Trial Outcomes & Findings for Open-label Leucovorin Pharmacokinetic Study in Patients Receiving High Dose Methotrexate With or Without Voraxaze (NCT NCT00634504)
NCT ID: NCT00634504
Last Updated: 2022-06-06
Results Overview
Geometric mean (6S)-leucovorin area under the plasma concentration vs. time curve from time 0 to the 3-hour time point.
Recruitment status
COMPLETED
Study phase
PHASE1
Target enrollment
20 participants
Primary outcome timeframe
5 minutes, 30 minutes, 1 hour, 2 hours and 3 hours post-LV administration
Results posted on
2022-06-06
Participant Flow
Participant milestones
| Measure |
A (High-dose Methotrexate, Leucovorin, and Glucarpidase)
Drug: High-dose methotrexate (HDMTX) and leucovorin (LV) with a single bolus intravenous injection of 50 units/kg glucarpidase over 5 minutes.
HDMTX followed by intravenous LV administered at doses recommended in the clinical treatment protocols.
LV doses administered as recommended in the package insert for Leucovorin Calcium USP for patients with delayed early MTX elimination and/or evidence of acute renal injury, and should be based upon the pre-glucarpidase MTX concentration. LV doses are maintained for at least 48 hours after dosing with glucarpidase. After this it may be administered at doses recommended in the clinical treatment protocols and existing labeling for LV based on post-Voraxaze MTX concentrations. Patients required IV LV rescue therapy with either ≥15 mg or ≥10 mg/m2 every 6 hours.
Other Names:
Voraxaze, carboxypeptidase G2, high dose methotrexate, leucovorin
|
B (High-dose Methotrexate and Leucovorin Without Glucarpidase)
High-dose methotrexate (HDMTX) and leucovorin (LV) without glucarpidase
HDMTX followed by intravenous LV should be administered at doses recommended in the clinical treatment protocols and as per standard of care. LV should be given every 6 hours at a dose of ≤25 mg/m2.
|
|---|---|---|
|
Overall Study
STARTED
|
11
|
9
|
|
Overall Study
COMPLETED
|
10
|
9
|
|
Overall Study
NOT COMPLETED
|
1
|
0
|
Reasons for withdrawal
| Measure |
A (High-dose Methotrexate, Leucovorin, and Glucarpidase)
Drug: High-dose methotrexate (HDMTX) and leucovorin (LV) with a single bolus intravenous injection of 50 units/kg glucarpidase over 5 minutes.
HDMTX followed by intravenous LV administered at doses recommended in the clinical treatment protocols.
LV doses administered as recommended in the package insert for Leucovorin Calcium USP for patients with delayed early MTX elimination and/or evidence of acute renal injury, and should be based upon the pre-glucarpidase MTX concentration. LV doses are maintained for at least 48 hours after dosing with glucarpidase. After this it may be administered at doses recommended in the clinical treatment protocols and existing labeling for LV based on post-Voraxaze MTX concentrations. Patients required IV LV rescue therapy with either ≥15 mg or ≥10 mg/m2 every 6 hours.
Other Names:
Voraxaze, carboxypeptidase G2, high dose methotrexate, leucovorin
|
B (High-dose Methotrexate and Leucovorin Without Glucarpidase)
High-dose methotrexate (HDMTX) and leucovorin (LV) without glucarpidase
HDMTX followed by intravenous LV should be administered at doses recommended in the clinical treatment protocols and as per standard of care. LV should be given every 6 hours at a dose of ≤25 mg/m2.
|
|---|---|---|
|
Overall Study
Protocol Violation
|
1
|
0
|
Baseline Characteristics
Open-label Leucovorin Pharmacokinetic Study in Patients Receiving High Dose Methotrexate With or Without Voraxaze
Baseline characteristics by cohort
| Measure |
A (High-dose Methotrexate, Leucovorin, and Glucarpidase)
n=11 Participants
High-dose methotrexate, leucovorin, and glucarpidase
glucarpidase, high-dose methotrexate, leucovorin: single intravenous dose
|
B (High-dose Methotrexate and Leucovorin Without Glucarpidase)
n=9 Participants
High-dose methotrexate and leucovorin without glucarpidase
high-dose methotrexate, leucovorin: standard of care, leucovorin every 6 hours
|
Total
n=20 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Continuous
|
26.4 years
STANDARD_DEVIATION 22.07 • n=5 Participants
|
12.6 years
STANDARD_DEVIATION 7.84 • n=7 Participants
|
20.2 years
STANDARD_DEVIATION 18.22 • n=5 Participants
|
|
Sex: Female, Male
Female
|
5 Participants
n=5 Participants
|
2 Participants
n=7 Participants
|
7 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
6 Participants
n=5 Participants
|
7 Participants
n=7 Participants
|
13 Participants
n=5 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
2 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
2 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Asian
|
1 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
1 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Black or African American
|
1 Participants
n=5 Participants
|
1 Participants
n=7 Participants
|
2 Participants
n=5 Participants
|
|
Race (NIH/OMB)
White
|
6 Participants
n=5 Participants
|
7 Participants
n=7 Participants
|
13 Participants
n=5 Participants
|
|
Race (NIH/OMB)
More than one race
|
1 Participants
n=5 Participants
|
1 Participants
n=7 Participants
|
2 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Pre-glucarpidase (Arm A) or Pre-LV (Arm B) methotrexate plasma conc (umol/L)
|
34.58 micromol/L
STANDARD_DEVIATION 48.59 • n=5 Participants
|
6.49 micromol/L
STANDARD_DEVIATION 11.00 • n=7 Participants
|
21.94 micromol/L
STANDARD_DEVIATION 21.94 • n=5 Participants
|
PRIMARY outcome
Timeframe: 5 minutes, 30 minutes, 1 hour, 2 hours and 3 hours post-LV administrationPopulation: 3 participants were excluded from the PK population (all from Arm A), hence why the total participants is 17, not 20.
Geometric mean (6S)-leucovorin area under the plasma concentration vs. time curve from time 0 to the 3-hour time point.
Outcome measures
| Measure |
A (High-dose Methotrexate, Leucovorin, and Glucarpidase)
n=8 Participants
High-dose methotrexate, leucovorin, and glucarpidase
glucarpidase, high-dose methotrexate, leucovorin: single intravenous dose
|
B (High-dose Methotrexate and Leucovorin Without Glucarpidase)
n=9 Participants
High-dose methotrexate and leucovorin without glucarpidase
high-dose methotrexate, leucovorin: standard of care, leucovorin every 6 hours
|
|---|---|---|
|
Pharmacokinetics (PK) of Leucovorin
|
6.43 micromol x hour/L
Interval 2.89 to 14.32
|
1.13 micromol x hour/L
Interval 0.72 to 1.75
|
Adverse Events
A (High-dose Methotrexate, Leucovorin, and Glucarpidase)
Serious events: 3 serious events
Other events: 7 other events
Deaths: 0 deaths
B (High-dose Methotrexate and Leucovorin Without Glucarpidase)
Serious events: 0 serious events
Other events: 0 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
A (High-dose Methotrexate, Leucovorin, and Glucarpidase)
n=11 participants at risk
High-dose methotrexate, leucovorin, and glucarpidase
glucarpidase, high-dose methotrexate, leucovorin: single intravenous dose
|
B (High-dose Methotrexate and Leucovorin Without Glucarpidase)
n=9 participants at risk
High-dose methotrexate and leucovorin without glucarpidase
high-dose methotrexate, leucovorin: standard of care, leucovorin every 6 hours
|
|---|---|---|
|
Renal and urinary disorders
renal failure
|
9.1%
1/11 • Number of events 1
|
0.00%
0/9
|
|
Blood and lymphatic system disorders
febrile neutropenia
|
9.1%
1/11 • Number of events 1
|
0.00%
0/9
|
|
Hepatobiliary disorders
hepatic failure
|
9.1%
1/11 • Number of events 1
|
0.00%
0/9
|
Other adverse events
| Measure |
A (High-dose Methotrexate, Leucovorin, and Glucarpidase)
n=11 participants at risk
High-dose methotrexate, leucovorin, and glucarpidase
glucarpidase, high-dose methotrexate, leucovorin: single intravenous dose
|
B (High-dose Methotrexate and Leucovorin Without Glucarpidase)
n=9 participants at risk
High-dose methotrexate and leucovorin without glucarpidase
high-dose methotrexate, leucovorin: standard of care, leucovorin every 6 hours
|
|---|---|---|
|
Blood and lymphatic system disorders
neutropenia
|
36.4%
4/11 • Number of events 4
|
0.00%
0/9
|
|
Blood and lymphatic system disorders
leukopenia
|
27.3%
3/11 • Number of events 3
|
0.00%
0/9
|
|
Blood and lymphatic system disorders
febrile neutropenia
|
18.2%
2/11 • Number of events 2
|
0.00%
0/9
|
|
Blood and lymphatic system disorders
thrombocytopenia
|
18.2%
2/11 • Number of events 2
|
0.00%
0/9
|
|
Blood and lymphatic system disorders
lymphopenia
|
9.1%
1/11 • Number of events 1
|
0.00%
0/9
|
|
Vascular disorders
hypertension
|
27.3%
3/11 • Number of events 3
|
0.00%
0/9
|
|
Vascular disorders
flushing
|
9.1%
1/11 • Number of events 1
|
0.00%
0/9
|
|
Investigations
hemoglobin decreased
|
18.2%
2/11 • Number of events 2
|
0.00%
0/9
|
|
Investigations
ALT increased
|
9.1%
1/11 • Number of events 1
|
0.00%
0/9
|
|
Investigations
AST increased
|
9.1%
1/11 • Number of events 1
|
0.00%
0/9
|
|
Investigations
serum creatinine increased
|
9.1%
1/11 • Number of events 1
|
0.00%
0/9
|
|
Metabolism and nutrition disorders
hypocalcemia
|
18.2%
2/11 • Number of events 2
|
0.00%
0/9
|
|
Metabolism and nutrition disorders
hypokalemia
|
18.2%
2/11 • Number of events 2
|
0.00%
0/9
|
|
Metabolism and nutrition disorders
acidosis
|
9.1%
1/11 • Number of events 1
|
0.00%
0/9
|
|
Metabolism and nutrition disorders
hyperglycemia
|
9.1%
1/11 • Number of events 1
|
0.00%
0/9
|
|
Metabolism and nutrition disorders
hyperkalemia
|
9.1%
1/11 • Number of events 1
|
0.00%
0/9
|
|
Metabolism and nutrition disorders
hypomagnesmia
|
9.1%
1/11 • Number of events 1
|
0.00%
0/9
|
|
Metabolism and nutrition disorders
hyponatremia
|
9.1%
1/11 • Number of events 1
|
0.00%
0/9
|
|
Metabolism and nutrition disorders
hypophosphatemia
|
9.1%
1/11 • Number of events 1
|
0.00%
0/9
|
|
Gastrointestinal disorders
abdominal pain lower
|
9.1%
1/11 • Number of events 1
|
0.00%
0/9
|
|
Gastrointestinal disorders
diarrhea
|
9.1%
1/11 • Number of events 1
|
0.00%
0/9
|
|
Gastrointestinal disorders
nausea
|
9.1%
1/11 • Number of events 1
|
0.00%
0/9
|
|
Gastrointestinal disorders
oral pain
|
9.1%
1/11 • Number of events 1
|
0.00%
0/9
|
|
Gastrointestinal disorders
vomiting
|
9.1%
1/11 • Number of events 1
|
0.00%
0/9
|
|
General disorders
mucosal inflammation
|
18.2%
2/11 • Number of events 2
|
0.00%
0/9
|
|
General disorders
pyrexia
|
9.1%
1/11 • Number of events 1
|
0.00%
0/9
|
|
Nervous system disorders
burning sensation
|
9.1%
1/11 • Number of events 1
|
0.00%
0/9
|
|
Nervous system disorders
hypoesthesia
|
9.1%
1/11 • Number of events 1
|
0.00%
0/9
|
|
Nervous system disorders
lethargy
|
9.1%
1/11 • Number of events 1
|
0.00%
0/9
|
|
Nervous system disorders
paresthesia
|
9.1%
1/11 • Number of events 1
|
0.00%
0/9
|
|
Renal and urinary disorders
renal failure
|
9.1%
1/11 • Number of events 1
|
0.00%
0/9
|
|
Renal and urinary disorders
renal impairment
|
9.1%
1/11 • Number of events 1
|
0.00%
0/9
|
|
Skin and subcutaneous tissue disorders
rash
|
9.1%
1/11 • Number of events 1
|
0.00%
0/9
|
|
Skin and subcutaneous tissue disorders
skin disorder
|
9.1%
1/11 • Number of events 1
|
0.00%
0/9
|
|
Cardiac disorders
bradycardia
|
9.1%
1/11 • Number of events 1
|
0.00%
0/9
|
|
Hepatobiliary disorders
liver disorder
|
9.1%
1/11 • Number of events 1
|
0.00%
0/9
|
|
Psychiatric disorders
confusional state
|
9.1%
1/11 • Number of events 1
|
0.00%
0/9
|
|
Respiratory, thoracic and mediastinal disorders
tachypnea
|
9.1%
1/11 • Number of events 1
|
0.00%
0/9
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place