Clinical trial NCT02283190: 1336GCC: Study of Erwinaze for Treatment of Acute Myeloid Leukemia (AML)
Official title: 1336GCC: Open-Label, Single-Arm PK Study of IV Erwinaze (Asparaginase Erwinia Chrysanthemi) to Find the Dose With Acceptable Therapeutic and Safety Profile in Adults With Acute Myeloid Leukemia With or Without Isocitrate Dehydrogenase Mutations
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Acute Myeloid Leukemia
Keywords: Asparaginase
Glutamine
Lead sponsor: University of Maryland, Baltimore
Sponsor class: OTHER
First posted: 2014-11-05
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Histologically or cytologically confirmed AML
* 18 years and older
* AML has relapsed after, or is refractory to, first-line therapy, with or without subsequent additional therapy
* Have received or are ineligible for immediate established curative regimens
* ASCT patients are eligible provided that they are \>= 4 weeks from stem cell infusion
* alloSCT patients are eligible if they are \>= 60 days post stem cell infusion, have no evidence of graft versus host disease (GVHD) \> Grade 1, and are \>= 2 weeks off all immunosuppressive therapy
* Previous cytotoxic chemotherapy completed at least 3 weeks and radiotherapy at least 2 weeks prior to day 1 of study treatment
* Biologic agents stopped at least 1 week prior to day 1 of study treatment
* DNA methyltransferase inhibitors stopped at least 3 weeks prior to day 1 of study treatment
* ECOG performance status ≤2
* Patients must have normal organ function
* Female patients of childbearing potential must have a negative pregnancy test.
* Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

* Patients receiving any other investigational agents, or concurrent chemotherapy, radiation therapy, or immunotherapy
* Patients with acute promyelocytic leukemia
* Patients with active central nervous system leukemia
* Prior treatment with Erwinaze
* Hyperleukocytosis with \> 50,000 blasts/μL
* History of a major thrombotic event
* History of pancreatitis
* Active, uncontrolled infection
* Uncontrolled intercurrent illness
* Pregnant women
* Uncontrolled active seizure disorder or a history of seizure

Primary outcomes:
measure: To determine the dose of Erwinase that produces a plasma glutamine level ≤120 μmol/L with an acceptable safety profile.
timeFrame: Day 3
measure: Efficacy of Erwinase doses as measured by plasma glutamine level
timeFrame: Day 5
measure: Efficacy of Erwinase doses as measured by plasma glutamine level
timeFrame: Day 8
measure: Efficacy of Erwinase doses as measured by plasma glutamine level
timeFrame: Day 10
measure: Efficacy of Erwinase doses as measured by plasma glutamine level
timeFrame: Day 12
measure: Efficacy of Erwinase doses as measured by plasma glutamine level
timeFrame: Day 42
Secondary outcomes:
measure: Efficacy of Erwinase doses as measured by nadir serum asparaginase activity
timeFrame: Days 3, 5,8,10,12, & 42
measure: Efficacy of Erwinase as measured by acute myeloid leukemia (AML) disease response
timeFrame: Days 15 and 29
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
timeFrame: 30 days from last dose of drug or until death, whichever occurs first
measure: Validity of serum and urine 2-hydroxyglutarate (2-HG) as a biomarker for AML with or without IDH mutation
timeFrame: Days 0, 8, & 42
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: University of Maryland Greenebaum Cancer Center
state: Maryland
Study officials:
affiliation: University of Maryland
name: Ashkan Emadi, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: