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1336GCC: Study of Erwinaze for Treatment of Acute Myeloid Leukemia (AML)

Primary Purpose

Acute Myeloid Leukemia

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Erwinase

Sponsored by

Ashkan Emadi

About this trial

This is an interventional other trial for Acute Myeloid Leukemia focused on measuring Asparaginase, Glutamine

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

University of Maryland Greenebaum Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Ewwinase

Arm Description

Six doses of Erwinase given three times weekly (Monday-Wednesday-Friday) for two weeks. Possible dose levels used are 20.000 IU/m2/day, 25,000IU/m2/day, and 30,000IU/m2/day.

Outcomes

Primary Outcome Measures

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.

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.

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.

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.

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.

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.

Secondary Outcome Measures

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.

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.

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

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

Full Information

NCT ID

First Posted

October 17, 2014

Last Updated

March 8, 2018

Sponsor

Ashkan Emadi

1. Study Identification

Unique Protocol Identification Number

NCT02283190

Brief Title

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

2. Study Status

Record Verification Date

February 2018

Overall Recruitment Status

Completed

Study Start Date

April 2014 (undefined)

Primary Completion Date

December 2015 (Actual)

Study Completion Date

September 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Ashkan Emadi

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Acute Myeloid Leukemia

Keywords

Asparaginase, Glutamine

7. Study Design

Primary Purpose

Other

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

5 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Ewwinase

Arm Type

Experimental

Arm Description

Six doses of Erwinase given three times weekly (Monday-Wednesday-Friday) for two weeks. Possible dose levels used are 20.000 IU/m2/day, 25,000IU/m2/day, and 30,000IU/m2/day.

Intervention Type

Drug

Intervention Name(s)

Erwinase

Other Intervention Name(s)

Asparaginase, Crisantaspase

Intervention Description

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.

Primary Outcome Measure Information:

Title

To determine the dose of Erwinase that produces a plasma glutamine level ≤120 μmol/L with an acceptable safety profile.

Description

The dose of Erwinase that produces a plasma glutamine level ≤120 µmol/L with an acceptable safety profile.

Time Frame

Day 3

Title

Efficacy of Erwinase doses as measured by plasma glutamine level

Description

The dose of Erwinase that produces a plasma glutamine level ≤120 µmol/L with an acceptable safety profile.

Time Frame

Day 5

Title

Efficacy of Erwinase doses as measured by plasma glutamine level

Description

The dose of Erwinase that produces a plasma glutamine level ≤120 µmol/L with an acceptable safety profile.

Time Frame

Day 8

Title

Efficacy of Erwinase doses as measured by plasma glutamine level

Description

The dose of Erwinase that produces a plasma glutamine level ≤120 µmol/L with an acceptable safety profile.

Time Frame

Day 10

Title

Efficacy of Erwinase doses as measured by plasma glutamine level

Description

The dose of Erwinase that produces a plasma glutamine level ≤120 µmol/L with an acceptable safety profile.

Time Frame

Day 12

Title

Efficacy of Erwinase doses as measured by plasma glutamine level

Description

The dose of Erwinase that produces a plasma glutamine level ≤120 µmol/L with an acceptable safety profile.

Time Frame

Day 42

Secondary Outcome Measure Information:

Title

Efficacy of Erwinase doses as measured by nadir serum asparaginase activity

Description

The dose of Erwinase that produces nadir serum asparaginase activity ≥0.1 IU/mL with acceptable safety profile.

Time Frame

Days 3, 5,8,10,12, & 42

Title

Efficacy of Erwinase as measured by acute myeloid leukemia (AML) disease response

Description

Bone marrow biopsy to determine the clinical response to 6 doses of Erwinaze at the administered dose.

Time Frame

Days 15 and 29

Title

Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Description

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

Title

Validity of serum and urine 2-hydroxyglutarate (2-HG) as a biomarker for AML with or without IDH mutation

Description

Measure the blood and urine 2-hydroxyglutarate (2-HG) levels

Time Frame

Days 0, 8, & 42

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

No

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Ashkan Emadi, MD, PhD

Organizational Affiliation

University of Maryland

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Maryland Greenebaum Cancer Center

City

Baltimore

State/Province

Maryland

ZIP/Postal Code

21201

Country

United States

12. IPD Sharing Statement

Learn more about this trial

1336GCC: Study of Erwinaze for Treatment of Acute Myeloid Leukemia (AML)

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