Study of Erwinaze for Treatment of Acute Myeloid Leukemia (AML) With Isocitrate Dehydrogenase (IDH) Mutations
Conditions
Acute Myeloid Leukemia
Conditions: official terms
Leukemia - Leukemia, Myeloid - Leukemia, Myeloid, Acute
Conditions: Keywords
Asparaginase, IDH mutation
Study Type
Interventional
Study Phase
Phase 1
Study Design
Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label
Intervention
Name: Erwinase
Type: Drug
Overall Status
Recruiting
Summary
Erwinaze will be administered intravenously at a dose of 25,000 IU/m2 (first dose cohort) for 6 doses Monday, Wednesday, Friday over a period of 2 weeks. Blood counts, chemistries including bilirubin, amylase and lipase, and coagulation studies will be measured and reviewed before each Erwinase dose. Management of laboratory abnormalities will be based on standard clinical practice for adult patients with diagnosis of acute leukemia. Treatment with Erwinase will be held if dose limiting toxicities occur.
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.
Criteria for eligibility
Healthy Volunteers: No
Maximum Age: N/A
Minimum Age: 18 Years
Gender: Both
Criteria: Inclusion Criteria:

- Histologically or cytologically confirmed AML

- AML must carry mutations in isocitrate dehydrogenase 1 (IDH1) or IDH2

- AML has relapsed after, or is refractory to, first-line therapy, with or without additional subsequent therapy

- Received or are ineligible for established curative regimens, including stem cell transplantation when applicable, can be enrolled on this study

- May have received any number of prior chemotherapy regimens, which may include allogeneic or autologous transplantation (see protocols for details), provided that performance status and organ function are maintained

- Previous cytotoxic chemotherapy should have been completed at least 4 weeks and radiotherapy at least 2 weeks prior to treatment. All adverse events (excluding alopecia, acne, rash) due to agents administered more than 4 weeks earlier should recover to less than or equal to Grade 1.

- All biologic agents should be stopped at least 1 week prior to treatment on study.

- DNA methyltransferase inhibitors should be stopped at least 4 weeks prior to treatment on the study.

- Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2 (Karnofsky greater than or equal to 60%).

- Normal organ function as defined in the protocol

- Female patients of childbearing potential must have a negative pregnancy test.

- Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

- Not be receiving any other investigational agents, or concurrent chemotherapy, radiation therapy, or immunotherapy

- Acute promyelocytic leukemia confirmed with t(15;17) is not eligible.

- Active central nervous system (CNS) leukemia is excluded from this clinical trial

- History of CNS leukemia must be stable with clear cerebrospinal fluid (CSF) for greater than 3 months and off steroid treatment for greater than 3 months prior to study entry

- Prior treatment with Erwinaze

- Hyperleukocytosis with greater than 50,000 blasts/μl.

- Prior history of a major thrombotic event, or any history of an asparaginase associated serious hemorrhage or thrombus requiring anticoagulation therapy with agents such as heparin

- Active, uncontrolled infection

- Uncontrolled intercurrent illness that would limit compliance with study requirements.

- Pregnant women are excluded from this study

- Known HIV infected patients

- Uncontrolled, active seizure disorder or a history of seizure.
Location
University of Maryland Greenebaum Cancer Center
Baltimore, Maryland, United States
Status: Recruiting
Contact: Isabella van der Merwe, RN - 410-328-8370
Start Date
April 2014
Completion Date
December 2020
Sponsors
Ashkan Emadi
Source
University of Maryland
Record processing date
ClinicalTrials.gov processed this data on July 28, 2015
ClinicalTrials.gov page