Back to resultsInvestigation of [6R] 5,10-methylenetetrahydrofolate (Arfolitixorin) as Rescue Therapy for Osteosarcoma Patients Treated With HDMTX.
Primary Purpose
Osteosarcoma
Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Calcium Folinate
[6R] 5,10-methylenetetrahydrofolate (arfolitixorin)
Sponsored by
About this trial
This is an interventional treatment trial for Osteosarcoma focused on measuring Methotrexate, Rescue treatment
Eligibility 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.
- Serum MTX: ≤0.1μmol/L
- Neutrophils: ≥0.25x109/L
- Platelets: ≥50x109/L
- Serum bilirubin: ≤1.25x upper limit of normal (ULN)
- Glomerular filtration rate (GFR) ≥70 mL/min/1.73m2
- 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.
Sites / Locations
- Fakultní nemocnice Brno Klinika detske onkologie
- Fakultní nemocnice v Motole
- Semmelweis Egyetem II. Sz. Gyermekgyógyászati Klinika
- Instytut Matki i Dziecka
- Department of Oncology, Skåne University Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Cohort 1
Cohort 2
Arm Description
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)
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
Outcomes
Primary Outcome Measures
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.
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.
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.
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.
Secondary Outcome Measures
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:
Serum MTX: ≤0.1μmol/L
Neutrophils: ≥0.25x109/L
Platelets: ≥50x109/L
Serum bilirubin: ≤1.25 x upper limit of normal (ULN)
Glomerular filtration rate (GFR) ≥70 mL/min/1.73m2
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:
Serum MTX: ≤0.1μmol/L
Neutrophils: ≥ 0.75 x 109/L
Platelets: ≥75x109/L
Serum bilirubin: ≤1.25xULN
GFR ≥70 mL/min/1.73m2
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 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:
Serum MTX: ≤ 0.1 μmol/L
Neutrophils: ≥ 0.25 x 109/L
Platelets: ≥ 50 x 109/L
Serum bilirubin: ≤ 1.25 x ULN
GFR ≥ 70 mL/min/1.73 m2
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.
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:
Serum MTX: ≤ 0.1 μmol/L
Neutrophils: ≥ 0.75 x 109/L
Platelets: ≥ 75 x 109/L
Serum bilirubin: ≤ 1.25 x ULN
GFR ≥ 70 mL/min/1.73 m2
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)
Definition C: Time to successful MTX elimination = 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
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
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.
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.
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.
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01987102
Brief Title
Investigation of [6R] 5,10-methylenetetrahydrofolate (Arfolitixorin) as Rescue Therapy for Osteosarcoma Patients Treated With HDMTX.
Official Title
An Open-Label, Multicenter, Phase I/II Clinical Trial to Identify the Modufolin® Dose With Most Favorable Safety Prospect and Confirmed Ability to Mitigate High-Dose Methotrexate Induced Toxicity During Treatment of Osteosarcoma Patients
Study Type
Interventional
2. Study Status
Record Verification Date
September 2020
Overall Recruitment Status
Completed
Study Start Date
December 2013 (Actual)
Primary Completion Date
January 3, 2017 (Actual)
Study Completion Date
January 3, 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Isofol Medical AB
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Osteosarcoma
Keywords
Methotrexate, Rescue treatment
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
18 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Cohort 1
Arm Type
Experimental
Arm Description
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)
Arm Title
Cohort 2
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Calcium Folinate
Other Intervention Name(s)
Leucovorin
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
[6R] 5,10-methylenetetrahydrofolate (arfolitixorin)
Other Intervention Name(s)
Modufolin, arfolitixorin
Intervention Description
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.
Primary Outcome Measure Information:
Title
Number of AEs Per Severity (All Courses)
Description
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
Title
Number of HDMTX Related AEs Per Severity (All Courses)
Description
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
Title
Number of Ongoing AEs Per HDMTX Course
Description
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
Title
Number of Ongoing HDMTX Related AEs Per HDMTX Course
Description
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
Secondary Outcome Measure Information:
Title
Number of Administered HDMTX Courses Classified as Having Met the Criteria for Successful Advancement According to Definition A and/or Definition B
Description
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:
Serum MTX: ≤0.1μmol/L
Neutrophils: ≥0.25x109/L
Platelets: ≥50x109/L
Serum bilirubin: ≤1.25 x upper limit of normal (ULN)
Glomerular filtration rate (GFR) ≥70 mL/min/1.73m2
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:
Serum MTX: ≤0.1μmol/L
Neutrophils: ≥ 0.75 x 109/L
Platelets: ≥75x109/L
Serum bilirubin: ≤1.25xULN
GFR ≥70 mL/min/1.73m2
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
Title
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.
Description
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:
Serum MTX: ≤ 0.1 μmol/L
Neutrophils: ≥ 0.25 x 109/L
Platelets: ≥ 50 x 109/L
Serum bilirubin: ≤ 1.25 x ULN
GFR ≥ 70 mL/min/1.73 m2
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
Title
Number of Administered MAP Cycles Classified as Having Met the Criteria for Successful Advancement to Next MAP Cycle According to Definition B.
Description
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:
Serum MTX: ≤ 0.1 μmol/L
Neutrophils: ≥ 0.75 x 109/L
Platelets: ≥ 75 x 109/L
Serum bilirubin: ≤ 1.25 x ULN
GFR ≥ 70 mL/min/1.73 m2
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
Title
Time to Successful MTX Elimination (Definition C)
Description
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
Title
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
Title
Number of HDMTX Courses With Delayed MTX Elimination (Definition D).
Description
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
Title
Number of HDMTX Courses With Delayed Early MTX Elimination (Definition E).
Description
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
Title
Number of HDMTX Courses With Delayed Late MTX Elimination (Definition F).
Description
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
Title
Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions
Description
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
Title
Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD.
Description
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
10. Eligibility
Sex
All
Minimum Age & Unit of Time
6 Years
Maximum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Serum MTX: ≤0.1μmol/L
Neutrophils: ≥0.25x109/L
Platelets: ≥50x109/L
Serum bilirubin: ≤1.25x upper limit of normal (ULN)
Glomerular filtration rate (GFR) ≥70 mL/min/1.73m2
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mikael Eriksson, MD PhD
Organizational Affiliation
Department of Oncology, Skåne University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Fakultní nemocnice Brno Klinika detske onkologie
City
Brno
ZIP/Postal Code
62500
Country
Czechia
Facility Name
Fakultní nemocnice v Motole
City
Prague
ZIP/Postal Code
15006
Country
Czechia
Facility Name
Semmelweis Egyetem II. Sz. Gyermekgyógyászati Klinika
City
Budapest
ZIP/Postal Code
1094
Country
Hungary
Facility Name
Instytut Matki i Dziecka
City
Warszawa
ZIP/Postal Code
01-211
Country
Poland
Facility Name
Department of Oncology, Skåne University Hospital
City
Lund
ZIP/Postal Code
22185
Country
Sweden
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Investigation of [6R] 5,10-methylenetetrahydrofolate (Arfolitixorin) as Rescue Therapy for Osteosarcoma Patients Treated With HDMTX.
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