Phase II Randomized Pilot Study of Pegaspargase vs Native E. coli Asparaginase in the Standard Treatment Arm of Protocol CCG-1952 for Standard-Risk Acute Lymphoblastic Leukemia
Last Modified: 2/5/2010
Comparison of Two Forms of Asparaginase in Treating Children With Previously Untreated Acute Lymphoblastic Leukemia
Basic Trial Information
I. Compare the safety of pegaspargase vs. native E. coli asparaginase administered during Induction and phases 1 and 2 of Delayed Intensification of the standard treatment arm on protocol CCG-1952 in children with newly diagnosed, standard-risk acute lymphocytic leukemia. II. Determine whether the incidence of high-titer anti-asparaginase antibodies in children treated with pegaspargase is decreased by at least 50% compared to children treated with native E. coli asparaginase during phases 1 and 2 of Delayed Intensification. III. Determine the length of time that serum asparaginase levels remain above 0.03 IU/microliter and that the serum asparagine concentration remains above 1 micromolar in children treated with pegaspargase vs. native E. coli asparaginase. IV. Compare pharmaco-economic data from PEG-asparaginase with native E. coli-asparaginase in induction and both delayed induction phases.
Newly diagnosed acute lymphoblastic leukemia (ALL) No more than 25% L3 lymphoblasts in marrow Initial white blood cell count less than 50,000/mm3 (performed at CCG institution) Massive lymphadenopathy, massive splenomegaly, or large mediastinal mass allowed CNS or testicular leukemia allowed
No prior treatment for ALL Biologic therapy: Not specified Chemotherapy: Intrathecal cytarabine (IT ARA-C) may begin prior to registration provided systemic chemotherapy initiated within 72 hours afterwards Endocrine therapy: See Radiotherapy At least 1 month since systemic corticosteroids Steroids given for less than 48 hours allowed Inhaled corticosteroids allowed at any time Radiotherapy: Radiotherapy or dexamethasone for mediastinal mass causing superior mediastinal syndrome allowed prior to registration, if indicated Surgery: Not specified
Age: 1 through 9
A total of 116 patients will be accrued for this study over 18 months.
This is a randomized study. Patients are stratified by randomizing institution. All patients receive Induction with prednisone on days 0-27 and vincristine weekly for 4 weeks. One group of patients receives pegaspargase on day 3, while a second group of patients receives native E. coli asparaginase three times per week for 3 weeks, beginning on day 2, 3, or 4. Consolidation begins on day 28 of Induction, with prednisone tapered over 10 days, vincristine given on day 0, and mercaptopurine given on days 1-27. Patients then receive Interim Maintenance 1 with prednisone on days 0-4 and 28-32, vincristine on days 0 and 28, methotrexate weekly through day 49, and mercaptopurine on days 0-49. Delayed Intensification 1 begins on day 56 of Interim Maintenance 1, with dexamethasone on days 0-6 and 14-20, vincristine and doxorubicin on days 0, 7, and 14, cyclophosphamide on day 28, thioguanine on days 28-41, and cytarabine on days 29-32 and 36-39. Patients in the first group receive pegaspargase on day 3, while those in the second group receive native E. coli asparaginase three times per week for 2 weeks, beginning on day 2, 3, or 4. Interim Maintenance 2 begins on day 56 of Delayed Intensification 1, with prednisone on days 0-4 and 28-32, vincristine on days 0 and 28, methotrexate weekly through day 49, and mercaptopurine on days 0-49. Delayed Intensification 2 begins on day 56 of Interim Maintenance 2 and is identical to Delayed Intensification 1. Maintenance begins on day 56 of Delayed Intensification 2, with prednisone on days 0-4, 28-32, and 56-60; vincristine on days 0, 28, and 56; mercaptopurine on days 0-83; and methotrexate weekly through day 77. Maintenance courses repeat every 84 days and continue, in the absence of progression, for 2 calendar years from the beginning of Interim Maintenance 1 for girls and for 3 calendar years for boys. CNS therapy/prophylaxis consists of intrathecal cytarabine/methotrexate during Induction and intrathecal methotrexate during Consolidation, Delayed Intensification 1 and 2, and Maintenance. Patients with CNS leukemia at diagnosis receive craniospinal irradiation at the beginning of Consolidation; those with testicular disease receive bilateral testicular irradiation during Consolidation. Patients are followed every 6-8 weeks for 1 year, every 3 months for 1 year, every 6 months for 1 year, then yearly.
Avramis VI, Sencer S, Periclou AP, et al.: A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children's Cancer Group study. Blood 99 (6): 1986-94, 2002.[PUBMED Abstract]
Kurre HA, Ettinger AG, Veenstra DL, et al.: A pharmacoeconomic analysis of pegaspargase versus native Escherichia coli L-asparaginase for the treatment of children with standard-risk, acute lymphoblastic leukemia: the Children's Cancer Group study (CCG-1962). J Pediatr Hematol Oncol 24 (3): 175-81, 2002 Mar-Apr.[PUBMED Abstract]
Avramis VI, Holcenberg JS, Ettinger AG, et al.: Failure of asparagine (ASN) depletion, not inadequate asparaginase (ASNase) activity, predicts relapse in standard risk (SR) childhood acute lymphoblastic leukemia (ALL): a Children's Oncology Group (COG) report. [Abstract] Blood 110 (11): A-588, 2007.
Avramis IA, Panosyan EH, Dorey F, et al.: Vascular endothelial growth factor (VEGF-A) serum levels in standard risk ALL pediatric patients (CCG-1962 study). [Abstract] J Clin Oncol 24 (Suppl 18): A-9026, 508s, 2006.
Avramis IA, Panosyan EH, Dorey F, et al.: Correlation between high vascular endothelial growth factor-A serum levels and treatment outcome in patients with standard-risk acute lymphoblastic leukemia: a report from Children's Oncology Group Study CCG-1962. Clin Cancer Res 12 (23): 6978-84, 2006.[PUBMED Abstract]
Avramis VI, Panosyan EH, Avramis IA, et al.: Pharmacodynamic relationships between asparagine INPUT (Imax) post asparaginase (ASNase) therapy and outcome in SR ALL patients (CCG-1962). [Abstract] J Clin Oncol 24 (Suppl 18): A-9025, 508s, 2006.
Avramis VI, Panosyan EH, Fu CH, et al.: Pharmacodynamic (PD) analyses of asparagine (Asn) deamination and asn input (Imax) in serum of pediatric patients with standard risk acute lymphoblastic leukemia (SR ALL) receiving native or pegylated E. coli asparaginases (ASNase) (CCG-1962). [Abstract] Blood 104 (11): A-2082, 2004.
Nguyen K, Devidas M, Cheng SC, et al.: Factors influencing survival after relapse from acute lymphoblastic leukemia: a Children's Oncology Group study. Leukemia 22 (12): 2142-50, 2008.[PUBMED Abstract]
Trial Contact Information
Trial Lead Organizations
Children's Cancer Group
John Holcenberg, MD, Protocol chair
Note: The purpose of most clinical trials listed in this database is to test new cancer treatments, or new methods of diagnosing, screening, or preventing cancer. Because all potentially harmful side effects are not known before a trial is conducted, dose and schedule modifications may be required for participants if they develop side effects from the treatment or test. The therapy or test described in this clinical trial is intended for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than standard treatment. A responsible investigator associated with this clinical trial should be consulted before using this protocol.