087Pearson Correlation
Comparison: Correlation for PCFT gene expressionp-value: 0.1277Pearson Correlation
Comparison: Correlation for PCFT gene expressionp-value: 0.0146Pearson Correlation
Comparison: Correlation for PCFT gene expressionp-value: 0.7863Pearson Correlation
Comparison: Correlation for FPGS gene expressionp-value: 0.0002Pearson Correlation
Comparison: Correlation for FPGS gene expressionp-value: 0.0033Pearson Correlation
Comparison: Correlation for FPGS gene expressionp-value: 0.1645Pearson Correlation
Comparison: Correlation for FPGS gene expressionp-value: 0.6756Pearson Correlation
Comparison: Correlation for MTHFS gene expressionp-value: 0.0014Pearson Correlation
Comparison: Correlation for MTHFS gene expressionp-value: 0.2852Pearson Correlation
Comparison: Correlation for MTHFS gene expressionp-value: 0.2234Pearson Correlation
Comparison: Correlation for MTHFS gene expressionp-value: 0.0002Pearson Correlation
Comparison: Correlation for ABCC3 gene expressionp-value: 0.3873Pearson Correlation
Comparison: Correlation for ABCC3 gene expressionp-value: 0.5358Pearson Correlation
Comparison: Correlation for ABCC3 gene expressionp-value: 0.0691Pearson Correlation
Comparison: Correlation for ABCC3 gene expressionp-value: 0.994Pearson Correlation
Comparison: Correlation for GGH gene expressionp-value: 0.0018Pearson Correlation
Comparison: Correlation for GGH gene expressionp-value: 0.2413Pearson Correlation
Comparison: Correlation for GGH gene expressionp-value: 0.8544Pearson Correlation
Comparison: Correlation for GGH gene expressionp-value: 0.0199Pearson Correlation
Comparison: Correlation for ABCC1 gene expressionp-value: 0.0209Pearson Correlation
Comparison: Correlation for MTHFD1L gene expressionp-value: 0.3647Pearson Correlation
Comparison: Correlation for MTHFD1L gene expressionp-value: 0.6903Pearson Correlation
Comparison: Correlation for MTHFD1L gene expressionp-value: 0.0341Pearson Correlation
Comparison: Correlation for SHMT1 gene expressionp-value: 0.2426Pearson Correlation
Comparison: Correlation for SHMT1 gene expressionp-value: 0.0643Pearson Correlation
Comparison: Correlation for SHMT1 gene expressionp-value: 0.9171Pearson Correlation
Comparison: Correlation for SHMT1 gene expressionp-value: 0.1222Pearson Correlation
Comparison: Correlation for SHMT2 gene expressionp-value: 0.0271Pearson Correlation
Comparison: Correlation for SHMT2 gene expressionp-value: 0.0058Pearson Correlation
Comparison: Correlation for SHMT2 gene expressionp-value: 0.109Pearson Correlation
Comparison: Correlation for SHMT2 gene expressionp-value: 0.1533Pearson Correlation
Comparison: Correlation for RFC-1 gene expressionp-value: 0.487Pearson Correlation
Comparison: Correlation for RFC-1 gene expressionp-value: 0.5785Pearson Correlation
Comparison: Correlation for RFC-1 gene expressionp-value: 0.9632Pearson Correlation
Comparison: Correlation for RFC-1 gene expressionp-value: 0.0838Pearson Correlation
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.
Time frame: Sample taken Day 1 (Day of Surgery)
Population: The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | GGH | 0.50 Ratio |
| Levoleucovorin 200 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | ABCC1 | 0.41 Ratio |
| Levoleucovorin 200 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | SHMT1 | 0.89 Ratio |
| Levoleucovorin 200 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | MTHFD1L | 0.15 Ratio |
| Levoleucovorin 200 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | RFC-1 | 0.48 Ratio |
| Levoleucovorin 200 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | FPGS | 0.47 Ratio |
| Levoleucovorin 200 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | AMT | 1.35 Ratio |
| Levoleucovorin 200 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | MTHFS | 0.51 Ratio |
| Levoleucovorin 200 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | ABCC3 | 1.83 Ratio |
| Levoleucovorin 200 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | PCFT | 2.03 Ratio |
| Levoleucovorin 200 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | SHMT2 | 0.31 Ratio |
| Levoleucovorin 60 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | FPGS | 0.70 Ratio |
| Levoleucovorin 60 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | SHMT1 | 1.13 Ratio |
| Levoleucovorin 60 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | SHMT2 | 0.34 Ratio |
| Levoleucovorin 60 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | ABCC1 | 0.55 Ratio |
| Levoleucovorin 60 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | PCFT | 2.75 Ratio |
| Levoleucovorin 60 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | GGH | 0.47 Ratio |
| Levoleucovorin 60 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | ABCC3 | 3.37 Ratio |
| Levoleucovorin 60 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | MTHFD1L | 0.24 Ratio |
| Levoleucovorin 60 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | AMT | 5.60 Ratio |
| Levoleucovorin 60 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | MTHFS | 0.87 Ratio |
| Levoleucovorin 60 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | RFC-1 | 0.66 Ratio |
| Modufolin 200 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | SHMT2 | 0.38 Ratio |
| Modufolin 200 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | GGH | 0.35 Ratio |
| Modufolin 200 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | AMT | 1.86 Ratio |
| Modufolin 200 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | PCFT | 2.92 Ratio |
| Modufolin 200 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | FPGS | 0.63 Ratio |
| Modufolin 200 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | MTHFS | 0.83 Ratio |
| Modufolin 200 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | ABCC3 | 2.48 Ratio |
| Modufolin 200 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | ABCC1 | 0.77 Ratio |
| Modufolin 200 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | MTHFD1L | 0.29 Ratio |
| Modufolin 200 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | SHMT1 | 0.72 Ratio |
| Modufolin 200 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | RFC-1 | 0.53 Ratio |
| Modufolin 60 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | GGH | 0.31 Ratio |
| Modufolin 60 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | RFC-1 | 1.18 Ratio |
| Modufolin 60 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | SHMT1 | 2.26 Ratio |
| Modufolin 60 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | ABCC3 | 4.15 Ratio |
| Modufolin 60 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | MTHFS | 0.72 Ratio |
| Modufolin 60 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | FPGS | 0.83 Ratio |
| Modufolin 60 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | SHMT2 | 0.48 Ratio |
| Modufolin 60 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | PCFT | 2.45 Ratio |
| Modufolin 60 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | AMT | 3.33 Ratio |
| Modufolin 60 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | MTHFD1L | 0.35 Ratio |
| Modufolin 60 mg/m2 | Gene Expression Ratios (Mucosa:Tumor) | ABCC1 | 0.43 Ratio |
p-value: 0.0451pearson
Secondary
Homocystein Concentration
Blood samples for folate biomarker (homocystein) analysis were collected at Screening, Day 2, and Day 5 (End of study visit).
Time frame: Samples taken at Screening visit, Day 2, and End of Study (Day 5)
Population: The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Levoleucovorin 200 mg/m2 | Homocystein Concentration | Concentration at Screening | 12.59 μmol/L | Standard Deviation 4.28 |
| Levoleucovorin 200 mg/m2 | Homocystein Concentration | Concentration at Day 5 | 9.04 μmol/L | Standard Deviation 2.53 |
| Levoleucovorin 200 mg/m2 | Homocystein Concentration | Concentration at Day 2 | 6.41 μmol/L | Standard Deviation 2.32 |
| Levoleucovorin 60 mg/m2 | Homocystein Concentration | Concentration at Screening | 11.27 μmol/L | Standard Deviation 3.98 |
| Levoleucovorin 60 mg/m2 | Homocystein Concentration | Concentration at Day 5 | 9.18 μmol/L | Standard Deviation 4.65 |
| Levoleucovorin 60 mg/m2 | Homocystein Concentration | Concentration at Day 2 | 6.40 μmol/L | Standard Deviation 3.1 |
| Modufolin 200 mg/m2 | Homocystein Concentration | Concentration at Day 2 | 7.06 μmol/L | Standard Deviation 1.97 |
| Modufolin 200 mg/m2 | Homocystein Concentration | Concentration at Screening | 14.53 μmol/L | Standard Deviation 6.22 |
| Modufolin 200 mg/m2 | Homocystein Concentration | Concentration at Day 5 | 10.20 μmol/L | Standard Deviation 3.34 |
| Modufolin 60 mg/m2 | Homocystein Concentration | Concentration at Screening | 13.80 μmol/L | Standard Deviation 3.83 |
| Modufolin 60 mg/m2 | Homocystein Concentration | Concentration at Day 5 | 10.10 μmol/L | Standard Deviation 2.64 |
| Modufolin 60 mg/m2 | Homocystein Concentration | Concentration at Day 2 | 8.14 μmol/L | Standard Deviation 2.63 |
Secondary
Number of AEs Per Severity
Number of reported AEs per treatment with respect to severity
Time frame: Screening visit until end of study, Day 5
Population: The safety population contained 31 of the 32 enrolled patients. One patient randomized to L-LV 60 mg/m2 was withdrawn prior to study drug administration and thus excluded from the safety analysis set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | Number of AEs Per Severity | AEs of mild severity | 1 Events |
| Levoleucovorin 200 mg/m2 | Number of AEs Per Severity | AEs of severe severity | 0 Events |
| Levoleucovorin 200 mg/m2 | Number of AEs Per Severity | AEs of moderate severity | 3 Events |
| Levoleucovorin 60 mg/m2 | Number of AEs Per Severity | AEs of mild severity | 0 Events |
| Levoleucovorin 60 mg/m2 | Number of AEs Per Severity | AEs of severe severity | 1 Events |
| Levoleucovorin 60 mg/m2 | Number of AEs Per Severity | AEs of moderate severity | 0 Events |
| Modufolin 200 mg/m2 | Number of AEs Per Severity | AEs of moderate severity | 7 Events |
| Modufolin 200 mg/m2 | Number of AEs Per Severity | AEs of mild severity | 1 Events |
| Modufolin 200 mg/m2 | Number of AEs Per Severity | AEs of severe severity | 2 Events |
| Modufolin 60 mg/m2 | Number of AEs Per Severity | AEs of mild severity | 5 Events |
| Modufolin 60 mg/m2 | Number of AEs Per Severity | AEs of severe severity | 2 Events |
| Modufolin 60 mg/m2 | Number of AEs Per Severity | AEs of moderate severity | 2 Events |
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).
Time frame: Samples taken at Screening visit, Day 2 and End of Study (Day 5)
Population: The Per Protocol analysis set contained 29 of the 32 enrolled patients. One patient was withdrawn prior to study drug administration and two patients were excluded due to major protocol deviations.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Levoleucovorin 200 mg/m2 | S-Folate Concentration | Concentration at Screening | 21.75 nmol/L | Standard Deviation 8.88 |
| Levoleucovorin 200 mg/m2 | S-Folate Concentration | Concentration at Day 5 | 44.75 nmol/L | Standard Deviation 0.71 |
| Levoleucovorin 200 mg/m2 | S-Folate Concentration | Concentration at Day 2 | 45.00 nmol/L | Standard Deviation 0 |
| Levoleucovorin 60 mg/m2 | S-Folate Concentration | Concentration at Screening | 21.00 nmol/L | Standard Deviation 6.54 |
| Levoleucovorin 60 mg/m2 | S-Folate Concentration | Concentration at Day 5 | 40.80 nmol/L | Standard Deviation 9.39 |
| Levoleucovorin 60 mg/m2 | S-Folate Concentration | Concentration at Day 2 | 45.00 nmol/L | Standard Deviation 0 |
| Modufolin 200 mg/m2 | S-Folate Concentration | Concentration at Day 2 | 45.00 nmol/L | Standard Deviation 0 |
| Modufolin 200 mg/m2 | S-Folate Concentration | Concentration at Screening | 15.03 nmol/L | Standard Deviation 5.2 |
| Modufolin 200 mg/m2 | S-Folate Concentration | Concentration at Day 5 | 44.14 nmol/L | Standard Deviation 2.27 |
| Modufolin 60 mg/m2 | S-Folate Concentration | Concentration at Screening | 18.71 nmol/L | Standard Deviation 7.65 |
| Modufolin 60 mg/m2 | S-Folate Concentration | Concentration at Day 5 | 40.29 nmol/L | Standard Deviation 3.73 |
| Modufolin 60 mg/m2 | S-Folate Concentration | Concentration at Day 2 | 45.00 nmol/L | Standard Deviation 0 |
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
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
Population: Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | T(1/2) of [6R]-5,10-methylene-THF | 3.07069184 h | Standard Deviation 2.48958159 |
| Levoleucovorin 60 mg/m2 | T(1/2) of [6R]-5,10-methylene-THF | 9.12204918 h | Standard Deviation 0 |
| Modufolin 200 mg/m2 | T(1/2) of [6R]-5,10-methylene-THF | 0.90893994 h | Standard Deviation 0.6258642 |
| Modufolin 60 mg/m2 | T(1/2) of [6R]-5,10-methylene-THF | 0.34368840 h | Standard Deviation 0.06725217 |
Comparison: The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0268Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0227Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0933Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Secondary
T(1/2) of [6S]-5-formyl-THF
Terminal plasma elimination half-life time for the metabolite \[6S\]-5-formyl-THF
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
Population: Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | T(1/2) of [6S]-5-formyl-THF | 1.51328500 h | Standard Deviation 0.34108131 |
| Levoleucovorin 60 mg/m2 | T(1/2) of [6S]-5-formyl-THF | 0.98944069 h | Standard Deviation 0.20217367 |
| Modufolin 200 mg/m2 | T(1/2) of [6S]-5-formyl-THF | 0.23180085 h | Standard Deviation 0.13438901 |
| Modufolin 60 mg/m2 | T(1/2) of [6S]-5-formyl-THF | 0 h | Standard Deviation 0 |
Comparison: The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0668Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0502Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0081Wilcoxon (Mann-Whitney)
Secondary
T(1/2) of [6S]-5-methyl-THF
Terminal plasma elimination half-life time for the metabolite \[6S\]-5-methyl-THF
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
Population: Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | T(1/2) of [6S]-5-methyl-THF | 7.0955575 h | Standard Deviation 1.18981597 |
| Levoleucovorin 60 mg/m2 | T(1/2) of [6S]-5-methyl-THF | 10.7281060 h | Standard Deviation 8.80812064 |
| Modufolin 200 mg/m2 | T(1/2) of [6S]-5-methyl-THF | 9.0743346 h | Standard Deviation 3.84317226 |
| Modufolin 60 mg/m2 | T(1/2) of [6S]-5-methyl-THF | 8.5121573 h | Standard Deviation 2.80644764 |
Comparison: The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Secondary
T(1/2) of [6S]-5-THF
Terminal plasma elimination half-life time for the metabolite \[6S\]-5-THF
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
Population: Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | T(1/2) of [6S]-5-THF | 5.59459251 h | Standard Deviation 1.76982092 |
| Levoleucovorin 60 mg/m2 | T(1/2) of [6S]-5-THF | 0 h | Standard Deviation 0 |
| Modufolin 200 mg/m2 | T(1/2) of [6S]-5-THF | 1.24808943 h | Standard Deviation 0.23995973 |
| Modufolin 60 mg/m2 | T(1/2) of [6S]-5-THF | 0.96378070 h | Standard Deviation 0.19174152 |
Comparison: The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0177Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0058Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0043Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t1/2 was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
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
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
Population: Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | T(Last) of [6R]-5,10-methylene-THF | 3.00000000 h | Standard Deviation 1.41421356 |
| Levoleucovorin 60 mg/m2 | T(Last) of [6R]-5,10-methylene-THF | 2.00000000 h | Standard Deviation 0 |
| Modufolin 200 mg/m2 | T(Last) of [6R]-5,10-methylene-THF | 3.25000000 h | Standard Deviation 1.38873015 |
| Modufolin 60 mg/m2 | T(Last) of [6R]-5,10-methylene-THF | 1.35714286 h | Standard Deviation 0.24397502 |
Comparison: The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0011Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0015Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.6691Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
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
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
Population: Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | T(Last) of [6S]-5-formyl-THF | 6.00000000 h | Standard Deviation 0 |
| Levoleucovorin 60 mg/m2 | T(Last) of [6S]-5-formyl-THF | 8.33333333 h | Standard Deviation 7.73735528 |
| Modufolin 200 mg/m2 | T(Last) of [6S]-5-formyl-THF | 0.33333500 h | Standard Deviation 0.23570226 |
| Modufolin 60 mg/m2 | T(Last) of [6S]-5-formyl-THF | 0.16667000 h | Standard Deviation 0 |
Comparison: The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0125Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0017Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.5286Wilcoxon (Mann-Whitney)
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
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
Population: Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | T(Last) of [6S]-5-methyl-THF | 24.0000000 h | Standard Deviation 0 |
| Levoleucovorin 60 mg/m2 | T(Last) of [6S]-5-methyl-THF | 12.0000000 h | Standard Deviation 9.29516003 |
| Modufolin 200 mg/m2 | T(Last) of [6S]-5-methyl-THF | 15.0000000 h | Standard Deviation 9.62140471 |
| Modufolin 60 mg/m2 | T(Last) of [6S]-5-methyl-THF | 8.5714286 h | Standard Deviation 6.80336051 |
Comparison: The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.1791Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.4945Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0014Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.599Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0303Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0107Wilcoxon (Mann-Whitney)
Secondary
T(Last) of [6S]-5-THF
The time-point for the last measurable concentration for the metabolite \[6S\]-5-TH in plasma
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
Population: Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | T(Last) of [6S]-5-THF | 4.75000000 h | Standard Deviation 1.48804762 |
| Levoleucovorin 60 mg/m2 | T(Last) of [6S]-5-THF | 2.00000000 h | Standard Deviation 0 |
| Modufolin 200 mg/m2 | T(Last) of [6S]-5-THF | 5.75000000 h | Standard Deviation 0.70710678 |
| Modufolin 60 mg/m2 | T(Last) of [6S]-5-THF | 3.42857143 h | Standard Deviation 0.78679579 |
Comparison: The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0015Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.064Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.1213Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of t(last) was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
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
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
Population: Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | Tmax of [6R]-5,10-methylene-THF | 1.14285857 h | Standard Deviation 0.53079605 |
| Levoleucovorin 60 mg/m2 | Tmax of [6R]-5,10-methylene-THF | 1.00000000 h | Standard Deviation 0 |
| Modufolin 200 mg/m2 | Tmax of [6R]-5,10-methylene-THF | 0.08333000 h | Standard Deviation 0 |
| Modufolin 60 mg/m2 | Tmax of [6R]-5,10-methylene-THF | 0.08333000 h | Standard Deviation 0 |
Comparison: The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 1Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.001Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0005Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Secondary
Tmax of [6S]-5-formyl-THF
Timepoint (tmax) when Cmax in plasma occurs for the metabolite \[6S\]-5-formyl-THF
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
Population: Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | Tmax of [6S]-5-formyl-THF | 0.12499750 h | Standard Deviation 0.08908753 |
| Levoleucovorin 60 mg/m2 | Tmax of [6S]-5-formyl-THF | 0.08333000 h | Standard Deviation 0 |
| Modufolin 200 mg/m2 | Tmax of [6S]-5-formyl-THF | 0.10416500 h | Standard Deviation 0.04167 |
| Modufolin 60 mg/m2 | Tmax of [6S]-5-formyl-THF | 0.08333000 h | Standard Deviation 0 |
Comparison: The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Secondary
Tmax of [6S]-5-methyl-THF
Timepoint (tmax) when Cmax in plasma occurs for the metabolite \[6S\]-5-methyl-THF
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
Population: Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | Tmax of [6S]-5-methyl-THF | 4.75000000 h | Standard Deviation 1.38873015 |
| Levoleucovorin 60 mg/m2 | Tmax of [6S]-5-methyl-THF | 2.41666667 h | Standard Deviation 0.66458007 |
| Modufolin 200 mg/m2 | Tmax of [6S]-5-methyl-THF | 3.75000000 h | Standard Deviation 1.16496475 |
| Modufolin 60 mg/m2 | Tmax of [6S]-5-methyl-THF | 2.92857143 h | Standard Deviation 0.93222724 |
Comparison: The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.1796Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.3243Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0263Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0268Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.2041Wilcoxon (Mann-Whitney)
p-value: 0.0061Wilcoxon (Mann-Whitney)
Secondary
Tmax of [6S]-5-THF
Timepoint (tmax) when Cmax in plasma occurs for the metabolite \[6S\]-5-THF
Time frame: Samples taken Day 1 (Day of surgery) and Day 2
Population: Per protocol population, all patients who complete the trial without any major deviations from the protocol procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levoleucovorin 200 mg/m2 | Tmax of [6S]-5-THF | 2.02083375 h | Standard Deviation 1.0367736 |
| Levoleucovorin 60 mg/m2 | Tmax of [6S]-5-THF | 1.50000000 h | Standard Deviation 0 |
| Modufolin 200 mg/m2 | Tmax of [6S]-5-THF | 0.38541750 h | Standard Deviation 0.24775936 |
| Modufolin 60 mg/m2 | Tmax of [6S]-5-THF | 0.09523571 h | Standard Deviation 0.03149956 |
Comparison: The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0056Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.001Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0.0014Wilcoxon (Mann-Whitney)
Comparison: The exploratory evaluation of tmax was done respectively for differences between treatments using Wilcoxon test. Differences in variability between the treatment groups were assessed using Proc GLM and Levene's test.p-value: 0Wilcoxon (Mann-Whitney)