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

Condition(s) targeted: Leukemia

Intervention: SC-PEG E. coli L-asparaginase (Drug); cyclophosphamide (Drug); cytarabine (Drug); daunorubicin hydrochloride (Drug); dexamethasone (Drug); doxorubicin hydrochloride (Drug); methotrexate (Drug); pegaspargase (Drug); prednisone (Drug); vincristine sulfate (Drug); radiation therapy (Procedure)

Phase: N/A

Status: Recruiting

Sponsored by: Children's Oncology Group

Official(s) and/or principal investigator(s):
Anne Angiolillo, MD, Study Chair, Affiliation: Childrens Research Institute

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells.

PURPOSE: This randomized clinical trial is studying giving EZN-2285 together with combination chemotherapy to see how well it works compared with giving pegaspargase together with combination chemotherapy in treating younger patients with newly diagnosed high-risk acute lymphoblastic leukemia.

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

Study design: Treatment, Randomized, Open Label

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

Secondary outcome:

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

Detailed description: OBJECTIVES:

Primary

- 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

- Describe the pharmacodynamics of EZN-2285 compared to pegaspargase in these patients.

- 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.

- Determine the complete remission rates for patients receiving EZN-2285, by day 29 of

induction, compared to pegaspargase.

- 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.

- 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.

- Determine the serum and cerebrospinal fluid concentrations of asparagine after

administration of EZN-2285 compared to pegaspargase.

- Assess the immunogenicity of EZN-2285, including the detection of binding and

neutralizing antibodies, compared to pegaspargase.

- 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 .

- Explore the relationship between the terminal PKs of EZN-2285 and the presence of

antibodies.

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.

Minimum age: 1 Year. Maximum age: 30 Years. Gender(s): Both.

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

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

PRIOR CONCURRENT THERAPY:

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

Children's Hospital of Orange County, Orange, California 92868, United States; Recruiting
Violet Shen, Phone: 714-532-8636

Stanford Cancer Center, Stanford, California 94305-5824, United States; Recruiting
Clinical Trials Office - Stanford Cancer Center, Phone: 650-498-7061, Email: cctoffice@stanford.edu

Children's Hospital Center for Cancer and Blood Disorders, Aurora, Colorado 80045, United States; Recruiting
Kelly Maloney, Phone: 720-777-6673

Carole and Ray Neag Comprehensive Cancer Center at the University of Connecticut Health Center, Farmington, Connecticut 06360-2875, United States; Recruiting
Clinical Trials Office - Carole and Ray Neag Comprehensive Can, Phone: 800-579-7822

Children's National Medical Center, Washington, District of Columbia 20010-2970, United States; Recruiting
Clinical Trials Office - Children's National Medical Center, Phone: 202-884-2549

Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana 46202-5289, United States; Recruiting
Clinical Trials Office - Indiana University Cancer Center, Phone: 317-274-2552

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231-2410, United States; Recruiting
Clinical Trials Office - Sidney Kimmel Comprehensive Cancer Ce, Phone: 410-955-8804, Email: jhcccro@jhmi.edu

Children's Hospitals and Clinics of Minnesota - Minneapolis, Minneapolis, Minnesota 55404, United States; Recruiting
Clinical Trials Office - Children's Hospitals and Clinics of M, Phone: 612-813-5193

Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis, St. Louis, Missouri 63110, United States; Recruiting
Robert J. Hayashi, Phone: 314-454-4118

Oregon Health and Science University Cancer Institute, Portland, Oregon 97239-3098, United States; Recruiting
Clinical Trials Office - Oregon Health and Science University, Phone: 503-494-1080, Email: trials@ohsu.edu

Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15213, United States; Recruiting
Clinical Trials Office - Children's Hospital of Pittsburgh, Phone: 412-692-5573

Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas, Dallas, Texas 75390, United States; Recruiting
Clinical Trials Office - Simmons Comprehensive Cancer Center a, Phone: 866-460-4673; 214-648-7097

Primary Children's Medical Center, Salt Lake City, Utah 84113-1100, United States; Recruiting
Phillip E. Barnette, Phone: 801-662-4700

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: July 2008
Last updated: November 1, 2008