Erwinia Asparaginase After Allergy to PEG-Asparaginase in Treating Young Patients With Acute Lymphoblastic Leukemia

• Sponsor: Children's Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT00537030
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 59
• Locations: 43
• Arm: 1
• Patients Per Site: 1.4

Study Details

Study Description

Brief Summary

This clinical trial is studying the side effects of Erwinia asparaginase and what happens to the drug in the body in treating young patients with acute lymphoblastic leukemia who are allergic to PEG-asparaginase. Drugs used in chemotherapy, such as Erwinia asparaginase, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing.

Condition or Disease	Intervention/Treatment	Phase
Adult Acute Lymphoblastic Leukemia; Childhood Acute Lymphoblastic Leukemia	Drug: Asparaginase; Other: Laboratory Biomarker Analysis; Other: Pharmacological Study	N/A

Detailed Description

PRIMARY OBJECTIVES:

1. To determine if the 48-hour trough serum asparaginase activity is ? 0.1 IU/mL in young patients with acute lymphoblastic leukemia treated with Erwinia asparaginase after allergy to PEG-asparaginase.

2. To determine the frequency of asparaginase-related toxicity in these patients.

3. To characterize the pharmacokinetics of Erwinia asparaginase in these patients.

SECONDARY OBJECTIVES:

1. To compare serum asparaginase activity and serum asparagine concentration between patients treated with Erwinia asparaginase on this trial and historical controls treated with PEG-asparaginase on CCG-1961 and CCG-1962.

2. To determine the 72-hour serum asparaginase activity on days 8 or 11 or 13 based on the starting date of Erwinia asparaginase therapy.

3. To determine the presence of anti-Erwinia asparaginase antibodies in patients treated with a course(s) of Erwinia asparaginase following clinical allergy to PEG-asparaginase (PEG, pegaspargase).

4. To determine if serum asparagine is adequately depleted on days 12 or 13 in a subset of these patients.

OUTLINE: This is a multicenter study.

Patients receive 6 doses of Erwinia asparaginase intramuscularly (IM) on a Monday/Wednesday/Friday schedule as a replacement for each scheduled dose of PEG-asparaginase remaining on the original treatment protocol. All other chemotherapy continues according to the original treatment protocol.

Blood samples are collected periodically for pharmacokinetic, pharmacodynamic, and antibody studies.

After completion of study treatment, patients are followed periodically.

Study Design

• Study Type: Interventional
• Actual Enrollment: 59 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pharmacology and Toxicity of Erwinia Asparaginase (Erwinase?; Crisantaspase; IND 290) Following Allergy to PEG-Asparaginase in Treatment of Children With Acute Lymphoblastic Leukemia (ALL)
• Actual Study Start Date: Feb 11, 2008
• Actual Primary Completion Date: Feb 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (chemotherapy) Patients receive 6 doses of Erwinia asparaginase IM on a Monday/Wednesday/Friday schedule as a replacement for each scheduled dose of PEG-asparaginase remaining on the original treatment protocol. All other chemotherapy continues according to the original treatment protocol.	Drug: Asparaginase; Given IM; Other Names: ASP-1 Asparaginase II Asparaginase-E.Coli Colaspase Elspar Kidrolase L-Asnase L-ASP L-Asparaginase L-Asparagine amidohydrolase Laspar Lcf-ASP Leucogen Leunase MK-965 Paronal Re-82-TAD-15 Serasa Spectrila ; Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Trough Serum Asparaginase Activity ≥ 0.1 IU/mL [48 hours post administration of Erwinia asparaginase]

   Percentage of participants who had trough serum asparaginase activity ≥ 0.1 IU/mL in the blood 48 hours post administration of Erwinia asparaginase

Secondary Outcome Measures

1. Determine if Plasma Asparagine is Adequately Depleted [On days 12 or 13]

   Plasma asparagine depletion will be determined in a subset of 20 patients limited to participating Phase I Institutions.

2. Presence of Anti-Erwinia Asparaginase Antibodies in Children Treated With a Course(s) of Erwinase® Following Clinical Allergy to PEG-asparaginase [At baseline, prior to doses 4, 5, and 6 and on days 15 and 22]

   An ELISA (enzyme-linked immunosorbent assay) method will be used to determine the presence of specific anti-Erwinia and anti-PEG-asparaginase antibodies at baseline, and of specific anti-Erwinia asparaginase antibodies after first and subsequent exposures to Erwinase®. The rate of antibody formation will be described and compared informally to experience in CCG-1962 and 1961. Serum asparaginase activity will be compared during Erwinase® courses as an indication of the neutralizing effect of antibodies on the enzyme effect.

3. Percentage of Participants Who Experienced Toxicities [up to 1 year]

   The percentage of participants who experienced toxicities: Allergy rate, Hyperglycemia Rate, Pancreatitis Rate, Hemorrhage/Thrombosis Rate

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 30 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of acute lymphoblastic leukemia

• Concurrently enrolled on a frontline Children's Oncology Group treatment trial (i.e., COG-AALL0232 or COG-AALL0531, COG-AALL0331, or COG-AALL0434) at a participating institution

• Must have 1 or more courses of asparaginase remaining to be administered on the treatment protocol

• Must have had a grade ? 2 hypersensitivity reaction to PEG-asparaginase

• No history of pancreatitis ? grade 2

• No prior Erwinia asparaginase

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama	United States	35233
2	Phoenix Childrens Hospital	Phoenix	Arizona	United States	85016
3	Kaiser Permanente Downey Medical Center	Downey	California	United States	90242
4	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
5	Children's Hospital Central California	Madera	California	United States	93636-8762
6	Children's Hospital of Orange County	Orange	California	United States	92868
7	Rady Children's Hospital - San Diego	San Diego	California	United States	92123
8	UCSF Medical Center-Mount Zion	San Francisco	California	United States	94115
9	UCSF Medical Center-Parnassus	San Francisco	California	United States	94143
10	Harbor-University of California at Los Angeles Medical Center	Torrance	California	United States	90502
11	Children's Hospital Colorado	Aurora	Colorado	United States	80045
12	Children's National Medical Center	Washington	District of Columbia	United States	20010
13	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida	United States	32207
14	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida	United States	33701
15	Lurie Children's Hospital-Chicago	Chicago	Illinois	United States	60611
16	Advocate Christ Medical Center	Oak Lawn	Illinois	United States	60453-2699
17	Advocate Children's Hospital-Oak Lawn	Oak Lawn	Illinois	United States	60453
18	Indiana University/Melvin and Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202
19	Norton Children's Hospital	Louisville	Kentucky	United States	40202
20	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	United States	21287
21	Spectrum Health at Butterworth Campus	Grand Rapids	Michigan	United States	49503
22	Kalamazoo Center for Medical Studies	Kalamazoo	Michigan	United States	49008
23	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota	United States	55404
24	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota	United States	55455
25	The Childrens Mercy Hospital	Kansas City	Missouri	United States	64108
26	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
27	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
28	The Steven and Alexandra Cohen Children's Medical Center of New York	New Hyde Park	New York	United States	11040
29	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York	United States	10016
30	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina	United States	27599
31	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
32	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
33	Rainbow Babies and Childrens Hospital	Cleveland	Ohio	United States	44106
34	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
35	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
36	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
37	Saint Christopher's Hospital for Children	Philadelphia	Pennsylvania	United States	19134
38	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
39	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee	United States	37232
40	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas	United States	75390
41	Cook Children's Medical Center	Fort Worth	Texas	United States	76104
42	Primary Children's Hospital	Salt Lake City	Utah	United States	84113
43	Seattle Children's Hospital	Seattle	Washington	United States	98105

Sponsors and Collaborators

• Children's Oncology Group
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Wanda Salzer, Children's Oncology Group

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Children's Oncology Group
• ClinicalTrials.gov Identifier: NCT00537030
• Other Study ID Numbers: AALL07P2; NCI-2009-00316; 07-162; COG-AALL07P2; CDR0000566349; AALL07P2; AALL07P2; U10CA098543
• First Posted: Sep 28, 2007
• Last Update Posted: Jul 9, 2019
• Last Verified: Jun 1, 2019

• Additional relevant MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Asparaginase

Study Results

Participant Flow

Pre-assignment Detail	Confirmation of the patient ineligibility was not confirmed by the COG study team until the patient received their first dose of Erwinia. Patient was removed from the COG frontline study (AALL08P1) prior to enrollment of this study.

Arm/Group Title	Erwinia Asparaginase
Arm/Group Description	Patients receive 6 doses of Erwinia asparaginase (dosage 25,000 IU/m2 intramuscularly (IM) on a Monday/Wednesday/Friday schedule as a replacement for each scheduled dose of PEG-asparaginase remaining on the original treatment protocol. All other chemotherapy continues according to the original treatment protocol. pharmacological study : Correlative studies laboratory biomarker analysis : Correlative studies asparaginase : Given IM
Period Title: Overall Study
STARTED	59
COMPLETED	43
NOT COMPLETED	16

Baseline Characteristics

Arm/Group Title	Erwinia Asparaginase
Arm/Group Description	Patients receive 6 doses of Erwinia asparaginase (dosage 25,000 IU/m2 intramuscularly (IM) on a Monday/Wednesday/Friday schedule as a replacement for each scheduled dose of PEG-asparaginase remaining on the original treatment protocol. All other chemotherapy continues according to the original treatment protocol. pharmacological study : Correlative studies laboratory biomarker analysis : Correlative studies asparaginase : Given IM
Overall Participants	59
Age (Count of Participants)
<=18 years	59 100%
Between 18 and 65 years	0 0%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	24 40.7%
Male	35 59.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	20 33.9%
Not Hispanic or Latino	39 66.1%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	3 5.1%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	6 10.2%
White	46 78%
More than one race	0 0%
Unknown or Not Reported	4 6.8%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Trough Serum Asparaginase Activity ≥ 0.1 IU/mL
Description	Percentage of participants who had trough serum asparaginase activity ≥ 0.1 IU/mL in the blood 48 hours post administration of Erwinia asparaginase
Time Frame	48 hours post administration of Erwinia asparaginase

Outcome Measure Data

Analysis Population Description

Of the 59 enrolled participants, there were 2 ineligible and 2 in-evaluable participants. From the remaining 55 participants, 52 participants had an acceptable sample that could be reported on.

Arm/Group Title	Erwinia Asparaginase
Arm/Group Description	Patients receive 6 doses of Erwinia asparaginase (dosage 25,000 IU/m2 intramuscularly (IM) on a Monday/Wednesday/Friday schedule as a replacement for each scheduled dose of PEG-asparaginase remaining on the original treatment protocol. All other chemotherapy continues according to the original treatment protocol. pharmacological study : Correlative studies laboratory biomarker analysis : Correlative studies asparaginase : Given IM
Measure Participants	52
Number [Percent of participants]	94.5 160.2%

2. Secondary Outcome

Title	Determine if Plasma Asparagine is Adequately Depleted
Description	Plasma asparagine depletion will be determined in a subset of 20 patients limited to participating Phase I Institutions.
Time Frame	On days 12 or 13

Outcome Measure Data

Analysis Population Description

No data available for this analysis.

Arm/Group Title	Erwinia Asparaginase
Arm/Group Description	Patients receive 6 doses of Erwinia asparaginase (dosage 25,000 IU/m2 intramuscularly (IM) on a Monday/Wednesday/Friday schedule as a replacement for each scheduled dose of PEG-asparaginase remaining on the original treatment protocol. All other chemotherapy continues according to the original treatment protocol. pharmacological study : Correlative studies laboratory biomarker analysis : Correlative studies asparaginase : Given IM
Measure Participants	0

3. Secondary Outcome

Title	Presence of Anti-Erwinia Asparaginase Antibodies in Children Treated With a Course(s) of Erwinase® Following Clinical Allergy to PEG-asparaginase
Description	An ELISA (enzyme-linked immunosorbent assay) method will be used to determine the presence of specific anti-Erwinia and anti-PEG-asparaginase antibodies at baseline, and of specific anti-Erwinia asparaginase antibodies after first and subsequent exposures to Erwinase®. The rate of antibody formation will be described and compared informally to experience in CCG-1962 and 1961. Serum asparaginase activity will be compared during Erwinase® courses as an indication of the neutralizing effect of antibodies on the enzyme effect.
Time Frame	At baseline, prior to doses 4, 5, and 6 and on days 15 and 22

Outcome Measure Data

Analysis Population Description

no data available for this analysis.

Arm/Group Title	Erwinia Asparaginase
Arm/Group Description	Patients receive 6 doses of Erwinia asparaginase (dosage 25,000 IU/m2 intramuscularly (IM) on a Monday/Wednesday/Friday schedule as a replacement for each scheduled dose of PEG-asparaginase remaining on the original treatment protocol. All other chemotherapy continues according to the original treatment protocol. pharmacological study : Correlative studies laboratory biomarker analysis : Correlative studies asparaginase : Given IM
Measure Participants	0

4. Secondary Outcome

Title	Percentage of Participants Who Experienced Toxicities
Description	The percentage of participants who experienced toxicities: Allergy rate, Hyperglycemia Rate, Pancreatitis Rate, Hemorrhage/Thrombosis Rate
Time Frame	up to 1 year

Outcome Measure Data

Analysis Population Description

Patients who had toxicity data collected.

Arm/Group Title	Erwinia Asparaginase
Arm/Group Description	Patients receive 6 doses of Erwinia asparaginase (dosage 25,000 IU/m2 intramuscularly (IM) on a Monday/Wednesday/Friday schedule as a replacement for each scheduled dose of PEG-asparaginase remaining on the original treatment protocol. All other chemotherapy continues according to the original treatment protocol. pharmacological study : Correlative studies laboratory biomarker analysis : Correlative studies asparaginase : Given IM
Measure Participants	55
Allergy Rate	10.9 18.5%
Hyperglycemia Rate	10.9 18.5%
Pancreatitis Rate	1.8 3.1%
Hemorrhage/Thrombosis Rate	0 0%

Adverse Events

Adverse Event Reporting Description	Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution, via expedited reporting (NCI AdEERs / CAeRs). The "AE Other" table reflects all CTCAEs collected excluding those that were reported as SAEs. There were 2 ineligible and 2 in-evaluable patients excluded from reporting of adverse events, leaving a total of 55 participants included in the AE
Arm/Group Title	Erwinia Asparaginase
Arm/Group Description	Patients receive 6 doses of Erwinia asparaginase (dosage 25,000 IU/m2 intramuscularly (IM) on a Monday/Wednesday/Friday schedule as a replacement for each scheduled dose of PEG-asparaginase remaining on the original treatment protocol. All other chemotherapy continues according to the original treatment protocol. pharmacological study : Correlative studies laboratory biomarker analysis : Correlative studies asparaginase : Given IM
All Cause Mortality
	Erwinia Asparaginase
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Erwinia Asparaginase
	Affected / at Risk (%)	# Events
Total	9/55 (16.4%)
Blood and lymphatic system disorders
Febrile neutropenia	1/55 (1.8%)
General disorders
Fever	1/55 (1.8%)
Immune system disorders
Allergic reaction	2/55 (3.6%)
Infections and infestations
Infections and infestations - Other, specify	4/55 (7.3%)
Investigations
Alanine aminotransferase increased	1/55 (1.8%)
Aspartate aminotransferase increased	3/55 (5.5%)
Blood bilirubin increased	1/55 (1.8%)
Neutrophil count decreased	1/55 (1.8%)
Platelet count decreased	1/55 (1.8%)
White blood cell decreased	1/55 (1.8%)
Metabolism and nutrition disorders
Hyperglycemia	1/55 (1.8%)
Other (Not Including Serious) Adverse Events
	Erwinia Asparaginase
	Affected / at Risk (%)	# Events
Total	15/55 (27.3%)
Blood and lymphatic system disorders
Febrile neutropenia	3/55 (5.5%)
Gastrointestinal disorders
Nausea	1/55 (1.8%)
Pancreatitis	1/55 (1.8%)
Vomiting	2/55 (3.6%)
General disorders
Fatigue	1/55 (1.8%)
Immune system disorders
Allergic reaction	4/55 (7.3%)
Injury, poisoning and procedural complications
Radiation recall reaction (dermatologic)	1/55 (1.8%)
Investigations
Alanine aminotransferase increased	4/55 (7.3%)
Aspartate aminotransferase increased	4/55 (7.3%)
Blood bilirubin increased	4/55 (7.3%)
Lipase increased	1/55 (1.8%)
Metabolism and nutrition disorders
Hyperglycemia	5/55 (9.1%)
Hypoalbuminemia	2/55 (3.6%)
Nervous system disorders
Headache	1/55 (1.8%)
Psychiatric disorders
Agitation	1/55 (1.8%)
Skin and subcutaneous tissue disorders
Urticaria	1/55 (1.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.