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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
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cohort 1 | Experimental | 1 MAP cycle (incl. 2 HDMTX Courses using Calcium Folinate rescue 15mg/m2) 1 MAP cycle (incl. 2 HDMTX Courses using [6R] 5,10-methylenetetrahydrofolate rescue 15mg/m2) |
|
| Cohort 2 | Experimental | 1 MAP cycle (incl. 2 HDMTX Courses using Calcium Folinate rescue 15mg/m2) 1 MAP cycle (incl. 2 HDMTX Courses using [6R] 5,10-methylenetetrahydrofolate rescue 7,5mg/m2 or 30mg/m2*) *Dose will depend on outcome from Cohort 1 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Calcium Folinate | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | From the start of HDMTX administration through 8 days post dose for each course of HDMTX in total |
| 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. | From the start of HDMTX administration through 8 days post dose for each course of HDMTX in total |
| 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. | From the start of HDMTX administration through 8 days post dose for each course of HDMTX |
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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:
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:
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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.
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:
Main Inclusion criteria for continuation (HDMTX treatment with Modufolin rescue):
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| Name | Affiliation | Role |
|---|---|---|
| Mikael Eriksson, MD PhD | Department of Oncology, Skåne University Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Fakultnà nemocnice Brno Klinika detske onkologie | Brno | 62500 | Czechia | |||
| Fakultnà nemocnice v Motole |
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| 2 Courses of HDMTX With SOC Rescue |
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| [6R] 5,10-methylenetetrahydrofolate (arfolitixorin) | Drug | 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. |
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| From the start of HDMTX administration through 8 days post dose for each course of HDMTX |
| 8 days after start of first and/or second HDMTX course in a MAP cycle |
| 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:
| 8 days after start of first HDMTX course in a MAP cycle |
| 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:
| 8 days after start of second HDMTX course in a MAP cycle |
| 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 from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L |
| 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). | 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 from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L |
| 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:
| Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L |
| 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 from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L |
| 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 from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L |
| 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. | From the start of HDMTX administration through 8 days post dose for all 4 courses of HDMTX in total |
| Prague |
| 15006 |
| Czechia |
| Semmelweis Egyetem II. Sz. Gyermekgyógyászati Klinika | Budapest | 1094 | Hungary |
| Instytut Matki i Dziecka | Warsaw | 01-211 | Poland |
| Department of Oncology, Skåne University Hospital | Lund | 22185 | Sweden |
| FG001 | 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. |
| COMPLETED |
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| NOT COMPLETED |
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| 2 Courses of HDMTX With MOD Rescue |
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | 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. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD). | Posted | Number | Number of AEs | From the start of HDMTX administration through 8 days post dose for each course of HDMTX in total |
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| 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. | The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD). | Posted | Number | Number of AEs | From the start of HDMTX administration through 8 days post dose for each course of HDMTX in total |
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| 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. | The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD). | Posted | Number | Number of AEs | From the start of HDMTX administration through 8 days post dose for each course of HDMTX |
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| 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. | The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD). | Posted | Number | Number of AEs | From the start of HDMTX administration through 8 days post dose for each course of HDMTX |
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| 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:
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:
| The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD). | Posted | Number | Number of courses | 8 days after start of first and/or second HDMTX course in a MAP cycle |
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| 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:
| The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD). | Posted | Number | Number of courses | 8 days after start of first HDMTX course in a MAP cycle |
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| 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:
| The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD). | Posted | Number | Number of courses | 8 days after start of second HDMTX course in a MAP cycle |
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| 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 | The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD). | Posted | Mean | Standard Deviation | hours | Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L |
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| Secondary | Number of HDMTX Courses in Which the Initial Hydration Was Increased | The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD). | Posted | Number | HDMTX courses | Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L |
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| 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 | The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD). | Posted | Number | Number of courses | Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L |
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| 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:
| The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD). | Posted | Number | Number of courses | Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L |
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| 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. | The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD). | Posted | Number | Number of courses | Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L |
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| 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. | The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD). | Posted | Number | Number of MTX excretion toxicities | Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L |
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| 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. | The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD). | Posted | Number | Number of AEs | From the start of HDMTX administration through 8 days post dose for all 4 courses of HDMTX in total |
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3 years, 1 month
The time-frame for reporting adverse events: From the start of HDMTX administration through 8 days post dose for each course of HDMTX.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Cohort 1 | 1 MAP cycle (incl. 2 HDMTX courses with SOC rescue 15mg/m2) 1 MAP cycle (incl. 2 HDMTX courses with MOD rescue 15mg/m2) SOC was administered as rescue in the 2 first HDMTX courses and MOD in the 2 following courses. 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. | 0 | 8 | 2 | 8 | 4 | 8 |
| EG001 | Cohort 2 | 1 MAP cycle (incl. 2 HDMTX courses with SOC rescue 15mg/m2) 1 MAP cycle (incl. 2 HDMTX courses with MOD rescue 7.5mg/m2) SOC was administered as rescue in the 2 first HDMTX courses and MOD in the 2 following courses. 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. | 0 | 10 | 3 | 10 | 4 | 10 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Platelet count decreased | Investigations | MedDRA 17.0 | Systematic Assessment |
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| Febrile neutropenia | Blood and lymphatic system disorders | MedDRA 17.0 | Systematic Assessment |
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| Convulsion | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
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| Mucosal inflammation | General disorders | MedDRA 17.0 | Systematic Assessment |
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| Candida sepsis | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
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| Neutropenic sepsis | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Alanine aminotransferase increased | Investigations | MedDRA 17.0 | Systematic Assessment |
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| Aspartate aminotransferase increased | Investigations | MedDRA 17.0 | Systematic Assessment |
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| Drug clearance decreased | Investigations | MedDRA 17.0 | Systematic Assessment |
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| Neutrophil count decreased | Investigations | MedDRA 17.0 | Systematic Assessment |
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| Platelet count decreased | Investigations | MedDRA 17.0 | Systematic Assessment |
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| White blood cell count decreased | Investigations | MedDRA 17.0 | Systematic Assessment |
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| Left ventricular dysfunction | Cardiac disorders | MedDRA 17.0 | Systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Epistaxis | Respiratory, thoracic and mediastinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Anaemia | Blood and lymphatic system disorders | MedDRA 17.0 | Systematic Assessment |
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| Neutropenia | Blood and lymphatic system disorders | MedDRA 17.0 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
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| Localised oedema | General disorders | MedDRA 17.0 | Systematic Assessment |
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| Mucosal inflammation | General disorders | MedDRA 17.0 | Systematic Assessment |
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| Pyrexia | General disorders | MedDRA 17.0 | Systematic Assessment |
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| Diarrhoea | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Stomatitis | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Vomiting | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Nephropathy | Renal and urinary disorders | MedDRA 17.0 | Systematic Assessment |
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| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
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| Bacterial disease carrier | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
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| Cheilitis | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
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| Conjunctivitis | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
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| Nasopharyngitis | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
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At least 30 d prior to submission the PI shall provide the Sponsor with results communication for review. The Sponsor shall notify the PI in writing about the review outcome within 30 d from receipt. No public release shall be made unless the Sponsor has consented in writing. The Sponsor may notify the PI that the material shall be withhold from submission for 90 days more to allow filing of applications to secure IPR or to take such measures to establish and preserve its proprietary rights.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Chief Medical Officer | Isofol Medical AB | +46 (0)702433750 | karin.ganlov@isofolmedical.com |
| ID | Term |
|---|---|
| D012516 | Osteosarcoma |
| ID | Term |
|---|---|
| D018213 | Neoplasms, Bone Tissue |
| D009372 | Neoplasms, Connective Tissue |
| D018204 | Neoplasms, Connective and Soft Tissue |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D012509 | Sarcoma |
Not provided
Not provided
| ID | Term |
|---|---|
| D002955 | Leucovorin |
| C013123 | 5,10-methylenetetrahydrofolic acid |
| ID | Term |
|---|---|
| D005575 | Formyltetrahydrofolates |
| D013763 | Tetrahydrofolates |
| D005492 | Folic Acid |
| D011622 | Pterins |
| D011621 | Pteridines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D003067 | Coenzymes |
| D045762 | Enzymes and Coenzymes |
Not provided
Not provided
| >=65 years |
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| Male |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| Hungary |
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| Czechia |
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| Poland |
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| Grade 3 |
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| Grade 4 |
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| OG001 | 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. |
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