Osteosarcoma
Conditions
Keywords
Methotrexate, Rescue treatment
Brief summary
An open-label, multicenter, phase I/II clinical trial to identify the \[6R\] 5,10-methylenetetrahydrofolate (arfolitixorin) dose with most favorable safety prospect and confirmed ability to mitigate high-dose methotrexate induced toxicity during treatment of osteosarcoma patients
Detailed description
This is a non-blinded, multicenter, exploratory study in osteosarcoma patients. The study focuses on the overall safety of the HDMTX courses given within a Methotrexate, Adriamycin (doxorubin) and cisPlatin (MAP) treatment schedule, which is closely related to the efficacy of the concomitantly administered folate rescue treatment. Additionally the study aimes to collect pharmacokinetic (PK) profiles of metotrexate (MTX) in serum, of folate metabolites in plasma and to decide the Modufolin® dose to use in future studies. Patients are enrolled in the study at the first, third or the fifth HDMTX course in a MAP treatment schedule and receive folate rescue therapy according to a strategy based on the Children's Oncology Group (COG) treatment management recommendations used in study protocol AOST0331. Folate rescue treatment with Calcium Folinate (SOC) or Modufolin® (MOD) commence 24 h after start of HDMTX administration and then every 6 h until the serum MTX levels are ≤0.1 μmol/L. In case delayed MTX elimination occurs with significant increase in S-creatinine and/or occurrence of oral mucositis or signs of hypo cellular bone marrow, the folate rescue dose and/or the administered hydration will be adjusted in accordance with the COG based MTX toxicity management recommendations. All patients receives SOC (15 mg/m2) in the first 2 HDMTX courses and MOD in the following 2 courses. Patients are enrolled in one of two MOD dose cohorts: Cohort 1 (15 mg/m2) and Cohort 2 (30 or 7.5 mg/m2 depending on outcome of Cohort 1). Only patients with successful advancements from the first 2 HDMTX courses with Calcium Folinate are allowed to continue with MOD as rescue in the following MAP cycle. Safety data will be reviewed by an independent board, Data and Safety Monitoring Board (DSMB) that will assess each patient and made recommendations regarding the enrolment of subsequent patients. Furthermore, the DSMB will make a dose level recommendation for Cohort 2 and also a recommendation whether younger children may be allowed in this cohort.
Interventions
DRUGCalcium Folinate
The enrolled patients will be treated according to the MAP schedule and will receive the study drug Calcium Folinate commencing 24 hours after the administration of HDMTX and then every 6 hours (q6h) thereafter until the S-MTX levels are ≤ 0.1 µmol/L, in accordance with COG management recommendations. All patients will receive standard o care (SOC) in the two (2) first HDMTX courses and \[6R\] 5,10-methylenetetrahydrofolate in the two (2) following courses. Patients will be enrolled in two (2) \[6R\] 5,10-methylenetetrahydrofolate dose cohort groups: with \[6R\] 5,10-methylenetetrahydrofolate start dose of 15 mg/m2 (i.e. the same as for SOC rescue) the first cohort will be administered, and 7.5 or 30 mg/m2 in the second cohort.
The enrolled patients will be treated according to the MAP schedule and will receive the study drug \[6R\] 5,10-methylenetetrahydrofolate commencing 24 hours after the administration of HDMTX and then every 6 hours (q6h) thereafter until the S-MTX levels are ≤ 0.1 µmol/L, in accordance with COG management recommendations. All patients will receive standard o care (SOC) in the two (2) first HDMTX courses and \[6R\] 5,10-methylenetetrahydrofolate in the two (2) following courses. Patients will be enrolled in two (2) \[6R\] 5,10-methylenetetrahydrofolate® dose cohort groups: with \[6R\] 5,10-methylenetetrahydrofolate start dose of 15 mg/m2 (i.e. the same as for SOC rescue) the first cohort will be administered, and 7.5 or 30 mg/m2 in the second cohort.
Sponsors
Isofol Medical AB
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to 40 Years
Healthy volunteers
No
Inclusion criteria
Main Inclusion Criteria (HDMTX with SOC rescue): * Patients must have histological evidence of osteosarcoma (metastatic disease accepted). * Patients must be eligible for HDMTX according to the MAP treatment schedule described in the study protocol and fulfill all of the criteria below prior to first course of HDMTX in the study. 1. Serum MTX: ≤0.1μmol/L 2. Neutrophils: ≥0.25x109/L 3. Platelets: ≥50x109/L 4. Serum bilirubin: ≤1.25x upper limit of normal (ULN) 5. Glomerular filtration rate (GFR) ≥70 mL/min/1.73m2 6. No adverse event (AE) Grade 2 or more (NCI CTCAE v4.0) related to HDMTX hindering a potential HDMTX administration, at the discretion of the investigator. * Patients must be 12-40 years of age. This age range may be extended with younger patients for enrolment in Cohort 2 if collected data from Cohort 1 support this and it is recommended by the DSMB.
Exclusion criteria
for enrolment: * Involvement in another clinical trial within 30 days before enrolment in the study. * Hypersensitivity to Calcium Folinate. * Previous treatment with glucarpidase. * Known serious concomitant systemic disorders (e.g., active infection including HIV, liver dysfunction, cardiac disease) that, in the opinion of the investigator, would compromise the patient's ability to complete the study Main Inclusion criteria for continuation (HDMTX treatment with Modufolin rescue): * Patients, who were included in the study in accordance with the inclusion criteria above, must have received 2 adjacent courses of HDMTX with SOC rescue according to the MAP treatment schedule in accordance with this study protocol. * Patients eligible for continued HDMTX according to the MAP treatment schedule and with a history of successful advancement from first to second HDMTX course within the previous MAP cycle * Patients eligible for continued HDMTX according to the MAP treatment schedule and with a history of successful advancement to next MAP cycle after end of previous MAP cycle * No significant changes to the patient's medical condition from the start of the study that in the opinion of the investigator would compromise the patient's ability to complete the study. * Patients who have undergone surgical resection of their tumor must have recovered from their surgery and be eligible to continue on the MAP regimen; any post-operative complications should be resolved to NCI CTCAE v4.0 Grade 1 or better.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of AEs Per Severity (All Courses) | From the start of HDMTX administration through 8 days post dose for each course of HDMTX in total | Characterization (number and severity grade) of toxicity reported for each course of HDMTX treatment with folate rescue therapy and continuing until eight (8) days after start of HDMTX administration, per NCI CTCAE v4.0 (Grade refers to the severity of the AE). The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE; Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening, and Grade 5 Death related to AE. |
| Number of HDMTX Related AEs Per Severity (All Courses) | From the start of HDMTX administration through 8 days post dose for each course of HDMTX in total | Characterization (frequency and severity grade) of toxicity reported for each course of HDMTX treatment with folate rescue therapy and continuing until eight (8) days after start of HDMTX administration, per NCI CTCAE v4.0 (Grade refers to the severity of the AE). The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE; Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening, and Grade 5 Death related to AE. |
| Number of Ongoing AEs Per HDMTX Course | From the start of HDMTX administration through 8 days post dose for each course of HDMTX | Characterization (frequency and severity grade) of toxicity reported for each course of HDMTX treatment with folate rescue therapy and continuing until eight (8) days after start of HDMTX administration, per NCI CTCAE v4.0 (Grade refers to the severity of the AE). The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE; Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening, and Grade 5 Death related to AE. |
| Number of Ongoing HDMTX Related AEs Per HDMTX Course | From the start of HDMTX administration through 8 days post dose for each course of HDMTX | Characterization (frequency and severity grade) of toxicity reported for each course of HDMTX treatment with folate rescue therapy and continuing until eight (8) days after start of HDMTX administration, per NCI CTCAE v4.0 (Grade refers to the severity of the AE). The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE; Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening, and Grade 5 Death related to AE. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of HDMTX Courses in Which the Initial Hydration Was Increased | Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L | — |
| Number of HDMTX Courses With Delayed MTX Elimination (Definition D). | Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L | Definition D: Delayed MTX elimination (according to COGs excretion toxicity management instructions) S-MTX levels of: \> 10 μmol/L at 24 h after start of MTX administration, OR \> 1 μmol/L at 48 h after start of MTX administration, OR \> 0.1 μmol/L at 72 h after start of MTX administration or later |
| Number of HDMTX Courses With Delayed Early MTX Elimination (Definition E). | Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L | Definition E: Delayed early MTX elimination (according to US label for Calcium Folinate) S-MTX levels of: * 50 μmol/L at 24 hours after start of MTX administration, OR * 5 μmol/L at 48 hours after start of MTX administration OR An increase in S-Creatinine level of 100% or greater at 24 hours after start of MTX administration. |
| Number of Administered HDMTX Courses Classified as Having Met the Criteria for Successful Advancement According to Definition A and/or Definition B | 8 days after start of first and/or second HDMTX course in a MAP cycle | Definition A: Successful advancement from 1st to 2nd HDMTX course within the same MAP cycle. Fulfilling all of the following criteria 8 days after start of first HDMTX course within the same MAP cycle: 1. Serum MTX: ≤0.1μmol/L 2. Neutrophils: ≥0.25x109/L 3. Platelets: ≥50x109/L 4. Serum bilirubin: ≤1.25 x upper limit of normal (ULN) 5. Glomerular filtration rate (GFR) ≥70 mL/min/1.73m2 6. No AE Grade 2 or more related to HDMTX hindering a potential HDMTX administration, at the discretion of the investigator Definition B: Successful advancement to next MAP cycle Fulfilling all of the following criteria 8 days after start of the second HDMTX course in previous MAP cycle: 1. Serum MTX: ≤0.1μmol/L 2. Neutrophils: ≥ 0.75 x 109/L 3. Platelets: ≥75x109/L 4. Serum bilirubin: ≤1.25xULN 5. GFR ≥70 mL/min/1.73m2 6. No AE Grade 2 or more related to HDMTX hindering a potential Adriamycin/Doxorubicin and Cisplatin (AP) administration, at the discretion of the investigator |
| Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L | The MTX-toxicity management instructions provided in the protocol are based on the Children's Oncology Group (COG) treatment management recommendations used in study protocol AOST0331, EURAMOS 1. The COG recommend changes in the hydration and the rescue frequency and/or dose to be done if pre-specified toxicities of different severity grades occur. |
| Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | From the start of HDMTX administration through 8 days post dose for all 4 courses of HDMTX in total | The severity of AEs have been done using NCI CTCAE v4.0. Total number of AEs per severity grade are presented for all AEs and for AEs related to MTX. For AEs related to MTX the number of AEs occurring per preferred term and severity grade are detailed.The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE; Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening, and Grade 5 Death related to AE. |
| Number of HDMTX Courses With Delayed Late MTX Elimination (Definition F). | Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L | Definition F: Delayed late MTX elimination (according to US label for Calcium Folinate) S-MTX level: \> 0.2 μmol/L at 72 hours AND \> 0.1 μmol/L at 96 hours after start of MTX administration. |
| Number of Administered MAP Cycles Classified as Having Met the Criteria for Successful Advancement From First to Second HDMTX Course Within the Same MAP Cycle According to Definition A. | 8 days after start of first HDMTX course in a MAP cycle | Definition A: Successful advancement from first to second HDMTX course within the same MAP cycle Fulfilling all of the following criteria 8 days after start of first HDMTX course within the same MAP cycle: 1. Serum MTX: ≤ 0.1 μmol/L 2. Neutrophils: ≥ 0.25 x 109/L 3. Platelets: ≥ 50 x 109/L 4. Serum bilirubin: ≤ 1.25 x ULN 5. GFR ≥ 70 mL/min/1.73 m2 6. No AE Grade 2 or more (NCI CTCAE v4.0) related to HDMTX hindering a potential HDMTX administration, at the discretion of the investigator |
| Number of Administered MAP Cycles Classified as Having Met the Criteria for Successful Advancement to Next MAP Cycle According to Definition B. | 8 days after start of second HDMTX course in a MAP cycle | Definition B: Successful advancement to next MAP cycle Fulfilling all of the following criteria 8 days after start of the second HDMTX course in previous MAP cycle: 1. Serum MTX: ≤ 0.1 μmol/L 2. Neutrophils: ≥ 0.75 x 109/L 3. Platelets: ≥ 75 x 109/L 4. Serum bilirubin: ≤ 1.25 x ULN 5. GFR ≥ 70 mL/min/1.73 m2 6. No AE Grade 2 or more (NCI CTCAE v4.0) related to HDMTX hindering a potential Adriamycin/Doxorubicin and Cisplatin (AP) administration, at the discretion of the investigator |
| Time to Successful MTX Elimination (Definition C) | Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L | Definition C: Time to successful MTX elimination = Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L |
Countries
Czechia, Hungary, Poland, Sweden
Participant flow
Recruitment details
Patients were pre-screened for eligibility to participate by the principal investigator among those patients who have received confirmed diagnosis of osteosarcoma and were planned for surgical resection of their tumor in combination with neoadjuvant or adjuvant chemotherapy.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 1 MAP cycle (incl. 2 HDMTX courses with Calcium Folinate (SOC) rescue 15mg/m2)
1 MAP cycle (incl. 2 HDMTX courses with Modufolin (MOD) rescue 15mg/m2)
Treatment according to the MAP schedule applied. SOC or MOD commenced 24 h after administration of HDMTX and then every 6 h until the serum-MTX levels were ≤ 0.1 µmol/L, in accordance with COG management recommendations. | 8 |
| Cohort 2 1 MAP cycle (incl. 2 HDMTX courses with Calcium Folinate (SOC) rescue 15mg/m2)
1 MAP cycle (incl. 2 HDMTX courses with Modufolin (MOD) rescue 7.5mg/m2)
Treatment according to the MAP schedule applied. SOC or MOD commenced 24 h after administration of HDMTX and then every 6 h until the serum-MTX levels were ≤ 0.1 µmol/L, in accordance with COG management recommendations. | 10 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| 2 Courses of HDMTX With MOD Rescue | Adverse Event | 0 | 1 |
| 2 Courses of HDMTX With SOC Rescue | Adverse Event | 2 | 2 |
| 2 Courses of HDMTX With SOC Rescue | Change in planned chemotherapy | 1 | 0 |
| 2 Courses of HDMTX With SOC Rescue | Incorrectly included | 0 | 1 |
| 2 Courses of HDMTX With SOC Rescue | Laboratory abnormality | 1 | 2 |
| 2 Courses of HDMTX With SOC Rescue | Protocol Violation | 0 | 1 |
Baseline characteristics
| Characteristic | Cohort 1 | Cohort 2 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 8 Participants | 8 Participants | 16 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 10 Participants | 18 Participants |
| Region of Enrollment Czechia | 5 Participants | 6 Participants | 11 Participants |
| Region of Enrollment Hungary | 2 Participants | 1 Participants | 3 Participants |
| Region of Enrollment Poland | 1 Participants | 2 Participants | 3 Participants |
| Region of Enrollment Sweden | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 7 Participants | 8 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 10 |
| other Total, other adverse events | 4 / 8 | 4 / 10 |
| serious Total, serious adverse events | 2 / 8 | 3 / 10 |
Outcome results
Primary
Number of AEs Per Severity (All Courses)
Characterization (number and severity grade) of toxicity reported for each course of HDMTX treatment with folate rescue therapy and continuing until eight (8) days after start of HDMTX administration, per NCI CTCAE v4.0 (Grade refers to the severity of the AE). The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE; Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening, and Grade 5 Death related to AE.
Time frame: From the start of HDMTX administration through 8 days post dose for each course of HDMTX in total
Population: The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Number of AEs Per Severity (All Courses) | Grade 1 | 40 Number of AEs |
| Cohort 1 | Number of AEs Per Severity (All Courses) | Grade 3 | 11 Number of AEs |
| Cohort 1 | Number of AEs Per Severity (All Courses) | Grade 2 | 8 Number of AEs |
| Cohort 1 | Number of AEs Per Severity (All Courses) | Grade 4 | 3 Number of AEs |
| Cohort 2 | Number of AEs Per Severity (All Courses) | Grade 2 | 15 Number of AEs |
| Cohort 2 | Number of AEs Per Severity (All Courses) | Grade 1 | 27 Number of AEs |
| Cohort 2 | Number of AEs Per Severity (All Courses) | Grade 4 | 1 Number of AEs |
| Cohort 2 | Number of AEs Per Severity (All Courses) | Grade 3 | 6 Number of AEs |
Primary
Number of HDMTX Related AEs Per Severity (All Courses)
Characterization (frequency and severity grade) of toxicity reported for each course of HDMTX treatment with folate rescue therapy and continuing until eight (8) days after start of HDMTX administration, per NCI CTCAE v4.0 (Grade refers to the severity of the AE). The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE; Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening, and Grade 5 Death related to AE.
Time frame: From the start of HDMTX administration through 8 days post dose for each course of HDMTX in total
Population: The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Number of HDMTX Related AEs Per Severity (All Courses) | Grade 1 | 25 Number of AEs |
| Cohort 1 | Number of HDMTX Related AEs Per Severity (All Courses) | Grade 2 | 6 Number of AEs |
| Cohort 1 | Number of HDMTX Related AEs Per Severity (All Courses) | Grade 3 | 6 Number of AEs |
| Cohort 1 | Number of HDMTX Related AEs Per Severity (All Courses) | Grade 4 | 1 Number of AEs |
| Cohort 2 | Number of HDMTX Related AEs Per Severity (All Courses) | Grade 4 | 1 Number of AEs |
| Cohort 2 | Number of HDMTX Related AEs Per Severity (All Courses) | Grade 1 | 20 Number of AEs |
| Cohort 2 | Number of HDMTX Related AEs Per Severity (All Courses) | Grade 2 | 12 Number of AEs |
| Cohort 2 | Number of HDMTX Related AEs Per Severity (All Courses) | Grade 3 | 5 Number of AEs |
Primary
Number of Ongoing AEs Per HDMTX Course
Characterization (frequency and severity grade) of toxicity reported for each course of HDMTX treatment with folate rescue therapy and continuing until eight (8) days after start of HDMTX administration, per NCI CTCAE v4.0 (Grade refers to the severity of the AE). The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE; Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening, and Grade 5 Death related to AE.
Time frame: From the start of HDMTX administration through 8 days post dose for each course of HDMTX
Population: The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Number of Ongoing AEs Per HDMTX Course | Course 1 (SOC) | 14 Number of AEs |
| Cohort 1 | Number of Ongoing AEs Per HDMTX Course | Course 2 (SOC) | 19 Number of AEs |
| Cohort 1 | Number of Ongoing AEs Per HDMTX Course | Course 1 (MOD) | 6 Number of AEs |
| Cohort 1 | Number of Ongoing AEs Per HDMTX Course | Course 2 (MOD) | 14 Number of AEs |
| Cohort 2 | Number of Ongoing AEs Per HDMTX Course | Course 2 (MOD) | 16 Number of AEs |
| Cohort 2 | Number of Ongoing AEs Per HDMTX Course | Course 1 (SOC) | 10 Number of AEs |
| Cohort 2 | Number of Ongoing AEs Per HDMTX Course | Course 1 (MOD) | 10 Number of AEs |
| Cohort 2 | Number of Ongoing AEs Per HDMTX Course | Course 2 (SOC) | 10 Number of AEs |
Primary
Number of Ongoing HDMTX Related AEs Per HDMTX Course
Characterization (frequency and severity grade) of toxicity reported for each course of HDMTX treatment with folate rescue therapy and continuing until eight (8) days after start of HDMTX administration, per NCI CTCAE v4.0 (Grade refers to the severity of the AE). The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE; Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening, and Grade 5 Death related to AE.
Time frame: From the start of HDMTX administration through 8 days post dose for each course of HDMTX
Population: The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Number of Ongoing HDMTX Related AEs Per HDMTX Course | Course 1 (SOC) | 13 Number of AEs |
| Cohort 1 | Number of Ongoing HDMTX Related AEs Per HDMTX Course | Course 2 (SOC) | 13 Number of AEs |
| Cohort 1 | Number of Ongoing HDMTX Related AEs Per HDMTX Course | Course 1 (MOD) | 5 Number of AEs |
| Cohort 1 | Number of Ongoing HDMTX Related AEs Per HDMTX Course | Course 2 (MOD) | 12 Number of AEs |
| Cohort 2 | Number of Ongoing HDMTX Related AEs Per HDMTX Course | Course 2 (MOD) | 16 Number of AEs |
| Cohort 2 | Number of Ongoing HDMTX Related AEs Per HDMTX Course | Course 1 (SOC) | 8 Number of AEs |
| Cohort 2 | Number of Ongoing HDMTX Related AEs Per HDMTX Course | Course 1 (MOD) | 10 Number of AEs |
| Cohort 2 | Number of Ongoing HDMTX Related AEs Per HDMTX Course | Course 2 (SOC) | 8 Number of AEs |
Secondary
Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD.
The severity of AEs have been done using NCI CTCAE v4.0. Total number of AEs per severity grade are presented for all AEs and for AEs related to MTX. For AEs related to MTX the number of AEs occurring per preferred term and severity grade are detailed.The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE; Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening, and Grade 5 Death related to AE.
Time frame: From the start of HDMTX administration through 8 days post dose for all 4 courses of HDMTX in total
Population: The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Drug clearance decreased (Related to MTX) Grade 1 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Anemia (Related to MTX) Grade 1 | 3 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Drug clearance decreased (Related to MTX) Grade 2 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Grade 3 (ALL AEs) | 11 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Drug clearance decreased (Related to MTX) Grade 3 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Drug clearance decreased (Related to MTX) Grade 4 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Anemia (Related to MTX) Grade 2 | 4 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Drug clearance decreased (Related to MTX) AnyGrade | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Diarrhoea (Related to MTX) Any Grade | 3 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Febrile neutropenia (Related to MTX) Grade 1 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Febrile neutropenia (Related to MTX) Grade 2 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Anemia (Related to MTX) Grade 3 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Febrile neutropenia (Related to MTX) Grade 3 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Febrile neutropenia (Related to MTX) Grade 4 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Grade 4 (ALL AEs) | 3 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Febrile neutropenia (Related to MTX) Any Grade | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Anemia (Related to MTX) Grade 4 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Headache (Related to MTX) Grade 1 | 1 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Neutrophil count decrease (Related to MTX) Grade 3 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Headache (Related to MTX) Grade 2 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Any Grade (ALL AEs) | 62 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Headache (Related to MTX) Grade 3 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | ASAT increased (Related to MTX) Grade 1 | 5 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Headache (Related to MTX) Grade 4 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Headache (Related to MTX) Any Grade | 1 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Nausea (Related to MTX) Grade 1 | 2 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | ASAT increased (Related to MTX) Grade 2 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Nausea (Related to MTX) Grade 2 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Grade 1 (AEs Related to MTX) | 25 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Nausea (Related to MTX) Grade 3 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | ASAT increased (Related to MTX) Grade 3 | 2 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Nausea (Related to MTX) Grade 4 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | ASAT increased (Related to MTX) Grade 4 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Nausea (Related to MTX) Any Grade | 2 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Pyrexia (Related to MTX) Grade 1 | 1 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Nephropathy (Related to MTX) Grade 3 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | ASAT increased (Related to MTX) Any Grade | 7 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Nephropathy (Related to MTX) Grade 4 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Grade 2 (AEs Related to MTX) | 6 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Nephropathy (Related to MTX) Any Grade | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Cheilitis (Related to MTX) Grade 1 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Neutropenia (Related to MTX) Grade 1 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | ALAT increase (Related to MTX) Grade 3 | 4 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Neutropenia (Related to MTX) Grade 2 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Cheilitis (Related to MTX) Grade 2 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Neutropenia (Related to MTX) Grade 3 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Grade 3 (AEs Related to MTX) | 6 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Neutropenia (Related to MTX) Grade 4 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Cheilitis (Related to MTX) Grade 3 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Neutropenia (Related to MTX) Any Grade | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | WBC count decreased (Related to MTX) Grade 3 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Neutrophil count decrease (Related to MTX) Grade 1 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Cheilitis (Related to MTX) Grade 4 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Grade 4 (AEs Related to MTX) | 1 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Neutrophil count decrease (Related to MTX) Grade 2 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Cheilitis (Related to MTX) Any Grade | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Convulsion (Related to MTX) Grade 1 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Neutrophil count decrease (Related to MTX) Grade 4 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Nephropathy (Related to MTX) Grade 1 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Neutrophil count decrease (Related to MTX)AnyGrade | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Convulsion (Related to MTX) Grade 2 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Pyrexia (Related to MTX) Grade 2 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Any Grade (AEs Related to MTX) | 38 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Pyrexia (Related to MTX) Grade 3 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Convulsion (Related to MTX) Grade 3 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Pyrexia (Related to MTX) Grade 4 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Grade 1 (ALL AEs) | 40 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Pyrexia (Related to MTX) Any Grade | 1 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Convulsion (Related to MTX) Grade 4 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Stomatitis (Related to MTX) Grade 1 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Stomatitis (Related to MTX) Grade 2 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | ALAT increase (Related to MTX) Grade 1 | 2 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Stomatitis (Related to MTX) Grade 3 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Convulsion (Related to MTX) Any Grade | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Stomatitis (Related to MTX) Grade 4 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | ALAT increase (Related to MTX) Grade 2 | 1 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Stomatitis (Related to MTX) Any Grade | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Diarrhoea (Related to MTX) Grade 1 | 2 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Vomiting (Related to MTX) Grade 1 | 9 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Anemia (Related to MTX) Any Grade | 7 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Vomiting (Related to MTX) Grade 2 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Diarrhoea (Related to MTX) Grade 2 | 1 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Vomiting (Related to MTX) Grade 3 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | ALAT increase (Related to MTX) Grade 4 | 1 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Vomiting (Related to MTX) Grade 4 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Diarrhoea (Related to MTX) Grade 3 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Vomiting (Related to MTX) Any Grade | 9 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Grade 2 (ALL AEs) | 8 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | WBC count decreased (Related to MTX) Grade 1 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Diarrhoea (Related to MTX) Grade 4 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | WBC count decreased (Related to MTX) Grade 2 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | WBC count decreased (Related to MTX) Grade 4 | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | ALAT increase (Related to MTX) Any Grade | 8 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | WBC count decreased (Related to MTX) Any Grade | 0 Number of AEs |
| Cohort 1 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Nephropathy (Related to MTX) Grade 21 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | WBC count decreased (Related to MTX) Any Grade | 1 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | ALAT increase (Related to MTX) Grade 3 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | ASAT increased (Related to MTX) Grade 3 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Cheilitis (Related to MTX) Any Grade | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Drug clearance decreased (Related to MTX) Grade 3 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Febrile neutropenia (Related to MTX) Grade 1 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Febrile neutropenia (Related to MTX) Grade 3 | 1 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Headache (Related to MTX) Any Grade | 1 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Nephropathy (Related to MTX) Grade 1 | 1 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Nephropathy (Related to MTX) Grade 21 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Neutrophil count decrease (Related to MTX)AnyGrade | 1 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | WBC count decreased (Related to MTX) Grade 2 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | WBC count decreased (Related to MTX) Grade 3 | 1 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Grade 1 (ALL AEs) | 27 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Grade 2 (ALL AEs) | 15 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Grade 3 (ALL AEs) | 6 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Grade 4 (ALL AEs) | 9 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Any Grade (ALL AEs) | 49 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Grade 1 (AEs Related to MTX) | 20 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Grade 2 (AEs Related to MTX) | 12 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Grade 3 (AEs Related to MTX) | 5 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Grade 4 (AEs Related to MTX) | 1 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Any Grade (AEs Related to MTX) | 38 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | ALAT increase (Related to MTX) Grade 2 | 3 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | ALAT increase (Related to MTX) Grade 4 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | ALAT increase (Related to MTX) Any Grade | 3 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Anemia (Related to MTX) Grade 1 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Anemia (Related to MTX) Grade 2 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Anemia (Related to MTX) Grade 3 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Anemia (Related to MTX) Grade 4 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Anemia (Related to MTX) Any Grade | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | ASAT increased (Related to MTX) Grade 1 | 2 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | ASAT increased (Related to MTX) Grade 2 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | ASAT increased (Related to MTX) Grade 4 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | ASAT increased (Related to MTX) Any Grade | 2 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Cheilitis (Related to MTX) Grade 1 | 1 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Cheilitis (Related to MTX) Grade 2 | 2 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Cheilitis (Related to MTX) Grade 3 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Cheilitis (Related to MTX) Grade 4 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Convulsion (Related to MTX) Grade 1 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Convulsion (Related to MTX) Grade 2 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Convulsion (Related to MTX) Grade 3 | 1 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Convulsion (Related to MTX) Grade 4 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Convulsion (Related to MTX) Any Grade | 1 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Diarrhoea (Related to MTX) Grade 1 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Diarrhoea (Related to MTX) Grade 2 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Diarrhoea (Related to MTX) Grade 3 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Diarrhoea (Related to MTX) Grade 4 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Diarrhoea (Related to MTX) Any Grade | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Drug clearance decreased (Related to MTX) Grade 1 | 1 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Drug clearance decreased (Related to MTX) Grade 2 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Drug clearance decreased (Related to MTX) Grade 4 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Drug clearance decreased (Related to MTX) AnyGrade | 1 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Febrile neutropenia (Related to MTX) Grade 2 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Febrile neutropenia (Related to MTX) Grade 4 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Febrile neutropenia (Related to MTX) Any Grade | 1 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Headache (Related to MTX) Grade 1 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Headache (Related to MTX) Grade 2 | 1 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Headache (Related to MTX) Grade 3 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Headache (Related to MTX) Grade 4 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Nausea (Related to MTX) Grade 1 | 4 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Nausea (Related to MTX) Grade 2 | 2 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Nausea (Related to MTX) Grade 3 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Nausea (Related to MTX) Grade 4 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Nausea (Related to MTX) Any Grade | 6 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Nephropathy (Related to MTX) Grade 3 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Nephropathy (Related to MTX) Grade 4 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Nephropathy (Related to MTX) Any Grade | 1 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Neutropenia (Related to MTX) Grade 1 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Neutropenia (Related to MTX) Grade 2 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Neutropenia (Related to MTX) Grade 3 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Neutropenia (Related to MTX) Grade 4 | 1 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Neutropenia (Related to MTX) Any Grade | 1 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Neutrophil count decrease (Related to MTX) Grade 1 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Stomatitis (Related to MTX) Grade 1 | 3 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Neutrophil count decrease (Related to MTX) Grade 2 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Neutrophil count decrease (Related to MTX) Grade 3 | 1 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Neutrophil count decrease (Related to MTX) Grade 4 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Pyrexia (Related to MTX) Grade 1 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Pyrexia (Related to MTX) Grade 2 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Pyrexia (Related to MTX) Grade 3 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Pyrexia (Related to MTX) Grade 4 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Pyrexia (Related to MTX) Any Grade | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Stomatitis (Related to MTX) Grade 2 | 2 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Stomatitis (Related to MTX) Grade 3 | 1 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Stomatitis (Related to MTX) Grade 4 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Stomatitis (Related to MTX) Any Grade | 6 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Vomiting (Related to MTX) Grade 1 | 8 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Vomiting (Related to MTX) Grade 2 | 2 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Vomiting (Related to MTX) Grade 3 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Vomiting (Related to MTX) Grade 4 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | Vomiting (Related to MTX) Any Grade | 10 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | WBC count decreased (Related to MTX) Grade 1 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | WBC count decreased (Related to MTX) Grade 4 | 0 Number of AEs |
| Cohort 2 | Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD. | ALAT increase (Related to MTX) Grade 1 | 0 Number of AEs |
Secondary
Number of Administered HDMTX Courses Classified as Having Met the Criteria for Successful Advancement According to Definition A and/or Definition B
Definition A: Successful advancement from 1st to 2nd HDMTX course within the same MAP cycle. Fulfilling all of the following criteria 8 days after start of first HDMTX course within the same MAP cycle: 1. Serum MTX: ≤0.1μmol/L 2. Neutrophils: ≥0.25x109/L 3. Platelets: ≥50x109/L 4. Serum bilirubin: ≤1.25 x upper limit of normal (ULN) 5. Glomerular filtration rate (GFR) ≥70 mL/min/1.73m2 6. No AE Grade 2 or more related to HDMTX hindering a potential HDMTX administration, at the discretion of the investigator Definition B: Successful advancement to next MAP cycle Fulfilling all of the following criteria 8 days after start of the second HDMTX course in previous MAP cycle: 1. Serum MTX: ≤0.1μmol/L 2. Neutrophils: ≥ 0.75 x 109/L 3. Platelets: ≥75x109/L 4. Serum bilirubin: ≤1.25xULN 5. GFR ≥70 mL/min/1.73m2 6. No AE Grade 2 or more related to HDMTX hindering a potential Adriamycin/Doxorubicin and Cisplatin (AP) administration, at the discretion of the investigator
Time frame: 8 days after start of first and/or second HDMTX course in a MAP cycle
Population: The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Number of Administered HDMTX Courses Classified as Having Met the Criteria for Successful Advancement According to Definition A and/or Definition B | Successful Course SOC 1 | 4 Number of courses |
| Cohort 1 | Number of Administered HDMTX Courses Classified as Having Met the Criteria for Successful Advancement According to Definition A and/or Definition B | Unsuccessful Course SOC 1 | 0 Number of courses |
| Cohort 1 | Number of Administered HDMTX Courses Classified as Having Met the Criteria for Successful Advancement According to Definition A and/or Definition B | Successful Course SOC 2 | 4 Number of courses |
| Cohort 1 | Number of Administered HDMTX Courses Classified as Having Met the Criteria for Successful Advancement According to Definition A and/or Definition B | Unsuccessful Course SOC 2 | 0 Number of courses |
| Cohort 1 | Number of Administered HDMTX Courses Classified as Having Met the Criteria for Successful Advancement According to Definition A and/or Definition B | Successful Course MOD 1 | 4 Number of courses |
| Cohort 1 | Number of Administered HDMTX Courses Classified as Having Met the Criteria for Successful Advancement According to Definition A and/or Definition B | Unsuccessful Course MOD 1 | 0 Number of courses |
| Cohort 1 | Number of Administered HDMTX Courses Classified as Having Met the Criteria for Successful Advancement According to Definition A and/or Definition B | Successful Course MOD 2 | 4 Number of courses |
| Cohort 1 | Number of Administered HDMTX Courses Classified as Having Met the Criteria for Successful Advancement According to Definition A and/or Definition B | Unsuccessful Course MOD 2 | 0 Number of courses |
| Cohort 2 | Number of Administered HDMTX Courses Classified as Having Met the Criteria for Successful Advancement According to Definition A and/or Definition B | Unsuccessful Course MOD 2 | 1 Number of courses |
| Cohort 2 | Number of Administered HDMTX Courses Classified as Having Met the Criteria for Successful Advancement According to Definition A and/or Definition B | Successful Course SOC 1 | 4 Number of courses |
| Cohort 2 | Number of Administered HDMTX Courses Classified as Having Met the Criteria for Successful Advancement According to Definition A and/or Definition B | Successful Course MOD 1 | 3 Number of courses |
| Cohort 2 | Number of Administered HDMTX Courses Classified as Having Met the Criteria for Successful Advancement According to Definition A and/or Definition B | Unsuccessful Course SOC 1 | 0 Number of courses |
| Cohort 2 | Number of Administered HDMTX Courses Classified as Having Met the Criteria for Successful Advancement According to Definition A and/or Definition B | Successful Course MOD 2 | 2 Number of courses |
| Cohort 2 | Number of Administered HDMTX Courses Classified as Having Met the Criteria for Successful Advancement According to Definition A and/or Definition B | Successful Course SOC 2 | 4 Number of courses |
| Cohort 2 | Number of Administered HDMTX Courses Classified as Having Met the Criteria for Successful Advancement According to Definition A and/or Definition B | Unsuccessful Course MOD 1 | 1 Number of courses |
| Cohort 2 | Number of Administered HDMTX Courses Classified as Having Met the Criteria for Successful Advancement According to Definition A and/or Definition B | Unsuccessful Course SOC 2 | 0 Number of courses |
Secondary
Number of Administered MAP Cycles Classified as Having Met the Criteria for Successful Advancement From First to Second HDMTX Course Within the Same MAP Cycle According to Definition A.
Definition A: Successful advancement from first to second HDMTX course within the same MAP cycle Fulfilling all of the following criteria 8 days after start of first HDMTX course within the same MAP cycle: 1. Serum MTX: ≤ 0.1 μmol/L 2. Neutrophils: ≥ 0.25 x 109/L 3. Platelets: ≥ 50 x 109/L 4. Serum bilirubin: ≤ 1.25 x ULN 5. GFR ≥ 70 mL/min/1.73 m2 6. No AE Grade 2 or more (NCI CTCAE v4.0) related to HDMTX hindering a potential HDMTX administration, at the discretion of the investigator
Time frame: 8 days after start of first HDMTX course in a MAP cycle
Population: The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Number of Administered MAP Cycles Classified as Having Met the Criteria for Successful Advancement From First to Second HDMTX Course Within the Same MAP Cycle According to Definition A. | Successful Course MOD 1 | 4 Number of courses |
| Cohort 1 | Number of Administered MAP Cycles Classified as Having Met the Criteria for Successful Advancement From First to Second HDMTX Course Within the Same MAP Cycle According to Definition A. | Unsuccessful Course SOC 1 | 0 Number of courses |
| Cohort 1 | Number of Administered MAP Cycles Classified as Having Met the Criteria for Successful Advancement From First to Second HDMTX Course Within the Same MAP Cycle According to Definition A. | Unsuccessful Course MOD 1 | 0 Number of courses |
| Cohort 1 | Number of Administered MAP Cycles Classified as Having Met the Criteria for Successful Advancement From First to Second HDMTX Course Within the Same MAP Cycle According to Definition A. | Successful Course SOC 1 | 4 Number of courses |
| Cohort 2 | Number of Administered MAP Cycles Classified as Having Met the Criteria for Successful Advancement From First to Second HDMTX Course Within the Same MAP Cycle According to Definition A. | Unsuccessful Course MOD 1 | 1 Number of courses |
| Cohort 2 | Number of Administered MAP Cycles Classified as Having Met the Criteria for Successful Advancement From First to Second HDMTX Course Within the Same MAP Cycle According to Definition A. | Unsuccessful Course SOC 1 | 0 Number of courses |
| Cohort 2 | Number of Administered MAP Cycles Classified as Having Met the Criteria for Successful Advancement From First to Second HDMTX Course Within the Same MAP Cycle According to Definition A. | Successful Course MOD 1 | 3 Number of courses |
| Cohort 2 | Number of Administered MAP Cycles Classified as Having Met the Criteria for Successful Advancement From First to Second HDMTX Course Within the Same MAP Cycle According to Definition A. | Successful Course SOC 1 | 4 Number of courses |
Secondary
Number of Administered MAP Cycles Classified as Having Met the Criteria for Successful Advancement to Next MAP Cycle According to Definition B.
Definition B: Successful advancement to next MAP cycle Fulfilling all of the following criteria 8 days after start of the second HDMTX course in previous MAP cycle: 1. Serum MTX: ≤ 0.1 μmol/L 2. Neutrophils: ≥ 0.75 x 109/L 3. Platelets: ≥ 75 x 109/L 4. Serum bilirubin: ≤ 1.25 x ULN 5. GFR ≥ 70 mL/min/1.73 m2 6. No AE Grade 2 or more (NCI CTCAE v4.0) related to HDMTX hindering a potential Adriamycin/Doxorubicin and Cisplatin (AP) administration, at the discretion of the investigator
Time frame: 8 days after start of second HDMTX course in a MAP cycle
Population: The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Number of Administered MAP Cycles Classified as Having Met the Criteria for Successful Advancement to Next MAP Cycle According to Definition B. | Successful Course SOC 2 | 4 Number of courses |
| Cohort 1 | Number of Administered MAP Cycles Classified as Having Met the Criteria for Successful Advancement to Next MAP Cycle According to Definition B. | Unsuccessful Course SOC 2 | 0 Number of courses |
| Cohort 1 | Number of Administered MAP Cycles Classified as Having Met the Criteria for Successful Advancement to Next MAP Cycle According to Definition B. | Successful Course MOD 2 | 4 Number of courses |
| Cohort 1 | Number of Administered MAP Cycles Classified as Having Met the Criteria for Successful Advancement to Next MAP Cycle According to Definition B. | Unsuccessful Course MOD 2 | 0 Number of courses |
| Cohort 2 | Number of Administered MAP Cycles Classified as Having Met the Criteria for Successful Advancement to Next MAP Cycle According to Definition B. | Unsuccessful Course MOD 2 | 1 Number of courses |
| Cohort 2 | Number of Administered MAP Cycles Classified as Having Met the Criteria for Successful Advancement to Next MAP Cycle According to Definition B. | Successful Course SOC 2 | 4 Number of courses |
| Cohort 2 | Number of Administered MAP Cycles Classified as Having Met the Criteria for Successful Advancement to Next MAP Cycle According to Definition B. | Successful Course MOD 2 | 2 Number of courses |
| Cohort 2 | Number of Administered MAP Cycles Classified as Having Met the Criteria for Successful Advancement to Next MAP Cycle According to Definition B. | Unsuccessful Course SOC 2 | 0 Number of courses |
Secondary
Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions
The MTX-toxicity management instructions provided in the protocol are based on the Children's Oncology Group (COG) treatment management recommendations used in study protocol AOST0331, EURAMOS 1. The COG recommend changes in the hydration and the rescue frequency and/or dose to be done if pre-specified toxicities of different severity grades occur.
Time frame: Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L
Population: The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade B (24h) MOD 2 | 1 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade A2 (72h) SOC 2 | 1 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade B (72h) SOC 1 | 0 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | None (72h) MOD 2 | 2 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade A2 (24h) SOC 1 | 2 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade A2 (24h) SOC 2 | 2 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade A2 (24h) MOD 1 | 1 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade A2 (24h) MOD 2 | 2 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade B (24h) SOC 1 | 1 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade B (24h) SOC 2 | 0 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade B (24h) MOD 1 | 1 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | None (24h) SOC 1 | 1 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | None (24h) SOC 2 | 2 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | None (24h) MOD 1 | 2 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | None (24h) MOD 2 | 1 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade A2 (48h) SOC 1 | 1 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade A2 (48h) SOC 2 | 1 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade A2 (48h) MOD 1 | 2 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade A2 (48h) MOD 2 | 2 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade B (48h) SOC 1 | 1 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade B (48h) SOC 2 | 0 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade B (48h) MOD 1 | 0 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade B (48h) MOD 2 | 0 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | None (48h) SOC 1 | 2 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | None (48h) SOC 2 | 3 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | None (48h) MOD 1 | 2 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | None (48h) MOD 2 | 2 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade A1 (72h) SOC 1 | 2 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade A1 (72h) SOC 2 | 2 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade A1 (72h) MOD 1 | 1 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade A1 (72h) MOD 2 | 2 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade A2 (72h) SOC 1 | 1 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade A2 (72h) MOD 1 | 1 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade A2 (72h) MOD 2 | 0 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade B (72h) SOC 2 | 0 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade B (72h) MOD 1 | 0 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade B (72h) MOD 2 | 0 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | None (72h) SOC 1 | 1 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | None (72h) SOC 2 | 1 Number of MTX excretion toxicities |
| Cohort 1 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | None (72h) MOD 1 | 2 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | None (72h) SOC 1 | 4 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade B (48h) SOC 2 | 0 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade A2 (72h) MOD 2 | 0 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade A1 (72h) MOD 2 | 0 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade B (48h) MOD 1 | 0 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | None (72h) MOD 2 | 2 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade B (72h) MOD 1 | 0 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade A2 (24h) SOC 1 | 2 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade B (48h) MOD 2 | 1 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade A2 (24h) SOC 2 | 2 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade A2 (72h) SOC 2 | 0 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade A2 (24h) MOD 1 | 3 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | None (48h) SOC 1 | 2 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade A2 (24h) MOD 2 | 1 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | None (72h) MOD 1 | 3 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade B (24h) SOC 1 | 0 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | None (48h) SOC 2 | 3 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade B (24h) SOC 2 | 0 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade A2 (72h) MOD 1 | 0 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade B (24h) MOD 1 | 0 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade A2 (72h) SOC 1 | 0 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade B (24h) MOD 2 | 1 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | None (48h) MOD 1 | 2 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | None (24h) SOC 1 | 2 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade B (72h) MOD 2 | 1 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | None (24h) SOC 2 | 2 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | None (48h) MOD 2 | 1 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | None (24h) MOD 1 | 1 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade B (72h) SOC 1 | 0 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | None (24h) MOD 2 | 1 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade A1 (72h) SOC 1 | 0 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade A2 (48h) SOC 1 | 2 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | None (72h) SOC 2 | 3 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade A2 (48h) SOC 2 | 1 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade A1 (72h) SOC 2 | 1 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade A2 (48h) MOD 1 | 2 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade B (72h) SOC 2 | 0 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade A2 (48h) MOD 2 | 1 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade A1 (72h) MOD 1 | 1 Number of MTX excretion toxicities |
| Cohort 2 | Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions | Grade B (48h) SOC 1 | 0 Number of MTX excretion toxicities |
Secondary
Number of HDMTX Courses in Which the Initial Hydration Was Increased
Time frame: Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L
Population: The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Number of HDMTX Courses in Which the Initial Hydration Was Increased | Hydration change in Course SOC 1 | 2 HDMTX courses |
| Cohort 1 | Number of HDMTX Courses in Which the Initial Hydration Was Increased | Unchanged hydration Course SOC 1 | 2 HDMTX courses |
| Cohort 1 | Number of HDMTX Courses in Which the Initial Hydration Was Increased | Hydration change in Course SOC 2 | 1 HDMTX courses |
| Cohort 1 | Number of HDMTX Courses in Which the Initial Hydration Was Increased | Unchanged hydration Course SOC 2 | 3 HDMTX courses |
| Cohort 1 | Number of HDMTX Courses in Which the Initial Hydration Was Increased | Hydration change in Course MOD 1 | 2 HDMTX courses |
| Cohort 1 | Number of HDMTX Courses in Which the Initial Hydration Was Increased | Unchanged hydration Course MOD 1 | 2 HDMTX courses |
| Cohort 1 | Number of HDMTX Courses in Which the Initial Hydration Was Increased | Hydration change in course MOD 2 | 2 HDMTX courses |
| Cohort 1 | Number of HDMTX Courses in Which the Initial Hydration Was Increased | Unchanged hydration Course MOD 2 | 2 HDMTX courses |
| Cohort 2 | Number of HDMTX Courses in Which the Initial Hydration Was Increased | Unchanged hydration Course MOD 2 | 2 HDMTX courses |
| Cohort 2 | Number of HDMTX Courses in Which the Initial Hydration Was Increased | Hydration change in Course SOC 1 | 0 HDMTX courses |
| Cohort 2 | Number of HDMTX Courses in Which the Initial Hydration Was Increased | Hydration change in Course MOD 1 | 2 HDMTX courses |
| Cohort 2 | Number of HDMTX Courses in Which the Initial Hydration Was Increased | Unchanged hydration Course SOC 1 | 4 HDMTX courses |
| Cohort 2 | Number of HDMTX Courses in Which the Initial Hydration Was Increased | Hydration change in course MOD 2 | 1 HDMTX courses |
| Cohort 2 | Number of HDMTX Courses in Which the Initial Hydration Was Increased | Hydration change in Course SOC 2 | 0 HDMTX courses |
| Cohort 2 | Number of HDMTX Courses in Which the Initial Hydration Was Increased | Unchanged hydration Course MOD 1 | 2 HDMTX courses |
| Cohort 2 | Number of HDMTX Courses in Which the Initial Hydration Was Increased | Unchanged hydration Course SOC 2 | 4 HDMTX courses |
Secondary
Number of HDMTX Courses With Delayed Early MTX Elimination (Definition E).
Definition E: Delayed early MTX elimination (according to US label for Calcium Folinate) S-MTX levels of: * 50 μmol/L at 24 hours after start of MTX administration, OR * 5 μmol/L at 48 hours after start of MTX administration OR An increase in S-Creatinine level of 100% or greater at 24 hours after start of MTX administration.
Time frame: Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L
Population: The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Number of HDMTX Courses With Delayed Early MTX Elimination (Definition E). | Delayed early MTX elimination in Course MOD 1 | 0 Number of courses |
| Cohort 1 | Number of HDMTX Courses With Delayed Early MTX Elimination (Definition E). | Undelayed early MTX elimination in Course SOC 1 | 4 Number of courses |
| Cohort 1 | Number of HDMTX Courses With Delayed Early MTX Elimination (Definition E). | Undelayed early MTX elimination in Course MOD 1 | 4 Number of courses |
| Cohort 1 | Number of HDMTX Courses With Delayed Early MTX Elimination (Definition E). | Delayed early MTX elimination in Course SOC 1 | 0 Number of courses |
| Cohort 1 | Number of HDMTX Courses With Delayed Early MTX Elimination (Definition E). | Delayed early MTX elimination in Course MOD 2 | 0 Number of courses |
| Cohort 1 | Number of HDMTX Courses With Delayed Early MTX Elimination (Definition E). | Delayed early MTX elimination in Course SOC 2 | 0 Number of courses |
| Cohort 1 | Number of HDMTX Courses With Delayed Early MTX Elimination (Definition E). | Undelayed early MTX elimination in Course MOD 2 | 4 Number of courses |
| Cohort 1 | Number of HDMTX Courses With Delayed Early MTX Elimination (Definition E). | Undelayed early MTX elimination in Course SOC 2 | 4 Number of courses |
| Cohort 2 | Number of HDMTX Courses With Delayed Early MTX Elimination (Definition E). | Undelayed early MTX elimination in Course MOD 2 | 3 Number of courses |
| Cohort 2 | Number of HDMTX Courses With Delayed Early MTX Elimination (Definition E). | Delayed early MTX elimination in Course SOC 1 | 0 Number of courses |
| Cohort 2 | Number of HDMTX Courses With Delayed Early MTX Elimination (Definition E). | Undelayed early MTX elimination in Course SOC 1 | 4 Number of courses |
| Cohort 2 | Number of HDMTX Courses With Delayed Early MTX Elimination (Definition E). | Undelayed early MTX elimination in Course SOC 2 | 4 Number of courses |
| Cohort 2 | Number of HDMTX Courses With Delayed Early MTX Elimination (Definition E). | Delayed early MTX elimination in Course MOD 1 | 0 Number of courses |
| Cohort 2 | Number of HDMTX Courses With Delayed Early MTX Elimination (Definition E). | Undelayed early MTX elimination in Course MOD 1 | 4 Number of courses |
| Cohort 2 | Number of HDMTX Courses With Delayed Early MTX Elimination (Definition E). | Delayed early MTX elimination in Course MOD 2 | 0 Number of courses |
| Cohort 2 | Number of HDMTX Courses With Delayed Early MTX Elimination (Definition E). | Delayed early MTX elimination in Course SOC 2 | 0 Number of courses |
Secondary
Number of HDMTX Courses With Delayed Late MTX Elimination (Definition F).
Definition F: Delayed late MTX elimination (according to US label for Calcium Folinate) S-MTX level: \> 0.2 μmol/L at 72 hours AND \> 0.1 μmol/L at 96 hours after start of MTX administration.
Time frame: Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L
Population: The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Number of HDMTX Courses With Delayed Late MTX Elimination (Definition F). | Delayed late MTX elimination in Course SOC 1 | 0 Number of courses |
| Cohort 1 | Number of HDMTX Courses With Delayed Late MTX Elimination (Definition F). | Undelayed late MTX elimination in Course SOC 1 | 3 Number of courses |
| Cohort 1 | Number of HDMTX Courses With Delayed Late MTX Elimination (Definition F). | Delayed late MTX elimination in Course SOC 2 | 0 Number of courses |
| Cohort 1 | Number of HDMTX Courses With Delayed Late MTX Elimination (Definition F). | Undelayed late MTX elimination in Course SOC 2 | 3 Number of courses |
| Cohort 1 | Number of HDMTX Courses With Delayed Late MTX Elimination (Definition F). | Delayed late MTX elimination in Course MOD 1 | 0 Number of courses |
| Cohort 1 | Number of HDMTX Courses With Delayed Late MTX Elimination (Definition F). | Undelayed late MTX elimination in Course MOD 1 | 2 Number of courses |
| Cohort 1 | Number of HDMTX Courses With Delayed Late MTX Elimination (Definition F). | Delayed late MTX elimination in Course MOD 2 | 0 Number of courses |
| Cohort 1 | Number of HDMTX Courses With Delayed Late MTX Elimination (Definition F). | Undelayed late MTX elimination in Course MOD 2 | 2 Number of courses |
| Cohort 2 | Number of HDMTX Courses With Delayed Late MTX Elimination (Definition F). | Undelayed late MTX elimination in Course MOD 2 | 0 Number of courses |
| Cohort 2 | Number of HDMTX Courses With Delayed Late MTX Elimination (Definition F). | Delayed late MTX elimination in Course SOC 1 | 0 Number of courses |
| Cohort 2 | Number of HDMTX Courses With Delayed Late MTX Elimination (Definition F). | Delayed late MTX elimination in Course MOD 1 | 0 Number of courses |
| Cohort 2 | Number of HDMTX Courses With Delayed Late MTX Elimination (Definition F). | Undelayed late MTX elimination in Course SOC 1 | 1 Number of courses |
| Cohort 2 | Number of HDMTX Courses With Delayed Late MTX Elimination (Definition F). | Delayed late MTX elimination in Course MOD 2 | 1 Number of courses |
| Cohort 2 | Number of HDMTX Courses With Delayed Late MTX Elimination (Definition F). | Delayed late MTX elimination in Course SOC 2 | 0 Number of courses |
| Cohort 2 | Number of HDMTX Courses With Delayed Late MTX Elimination (Definition F). | Undelayed late MTX elimination in Course MOD 1 | 1 Number of courses |
| Cohort 2 | Number of HDMTX Courses With Delayed Late MTX Elimination (Definition F). | Undelayed late MTX elimination in Course SOC 2 | 1 Number of courses |
Secondary
Number of HDMTX Courses With Delayed MTX Elimination (Definition D).
Definition D: Delayed MTX elimination (according to COGs excretion toxicity management instructions) S-MTX levels of: \> 10 μmol/L at 24 h after start of MTX administration, OR \> 1 μmol/L at 48 h after start of MTX administration, OR \> 0.1 μmol/L at 72 h after start of MTX administration or later
Time frame: Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L
Population: The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Number of HDMTX Courses With Delayed MTX Elimination (Definition D). | Delayed MTX elimination in Course SOC 1 | 3 Number of courses |
| Cohort 1 | Number of HDMTX Courses With Delayed MTX Elimination (Definition D). | Undelayed MTX elimination in Course SOC 1 | 1 Number of courses |
| Cohort 1 | Number of HDMTX Courses With Delayed MTX Elimination (Definition D). | Delayed MTX elimination in Course SOC 2 | 3 Number of courses |
| Cohort 1 | Number of HDMTX Courses With Delayed MTX Elimination (Definition D). | Undelayed MTX elimination in Course SOC 2 | 1 Number of courses |
| Cohort 1 | Number of HDMTX Courses With Delayed MTX Elimination (Definition D). | Delayed MTX elimination in Course MOD 1 | 2 Number of courses |
| Cohort 1 | Number of HDMTX Courses With Delayed MTX Elimination (Definition D). | Undelayed MTX elimination in Course MOD 1 | 2 Number of courses |
| Cohort 1 | Number of HDMTX Courses With Delayed MTX Elimination (Definition D). | Delayed MTX elimination in Course MOD 2 | 2 Number of courses |
| Cohort 1 | Number of HDMTX Courses With Delayed MTX Elimination (Definition D). | Undelayed MTX elimination in Course MOD 2 | 2 Number of courses |
| Cohort 2 | Number of HDMTX Courses With Delayed MTX Elimination (Definition D). | Undelayed MTX elimination in Course MOD 2 | 2 Number of courses |
| Cohort 2 | Number of HDMTX Courses With Delayed MTX Elimination (Definition D). | Delayed MTX elimination in Course SOC 1 | 0 Number of courses |
| Cohort 2 | Number of HDMTX Courses With Delayed MTX Elimination (Definition D). | Delayed MTX elimination in Course MOD 1 | 1 Number of courses |
| Cohort 2 | Number of HDMTX Courses With Delayed MTX Elimination (Definition D). | Undelayed MTX elimination in Course SOC 1 | 4 Number of courses |
| Cohort 2 | Number of HDMTX Courses With Delayed MTX Elimination (Definition D). | Delayed MTX elimination in Course MOD 2 | 1 Number of courses |
| Cohort 2 | Number of HDMTX Courses With Delayed MTX Elimination (Definition D). | Delayed MTX elimination in Course SOC 2 | 1 Number of courses |
| Cohort 2 | Number of HDMTX Courses With Delayed MTX Elimination (Definition D). | Undelayed MTX elimination in Course MOD 1 | 3 Number of courses |
| Cohort 2 | Number of HDMTX Courses With Delayed MTX Elimination (Definition D). | Undelayed MTX elimination in Course SOC 2 | 3 Number of courses |
Secondary
Time to Successful MTX Elimination (Definition C)
Definition C: Time to successful MTX elimination = Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L
Time frame: Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L
Population: The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Time to Successful MTX Elimination (Definition C) | Time (h) Course SOC 1 | 84.52 hours | Standard Deviation 15 |
| Cohort 1 | Time to Successful MTX Elimination (Definition C) | Time (h) Course SOC 2 | 77.0 hours | Standard Deviation 19.6 |
| Cohort 1 | Time to Successful MTX Elimination (Definition C) | Time (h) Course MOD 1 | 74.00 hours | Standard Deviation 15.87 |
| Cohort 1 | Time to Successful MTX Elimination (Definition C) | Time (h) Course MOD 2 | 72.50 hours | Standard Deviation 15.78 |
| Cohort 2 | Time to Successful MTX Elimination (Definition C) | Time (h) Course MOD 2 | 88.0 hours | Standard Deviation 43.41 |
| Cohort 2 | Time to Successful MTX Elimination (Definition C) | Time (h) Course SOC 1 | 62.75 hours | Standard Deviation 3.21 |
| Cohort 2 | Time to Successful MTX Elimination (Definition C) | Time (h) Course MOD 1 | 65.75 hours | Standard Deviation 11.5 |
| Cohort 2 | Time to Successful MTX Elimination (Definition C) | Time (h) Course SOC 2 | 62.75 hours | Standard Deviation 9.91 |