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Trial record 4 of 13 for:    "Bone Osteosarcoma" | "Bone Density Conservation Agents"

Investigation of [6R] 5,10-methylenetetrahydrofolate as Rescue Therapy for Osteosarcoma Patients Treated With HDMTX.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01987102
Recruitment Status : Completed
First Posted : November 19, 2013
Results First Posted : June 26, 2019
Last Update Posted : June 26, 2019
Sponsor:
Information provided by (Responsible Party):
Isofol Medical AB

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Sequential Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Osteosarcoma
Interventions Drug: Calcium Folinate
Drug: [6R] 5,10-methylenetetrahydrofolate
Enrollment 18
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.
Pre-assignment Details  
Arm/Group Title Cohort 1 Cohort 2
Hide Arm/Group Description

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.

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.

Period Title: 2 Courses of HDMTX With SOC Rescue
Started 8 10
Completed 4 4
Not Completed 4 6
Reason Not Completed
Adverse Event             2             2
Laboratory abnormality             1             2
Change in planned chemotherapy             1             0
Protocol Violation             0             1
Incorrectly included             0             1
Period Title: 2 Courses of HDMTX With MOD Rescue
Started 4 4
Completed 4 3
Not Completed 0 1
Reason Not Completed
Adverse Event             0             1
Arm/Group Title Cohort 1 Cohort 2 Total
Hide Arm/Group Description

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.

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.

Total of all reporting groups
Overall Number of Baseline Participants 8 10 18
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 8 participants 10 participants 18 participants
<=18 years
8
 100.0%
8
  80.0%
16
  88.9%
Between 18 and 65 years
0
   0.0%
2
  20.0%
2
  11.1%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 8 participants 10 participants 18 participants
Female
1
  12.5%
2
  20.0%
3
  16.7%
Male
7
  87.5%
8
  80.0%
15
  83.3%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 8 participants 10 participants 18 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
0
   0.0%
0
   0.0%
White
8
 100.0%
10
 100.0%
18
 100.0%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 8 participants 10 participants 18 participants
Sweden
0
   0.0%
1
  10.0%
1
   5.6%
Hungary
2
  25.0%
1
  10.0%
3
  16.7%
Czechia
5
  62.5%
6
  60.0%
11
  61.1%
Poland
1
  12.5%
2
  20.0%
3
  16.7%
1.Primary Outcome
Title Number of AEs Per Severity (All Courses)
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD).
Arm/Group Title Cohort 1 Cohort 2
Hide Arm/Group Description:

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.

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)

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.

Overall Number of Participants Analyzed 4 4
Measure Type: Number
Unit of Measure: Number of AEs
Grade 1 40 27
Grade 2 8 15
Grade 3 11 6
Grade 4 3 1
2.Primary Outcome
Title Number of HDMTX Related AEs Per Severity (All Courses)
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD).
Arm/Group Title Cohort 1 Cohort 2
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 4 4
Measure Type: Number
Unit of Measure: Number of AEs
Grade 1 25 20
Grade 2 6 12
Grade 3 6 5
Grade 4 1 1
3.Primary Outcome
Title Number of Ongoing AEs Per HDMTX Course
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD).
Arm/Group Title Cohort 1 Cohort 2
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 4 4
Measure Type: Number
Unit of Measure: Number of AEs
Course 1 (SOC) 14 10
Course 2 (SOC) 19 10
Course 1 (MOD) 6 10
Course 2 (MOD) 14 16
4.Primary Outcome
Title Number of Ongoing HDMTX Related AEs Per HDMTX Course
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD).
Arm/Group Title Cohort 1 Cohort 2
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 4 4
Measure Type: Number
Unit of Measure: Number of AEs
Course 1 (SOC) 13 8
Course 2 (SOC) 13 8
Course 1 (MOD) 5 10
Course 2 (MOD) 12 16
5.Secondary Outcome
Title Number of Administered HDMTX Courses Classified as Having Met the Criteria for Successful Advancement According to Definition A and/or Definition B
Hide 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:

  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
Hide Outcome Measure Data
Hide Analysis Population Description
The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD).
Arm/Group Title Cohort 1 Cohort 2
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 4 4
Measure Type: Number
Unit of Measure: Number of courses
Successful Course SOC 1 4 4
Unsuccessful Course SOC 1 0 0
Successful Course SOC 2 4 4
Unsuccessful Course SOC 2 0 0
Successful Course MOD 1 4 3
Unsuccessful Course MOD 1 0 1
Successful Course MOD 2 4 2
Unsuccessful Course MOD 2 0 1
6.Secondary Outcome
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.
Hide 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:

  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
Hide Outcome Measure Data
Hide Analysis Population Description
The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD).
Arm/Group Title Cohort 1 Cohort 2
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 4 4
Measure Type: Number
Unit of Measure: Number of courses
Successful Course SOC 1 4 4
Unsuccessful Course SOC 1 0 0
Successful Course MOD 1 4 3
Unsuccessful Course MOD 1 0 1
7.Secondary Outcome
Title Number of Administered MAP Cycles Classified as Having Met the Criteria for Successful Advancement to Next MAP Cycle According to Definition B.
Hide 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:

  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
Hide Outcome Measure Data
Hide Analysis Population Description
The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD).
Arm/Group Title Cohort 1 Cohort 2
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 4 4
Measure Type: Number
Unit of Measure: Number of courses
Successful Course SOC 2 4 4
Unsuccessful Course SOC 2 0 0
Successful Course MOD 2 4 2
Unsuccessful Course MOD 2 0 1
8.Secondary Outcome
Title Time to Successful MTX Elimination (Definition C)
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD).
Arm/Group Title Cohort 1 Cohort 2
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 4 4
Mean (Standard Deviation)
Unit of Measure: hours
Time (h) Course SOC 1 84.52  (15.00) 62.75  (3.21)
Time (h) Course SOC 2 77.0  (19.60) 62.75  (9.91)
Time (h) Course MOD 1 74.00  (15.87) 65.75  (11.50)
Time (h) Course MOD 2 72.50  (15.78) 88.0  (43.41)
9.Secondary Outcome
Title Number of HDMTX Courses in Which the Initial Hydration Was Increased
Hide Description [Not Specified]
Time Frame Time from start of MTX treatment until serum MTX level is ≤ 0.1 μmol/L
Hide Outcome Measure Data
Hide Analysis Population Description
The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD).
Arm/Group Title Cohort 1 Cohort 2
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 4 4
Measure Type: Number
Unit of Measure: HDMTX courses
Hydration change in Course SOC 1 2 0
Unchanged hydration Course SOC 1 2 4
Hydration change in Course SOC 2 1 0
Unchanged hydration Course SOC 2 3 4
Hydration change in Course MOD 1 2 2
Unchanged hydration Course MOD 1 2 2
Hydration change in course MOD 2 2 1
Unchanged hydration Course MOD 2 2 2
10.Secondary Outcome
Title Number of HDMTX Courses With Delayed MTX Elimination (Definition D).
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD).
Arm/Group Title Cohort 1 Cohort 2
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 4 4
Measure Type: Number
Unit of Measure: Number of courses
Delayed MTX elimination in Course SOC 1 3 0
Undelayed MTX elimination in Course SOC 1 1 4
Delayed MTX elimination in Course SOC 2 3 1
Undelayed MTX elimination in Course SOC 2 1 3
Delayed MTX elimination in Course MOD 1 2 1
Undelayed MTX elimination in Course MOD 1 2 3
Delayed MTX elimination in Course MOD 2 2 1
Undelayed MTX elimination in Course MOD 2 2 2
11.Secondary Outcome
Title Number of HDMTX Courses With Delayed Early MTX Elimination (Definition E).
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD).
Arm/Group Title Cohort 1 Cohort 2
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 4 4
Measure Type: Number
Unit of Measure: Number of courses
Delayed early MTX elimination in Course SOC 1 0 0
Undelayed early MTX elimination in Course SOC 1 4 4
Delayed early MTX elimination in Course SOC 2 0 0
Undelayed early MTX elimination in Course SOC 2 4 4
Delayed early MTX elimination in Course MOD 1 0 0
Undelayed early MTX elimination in Course MOD 1 4 4
Delayed early MTX elimination in Course MOD 2 0 0
Undelayed early MTX elimination in Course MOD 2 4 3
12.Secondary Outcome
Title Number of HDMTX Courses With Delayed Late MTX Elimination (Definition F).
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD).
Arm/Group Title Cohort 1 Cohort 2
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 4 4
Measure Type: Number
Unit of Measure: Number of courses
Delayed late MTX elimination in Course SOC 1 0 0
Undelayed late MTX elimination in Course SOC 1 3 1
Delayed late MTX elimination in Course SOC 2 0 0
Undelayed late MTX elimination in Course SOC 2 3 1
Delayed late MTX elimination in Course MOD 1 0 0
Undelayed late MTX elimination in Course MOD 1 2 1
Delayed late MTX elimination in Course MOD 2 0 1
Undelayed late MTX elimination in Course MOD 2 2 0
13.Secondary Outcome
Title Number of Grade A1, Grade A2, Grade B, Grade C, or Grade D Excretion Toxicities as Listed in the MTX-toxicity Management Instructions
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD).
Arm/Group Title Cohort 1 Cohort 2
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 4 4
Measure Type: Number
Unit of Measure: Number of MTX excretion toxicities
Grade A2 (24h) SOC 1 2 2
Grade A2 (24h) SOC 2 2 2
Grade A2 (24h) MOD 1 1 3
Grade A2 (24h) MOD 2 2 1
Grade B (24h) SOC 1 1 0
Grade B (24h) SOC 2 0 0
Grade B (24h) MOD 1 1 0
Grade B (24h) MOD 2 1 1
None (24h) SOC 1 1 2
None (24h) SOC 2 2 2
None (24h) MOD 1 2 1
None (24h) MOD 2 1 1
Grade A2 (48h) SOC 1 1 2
Grade A2 (48h) SOC 2 1 1
Grade A2 (48h) MOD 1 2 2
Grade A2 (48h) MOD 2 2 1
Grade B (48h) SOC 1 1 0
Grade B (48h) SOC 2 0 0
Grade B (48h) MOD 1 0 0
Grade B (48h) MOD 2 0 1
None (48h) SOC 1 2 2
None (48h) SOC 2 3 3
None (48h) MOD 1 2 2
None (48h) MOD 2 2 1
Grade A1 (72h) SOC 1 2 0
Grade A1 (72h) SOC 2 2 1
Grade A1 (72h) MOD 1 1 1
Grade A1 (72h) MOD 2 2 0
Grade A2 (72h) SOC 1 1 0
Grade A2 (72h) SOC 2 1 0
Grade A2 (72h) MOD 1 1 0
Grade A2 (72h) MOD 2 0 0
Grade B (72h) SOC 1 0 0
Grade B (72h) SOC 2 0 0
Grade B (72h) MOD 1 0 0
Grade B (72h) MOD 2 0 1
None (72h) SOC 1 1 4
None (72h) SOC 2 1 3
None (72h) MOD 1 2 3
None (72h) MOD 2 2 2
14.Secondary Outcome
Title Characterization (Number/Severity) of All Reported AEs During the ENTIRE STUDY PERIOD.
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
The All Patients Treated Set (APTS) included all patients receiving at least one bolus injection of Modufolin (MOD).
Arm/Group Title Cohort 1 Cohort 2
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 4 4
Measure Type: Number
Unit of Measure: Number of AEs
Grade 1 (ALL AEs) 40 27
Grade 2 (ALL AEs) 8 15
Grade 3 (ALL AEs) 11 6
Grade 4 (ALL AEs) 3 9
Any Grade (ALL AEs) 62 49
Grade 1 (AEs Related to MTX) 25 20
Grade 2 (AEs Related to MTX) 6 12
Grade 3 (AEs Related to MTX) 6 5
Grade 4 (AEs Related to MTX) 1 1
Any Grade (AEs Related to MTX) 38 38
ALAT increase (Related to MTX) Grade 1 2 0
ALAT increase (Related to MTX) Grade 2 1 3
ALAT increase (Related to MTX) Grade 3 4 0
ALAT increase (Related to MTX) Grade 4 1 0
ALAT increase (Related to MTX) Any Grade 8 3
Anemia (Related to MTX) Grade 1 3 0
Anemia (Related to MTX) Grade 2 4 0
Anemia (Related to MTX) Grade 3 0 0
Anemia (Related to MTX) Grade 4 0 0
Anemia (Related to MTX) Any Grade 7 0
ASAT increased (Related to MTX) Grade 1 5 2
ASAT increased (Related to MTX) Grade 2 0 0
ASAT increased (Related to MTX) Grade 3 2 0
ASAT increased (Related to MTX) Grade 4 0 0
ASAT increased (Related to MTX) Any Grade 7 2
Cheilitis (Related to MTX) Grade 1 0 1
Cheilitis (Related to MTX) Grade 2 0 2
Cheilitis (Related to MTX) Grade 3 0 0
Cheilitis (Related to MTX) Grade 4 0 0
Cheilitis (Related to MTX) Any Grade 0 0
Convulsion (Related to MTX) Grade 1 0 0
Convulsion (Related to MTX) Grade 2 0 0
Convulsion (Related to MTX) Grade 3 0 1
Convulsion (Related to MTX) Grade 4 0 0
Convulsion (Related to MTX) Any Grade 0 1
Diarrhoea (Related to MTX) Grade 1 2 0
Diarrhoea (Related to MTX) Grade 2 1 0
Diarrhoea (Related to MTX) Grade 3 0 0
Diarrhoea (Related to MTX) Grade 4 0 0
Diarrhoea (Related to MTX) Any Grade 3 0
Drug clearance decreased (Related to MTX) Grade 1 0 1
Drug clearance decreased (Related to MTX) Grade 2 0 0
Drug clearance decreased (Related to MTX) Grade 3 0 0
Drug clearance decreased (Related to MTX) Grade 4 0 0
Drug clearance decreased (Related to MTX) AnyGrade 0 1
Febrile neutropenia (Related to MTX) Grade 1 0 0
Febrile neutropenia (Related to MTX) Grade 2 0 0
Febrile neutropenia (Related to MTX) Grade 3 0 1
Febrile neutropenia (Related to MTX) Grade 4 0 0
Febrile neutropenia (Related to MTX) Any Grade 0 1
Headache (Related to MTX) Grade 1 1 0
Headache (Related to MTX) Grade 2 0 1
Headache (Related to MTX) Grade 3 0 0
Headache (Related to MTX) Grade 4 0 0
Headache (Related to MTX) Any Grade 1 1
Nausea (Related to MTX) Grade 1 2 4
Nausea (Related to MTX) Grade 2 0 2
Nausea (Related to MTX) Grade 3 0 0
Nausea (Related to MTX) Grade 4 0 0
Nausea (Related to MTX) Any Grade 2 6
Nephropathy (Related to MTX) Grade 1 0 1
Nephropathy (Related to MTX) Grade 21 0 0
Nephropathy (Related to MTX) Grade 3 0 0
Nephropathy (Related to MTX) Grade 4 0 0
Nephropathy (Related to MTX) Any Grade 0 1
Neutropenia (Related to MTX) Grade 1 0 0
Neutropenia (Related to MTX) Grade 2 0 0
Neutropenia (Related to MTX) Grade 3 0 0
Neutropenia (Related to MTX) Grade 4 0 1
Neutropenia (Related to MTX) Any Grade 0 1
Neutrophil count decrease (Related to MTX) Grade 1 0 0
Neutrophil count decrease (Related to MTX) Grade 2 0 0
Neutrophil count decrease (Related to MTX) Grade 3 0 1
Neutrophil count decrease (Related to MTX) Grade 4 0 0
Neutrophil count decrease (Related to MTX)AnyGrade 0 1
Pyrexia (Related to MTX) Grade 1 1 0
Pyrexia (Related to MTX) Grade 2 0 0
Pyrexia (Related to MTX) Grade 3 0 0
Pyrexia (Related to MTX) Grade 4 0 0
Pyrexia (Related to MTX) Any Grade 1 0
Stomatitis (Related to MTX) Grade 1 0 3
Stomatitis (Related to MTX) Grade 2 0 2
Stomatitis (Related to MTX) Grade 3 0 1
Stomatitis (Related to MTX) Grade 4 0 0
Stomatitis (Related to MTX) Any Grade 0 6
Vomiting (Related to MTX) Grade 1 9 8
Vomiting (Related to MTX) Grade 2 0 2
Vomiting (Related to MTX) Grade 3 0 0
Vomiting (Related to MTX) Grade 4 0 0
Vomiting (Related to MTX) Any Grade 9 10
WBC count decreased (Related to MTX) Grade 1 0 0
WBC count decreased (Related to MTX) Grade 2 0 0
WBC count decreased (Related to MTX) Grade 3 0 1
WBC count decreased (Related to MTX) Grade 4 0 0
WBC count decreased (Related to MTX) Any Grade 0 1
Time Frame 3 years, 1 month
Adverse Event Reporting Description The time-frame for reporting adverse events: From the start of HDMTX administration through 8 days post dose for each course of HDMTX.
 
Arm/Group Title Cohort 1 Cohort 2
Hide Arm/Group Description

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.

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.

All-Cause Mortality
Cohort 1 Cohort 2
Affected / at Risk (%) Affected / at Risk (%)
Total   0/8 (0.00%)      0/10 (0.00%)    
Show Serious Adverse Events Hide Serious Adverse Events
Cohort 1 Cohort 2
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   2/8 (25.00%)      3/10 (30.00%)    
Blood and lymphatic system disorders     
Febrile neutropenia  1  1/8 (12.50%)  1 1/10 (10.00%)  1
General disorders     
Mucosal inflammation  1  0/8 (0.00%)  0 1/10 (10.00%)  1
Infections and infestations     
Candida sepsis  1  1/8 (12.50%)  1 0/10 (0.00%)  0
Neutropenic sepsis  1  0/8 (0.00%)  0 1/10 (10.00%)  1
Investigations     
Platelet count decreased  1  1/8 (12.50%)  3 0/10 (0.00%)  0
Nervous system disorders     
Convulsion  1  0/8 (0.00%)  0 1/10 (10.00%)  1
1
Term from vocabulary, MedDRA 17.0
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Cohort 1 Cohort 2
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   4/8 (50.00%)      4/10 (40.00%)    
Blood and lymphatic system disorders     
Anaemia  1  1/8 (12.50%)  9 0/10 (0.00%)  0
Neutropenia  1  0/8 (0.00%)  0 1/10 (10.00%)  1
Cardiac disorders     
Left ventricular dysfunction  1  1/8 (12.50%)  1 0/10 (0.00%)  0
Gastrointestinal disorders     
Diarrhoea  1  2/8 (25.00%)  4 0/10 (0.00%)  0
Nausea  1  2/8 (25.00%)  2 3/10 (30.00%)  7
Stomatitis  1  2/8 (25.00%)  2 2/10 (20.00%)  4
Vomiting  1  4/8 (50.00%)  14 4/10 (40.00%)  13
General disorders     
Localised oedema  1  0/8 (0.00%)  0 1/10 (10.00%)  1
Mucosal inflammation  1  0/8 (0.00%)  0 2/10 (20.00%)  3
Pyrexia  1  2/8 (25.00%)  2 0/10 (0.00%)  0
Infections and infestations     
Bacterial disease carrier  1  1/8 (12.50%)  1 0/10 (0.00%)  0
Cheilitis  1  0/8 (0.00%)  0 1/10 (10.00%)  3
Conjunctivitis  1  0/8 (0.00%)  0 1/10 (10.00%)  1
Nasopharyngitis  1  0/8 (0.00%)  0 1/10 (10.00%)  1
Investigations     
Alanine aminotransferase increased  1  2/8 (25.00%)  8 1/10 (10.00%)  3
Aspartate aminotransferase increased  1  2/8 (25.00%)  7 1/10 (10.00%)  2
Drug clearance decreased  1  0/8 (0.00%)  0 1/10 (10.00%)  1
Neutrophil count decreased  1  0/8 (0.00%)  0 1/10 (10.00%)  1
Platelet count decreased  1  1/8 (12.50%)  1 0/10 (0.00%)  0
White blood cell count decreased  1  1/8 (12.50%)  2 1/4 (25.00%)  1
Musculoskeletal and connective tissue disorders     
Muscle spasms  1  1/8 (12.50%)  1 0/10 (0.00%)  0
Nervous system disorders     
Headache  1  2/8 (25.00%)  2 1/10 (10.00%)  1
Renal and urinary disorders     
Nephropathy  1  0/8 (0.00%)  0 1/10 (10.00%)  1
Respiratory, thoracic and mediastinal disorders     
Cough  1  0/8 (0.00%)  0 1/10 (10.00%)  1
Epistaxis  1  1/8 (12.50%)  1 0/10 (0.00%)  0
1
Term from vocabulary, MedDRA 17.0
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Chief Medical Officer
Organization: Isofol Medical AB
Phone: +46 (0)702433750
EMail: karin.ganlov@isofolmedical.com
Layout table for additonal information
Responsible Party: Isofol Medical AB
ClinicalTrials.gov Identifier: NCT01987102     History of Changes
Other Study ID Numbers: ISO-MTX-003
First Submitted: November 5, 2013
First Posted: November 19, 2013
Results First Submitted: November 14, 2018
Results First Posted: June 26, 2019
Last Update Posted: June 26, 2019