Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Related Information
Registry Information

Alternate Title

EZN-2285 or Pegaspargase and Combination Chemotherapy in Treating Younger Patients With Newly Diagnosed High-Risk Acute Lymphoblastic Leukemia

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
No phase specified	Biomarker/Laboratory analysis, Treatment	Active	1 to 30	NCI	COG-AALL07P4 AALL07P4, NCT00671034

Objectives

Primary

1. Determine the pharmacokinetic (PK) comparability of SC-PEG E. coli L-asparaginase (EZN-2285) to pegaspargase given intravenously during induction and consolidation in patients with high-risk acute lymphoblastic leukemia (ALL) receiving augmented Berlin-Frankfurt-Munster (BFM) therapy.

Secondary

1. Describe the pharmacodynamics of EZN-2285 compared to pegaspargase in these patients.
2. Determine, at end of induction therapy by day 29, minimal residual disease for patients randomized to the EZN-2285-containing regimen compared to the pegaspargase-containing regimen.
3. Determine the complete remission rates for patients receiving EZN-2285, by day 29 of induction, compared to pegaspargase.
4. Assess event-free survival associated with the administration of EZN-2285 compared to pegaspargase given during augmented post-induction intensification therapy in patients with high-risk ALL.
5. Determine the proportion of patients with an asparaginase level of at least 0.1 IU/mL and the proportion of patients with that of at least 0.4 IU/mL on days 4, 15, 22, and 29 of induction in both arms.
6. Determine the serum and cerebrospinal fluid concentrations of asparagine after administration of EZN-2285 compared to pegaspargase.
7. Assess the immunogenicity of EZN-2285, including the detection of binding and neutralizing antibodies, compared to pegaspargase.
8. Assess the tolerability and toxicities associated with the administration of EZN-2285 compared to pegaspargase given during augmented post induction intensification therapy in patients with high-risk ALL .
9. Explore the relationship between the terminal PKs of EZN-2285 and the presence of antibodies.

Entry Criteria

Disease Characteristics:

• Newly diagnosed high-risk B-precursor acute lymphoblastic leukemia



• No Down syndrome



• No testicular leukemia



• Enrolled on COG-AALL03B1 study or the successor classification study

Prior/Concurrent Therapy:

• No prior cytotoxic chemotherapy except for steroid therapy or intrathecal cytarabine

Patient Characteristics:

• WBC ≥ 50,000/μL for patients age 1-9 OR any WBC count for patients age 10-30 or for patients treated with prior steroids
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

Expected Enrollment

Outcomes

Pharmacokinetics of SC-PEG E. coli L-asparaginase (EZN-2285) compared to pegaspargase during induction and consolidation therapy

Pharmacodynamics of EZN-2285 compared to pegaspargase during induction and consolidation therapy
Response rate
Event-free survival
Minimal residual disease at day 29 of induction therapy
Complete remission rates
Immunogenicity of EZN-2285 compared to pegaspargase
Toxicities

Outline

This is a multicenter study. Patients are stratified according to response to induction therapy (slow early responders [SER] vs rapid early responders [RER]. Patients are randomized to 1 of 2 treatment arms in 2:1 ratio (arm I:arm II) (patients randomized to arm I receive study drug SC-PEG E. coli L-asparaginase [EZN-2285]; patients randomized to arm II receive study drug pegaspargase).

• Induction therapy (all patients): Patients receive cytarabine intrathecally (IT) on day 1; vincristine IV and daunorubicin hydrochloride IV over 15 minutes on days 1, 8, 15, and 22; prednisone orally or IV twice a day on days 1-28; study drug IV over 1 hour on day 4; and methotrexate IT on days 8, 15*, 22*, and 29.

  Patients are assessed for response on day 8 and/or day 15 and day 29. Patients who achieve M1 marrow on day 8 or 15 and negative minimum residual disease (MRD) (i.e., < 0.1%) on day 29 are considered RER. Patients who achieve M2 or M3 marrow on day 15 OR MRD ≥ 0.1% but < 1% on day 29 are considered SER. Patients with M3 bone marrow are removed from the study. RER and SER proceed to consolidation therapy. Patients with M2 marrow or M1 marrow with ≥ 1% MRD receive extended induction therapy.

   [Note: *For patients with CNS3 disease only.]




• Extended induction therapy: Patients receive vincristine IV on days 1 and 8; prednisone orally or IV twice a day on days 1-14; daunorubicin hydrochloride IV over 15 minutes on day 1; and study drug IV over 1 hour on day 4.

  Patients are assessed for response on day 43. Patients who achieve M1 and MRD < 1% are treated as SER (proceed to consolidation therapy). All other patients are removed from study.




• Consolidation therapy (all patients): Beginning on day 36 (after completion of induction therapy) or after completion of extended induction therapy, patients (RER and SER) receive cyclophosphamide IV over 30 minutes on days 1 and 29; cytarabine IV or SC on days 1-4, 8-11, 29-32, and 36-39; oral mercaptopurine on days 1-14 and 29-42; vincristine IV on days 15, 22, 43, and 50; study drug IV over 1 hour on days 15 and 43; and methotrexate IT on days 1, 8, 15*, and 22*. Patients who were initially diagnosed with CNS3 disease receive cranial radiotherapy on days 1-5 and 8-12. Patients then proceed to interim maintenance I therapy.

   [Note: *Omit doses for patients with CNS3 disease.]




• Interim maintenance I (all patients): Patients receive vincristine IV and methotrexate IV on days 1, 11, 21, 31, and 41; study drug IV over 1 hour on days 2 and 22; and methotrexate IT on days 1 and 31. Patients then proceed to delayed intensification I therapy.



• Delayed intensification I (all patients): Patients receive vincristine IV on days 1, 8, 15, 43, and 50; dexamethasone orally or IV twice a day on days 1-21 for patients age 1-9, or on days 1-7 and 15-21 for patients age ≥ 10; doxorubicin hydrochloride IV over 15 minutes on days 1, 8, and 15; study drug IV over 1 hour on days 4 and 43; cyclophosphamide IV over 30 minutes on day 29; cytarabine IV or subcutaneously (SC) on days 29-32 and 36-39; oral thioguanine on days 29-42; and methotrexate IT on days 1, 29, and 36.

  Patients treated as RER proceed to maintenance therapy. Patients treated as SER (i.e., patients with CNS3 disease at diagnosis, or pre-treated with steroids, or who are RERs with mixed lineage leukemia [MLL] gene rearrangements) proceed to interim maintenance II followed by delayed intensification II.




• Interim maintenance II (SER only): Patients receive vincristine IV, methotrexate IV, study drug IV, and methotrexate IT as in interim maintenance I.



• Delayed intensification II (SER only): Beginning on day 29, patients (except patients with CNS3 disease) receive 8 daily fractions of cranial radiotherapy. All patients then receive vincristine IV, dexamethasone orally or IV, doxorubicin hydrochloride IV, study drug IV, cyclophosphamide IV, cytarabine IV or SC, oral thioguanine, and methotrexate IT as in delayed intensification I. Patients then proceed to maintenance therapy.



• Maintenance therapy (all patients): Patients receive vincristine IV on days 1, 29, and 57; oral dexamethasone on days 1-5, 29-33, and 57-61; oral mercaptopurine on days 1-84; methotrexate IT on day 29; and oral methotrexate on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Treatment repeats every 12 weeks for up to 2 years (for female patients) or up to 3 years (for male patients) from the start of interim maintenance I.

Blood samples, bone marrow tissue, and cerebrospinal fluid are collected periodically for disease evaluation and correlative studies, including pharmacokinetics and pharmacodynamics.

After completion of study therapy, patients are followed every 2 months for 2 years, every 3 months for 1 year, and then every 6-12 months for 2 years.

Trial Contact Information

Trial Lead Organizations

Children's Oncology Group

Anne Angiolillo, MD, Protocol chair		Ph: 202-476-5000

U.S.A.
Alabama
	Birmingham
	UAB Comprehensive Cancer Center
		Clinical Trials Office - Lurleen Wallace Comprehensive Cancer	Ph:  205-934-0309
California
	Orange
	Children's Hospital of Orange County
		Violet Shen	Ph:  714-532-8636
	Stanford
	Stanford Cancer Center
		Clinical Trials Office - Stanford Cancer Center	Ph:  650-498-7061
			Email: cctoffice@stanford.edu
Colorado
	Aurora
	Children's Hospital Center for Cancer and Blood Disorders
		Kelly Maloney	Ph:  720-777-6673
Connecticut
	Farmington
	Carole and Ray Neag Comprehensive Cancer Center at the University of Connecticut Health Center
		Clinical Trials Office - Carole and Ray Neag Comprehensive Cancer Center	Ph:  800-579-7822
District of Columbia
	Washington
	Children's National Medical Center
		Clinical Trials Office - Children's National Medical Center	Ph:  202-884-2549
Illinois
	Chicago
	Children's Memorial Hospital - Chicago
		Stewart Goldman	Ph:  773-880-4598x3270
Indiana
	Indianapolis
	Indiana University Melvin and Bren Simon Cancer Center
		Clinical Trials Office - Indiana University Cancer Center	Ph:  317-274-2552
Maryland
	Baltimore
	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
		Clinical Trials Office - Sidney Kimmel Comprehensive Cancer Center at John Hopkins	Ph:  410-955-8804
			Email: jhcccro@jhmi.edu
Michigan
	Detroit
	Barbara Ann Karmanos Cancer Institute
		Clinical Trials Office - Barbara Ann Karmanos Cancer Institute	Ph:  313-576-9363
Minnesota
	Minneapolis
	Children's Hospitals and Clinics of Minnesota - Minneapolis
		Clinical Trials Office - Children's Hospitals and Clinics of Minnesota	Ph:  612-813-5193
	Masonic Cancer Center at University of Minnesota
		Clinical Trials Office - Masonic Cancer Center at University of Minnesota	Ph:  612-624-2620
Missouri
	St. Louis
	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
		Robert Hayashi	Ph:  314-454-4118
New Jersey
	Hackensack
	Hackensack University Medical Center Cancer Center
		Clinical Trials Office - Hackensack University Medical Center Cancer Center	Ph:  201-996-2879
New York
	New York
	NYU Cancer Institute at New York University Medical Center
		Elizabeth Raetz	Ph:  212-263-8400
Ohio
	Cincinnati
	Cincinnati Children's Hospital Medical Center
		Clinical Trials Office - Cincinnati Children's Hospital Medical Center	Ph:  513-636-2799
Oklahoma
	Oklahoma City
	Oklahoma University Cancer Institute
		Rene McNall-Knapp	Ph:  405-271-5311
Oregon
	Portland
	Knight Cancer Institute at Oregon Health and Science University
		Clinical Trials Office - Knight Cancer Institute at Oregon Health and Science University	Ph:  503-494-1080
			Email: trials@ohsu.edu
Pennsylvania
	Philadelphia
	Children's Hospital of Philadelphia
		Richard Aplenc	Ph:  267-426-7252
	Pittsburgh
	Children's Hospital of Pittsburgh
		Clinical Trials Office - Children's Hospital of Pittsburgh	Ph:  412-692-5573
Tennessee
	Nashville
	Vanderbilt-Ingram Cancer Center
		Clinical Trials Office - Vanderbilt-Ingram Cancer Center	Ph:  1-800-811-8480;
Texas
	Dallas
	Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas
		Clinical Trials Office - Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas	Ph:  866-460-4673; 214-648-7097
Utah
	Salt Lake City
	Primary Children's Medical Center
		Phillip Barnette	Ph:  801-662-4700
Washington
	Seattle
	Children's Hospital and Regional Medical Center - Seattle
		Julie Park	Ph:  206-987-1947

Related Information

PDQ® clinical trial COG-AALL03B1

Registry Information
Official Title		A Pilot Study of Intravenous EZN-2285 (SC-PEG E. coli L-asparaginase, IND# 100594) or Intravenous Oncaspar® in the Treatment of Patients with High-Risk Acute Lymphoblastic Leukemia
Trial Start Date		2008-07-21
Trial Completion Date		2018-03-12 (estimated)
Registered in ClinicalTrials.gov		NCT00671034
Date Submitted to PDQ		2008-04-16
Information Last Verified		2009-04-18
NCI Grant/Contract Number		CA98543

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