Erwinaze will be administered intravenously at a dose of 25,000 IU/m2 (dose cohort 0) for 6 doses MWF over a period of 2 weeks to 9 patients (as described below and in the following schema). Blood counts, chemistries including bilirubin, amylase and lipase, and coagulation studies including fibrinogen will be measured and reviewed before each asparaginase dose. Fibrinogen (\<100 mg/dL) can be replaced with cryoprecipitate before each dose at the discretion of treating physician. Treatment will be stopped for elevation of amylase, lipase or direct bilirubin above normal range.
For safety: Erwinaze has been already used in clinical practice for treatment of patients with acute leukemia with known side effect profile. For this reason, in this protocol, we use the "3+3+3" design for evaluation of safety based on pre-determined dose-limiting toxicities (DLT). In the "3+3+3" design, the dose escalation rules proceed by adjusting the dose in cohorts of 3 to 9 patients per three dose levels:20,000 IU/m2 (dose cohort -1), 25,000 IU/m2 (dose cohort 0), 30,000 IU/m2 (dose cohort +1). The goal is to determine the Recommended Phase 2 Dose (RP2D) For anti-leukemic activity: To evaluate the activity of Erwinaze to reduce the serum glutamine to the desired level, the dose will be adjusted according to a pre-defined algorithm based on 48-hour trough serum glutamine level (biochemical response) prior to dose 6 of each patient. If the safety profile is acceptable, we will enroll up to a total of 15 patients at that dose level to better study and analyze the glutamine-reducing effect of Erwinaze at the defined dose. In summary, if 9 patients are treated at a certain dose and at least 7 out of 9 individuals respond to treatment (per serum glutamine levels) and \< 3 develop DLT, this dose level will be declared the Recommended Phase 2 Dose (RP2D). Six additional patients (total of 15 to 18 patients) will be enrolled at the RP2D level to better assess toxicity and to document responses. There will be no intra-patient dose escalation or reduction.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
OTHER
Masking
NONE
Six doses of Erwinase, given Monday-Wednesday-Friday for 2 weeks. Dosage levels to be used are: 20,000 IU/ m2 /day, 25,000 IU/ m2 /day, 30,000 IU/ m2 /day.
University of Maryland Greenebaum Cancer Center
Baltimore, Maryland, United States
To determine the dose of Erwinase that produces a plasma glutamine level ≤120 μmol/L with an acceptable safety profile.
The dose of Erwinase that produces a plasma glutamine level ≤120 µmol/L with an acceptable safety profile.
Time frame: Day 3
Efficacy of Erwinase doses as measured by plasma glutamine level
The dose of Erwinase that produces a plasma glutamine level ≤120 µmol/L with an acceptable safety profile.
Time frame: Day 5
Efficacy of Erwinase doses as measured by plasma glutamine level
The dose of Erwinase that produces a plasma glutamine level ≤120 µmol/L with an acceptable safety profile.
Time frame: Day 8
Efficacy of Erwinase doses as measured by plasma glutamine level
The dose of Erwinase that produces a plasma glutamine level ≤120 µmol/L with an acceptable safety profile.
Time frame: Day 10
Efficacy of Erwinase doses as measured by plasma glutamine level
The dose of Erwinase that produces a plasma glutamine level ≤120 µmol/L with an acceptable safety profile.
Time frame: Day 12
Efficacy of Erwinase doses as measured by plasma glutamine level
The dose of Erwinase that produces a plasma glutamine level ≤120 µmol/L with an acceptable safety profile.
Time frame: Day 42
Efficacy of Erwinase doses as measured by nadir serum asparaginase activity
The dose of Erwinase that produces nadir serum asparaginase activity ≥0.1 IU/mL with acceptable safety profile.
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Enrollment
5
Time frame: Days 3, 5,8,10,12, & 42
Efficacy of Erwinase as measured by acute myeloid leukemia (AML) disease response
Bone marrow biopsy to determine the clinical response to 6 doses of Erwinaze at the administered dose.
Time frame: Days 15 and 29
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
To establish safety and tolerability of Erwinaze in patients with AML with or without mIDH
Time frame: 30 days from last dose of drug or until death, whichever occurs first
Validity of serum and urine 2-hydroxyglutarate (2-HG) as a biomarker for AML with or without IDH mutation
Measure the blood and urine 2-hydroxyglutarate (2-HG) levels
Time frame: Days 0, 8, & 42