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

Alternate Title

Pegasparaginase or Asparaginase and Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Acute Lymphoblastic Leukemia

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Active	1 to 17	NCI	DFCI-05001 NCT00400946

Objectives

Primary

1. Compare the relative toxicity of pegasparaginase vs E. coli asparaginase when administered with combination chemotherapy in children with newly diagnosed acute lymphoblastic leukemia (ALL).

Secondary

1. Compare the relative efficacy of these regimens in these patients.
2. Determine the prognostic significance of asparaginase antibody formation.
3. Correlate trough enzyme levels with outcome (toxicity and relapse).
4. Compare the quality of life in patients treated with pegasparaginase vs E. coli asparaginase.
5. Compare trough serum asparaginase enzyme levels, asparagine levels, and anti-asparaginase antibody levels in patients treated with these regimens.
6. Determine the rate of infections (episodes of bacteremia and disseminated fungal infections) during the remission induction phase of combination chemotherapy in these patients.
7. Determine the prognostic significance of response to remission induction chemotherapy as measured by morphology and minimal residual disease (MRD) measures.
8. Determine the outcome of patients based on MRD status after 28 days of multiagent chemotherapy that intensifies treatment for B-lineage patients with MRD levels greater than 0.001 at the end of remission induction therapy.
9. Determine the outcome of patients based on MRD status after 14 days of multiagent chemotherapy and at various other time points while on treatment (every 18 weeks after achieving complete remission and at the completion of all chemotherapy).
10. Compare the outcome (based on bone marrow morphology after 14 days of multiagent chemotherapy) of patients with M2/M3 status at that time point vs M1 status or hypoplastic marrows.
11. Determine the efficacy and CNS-related toxicity of CNS-directed treatments in these patients.
12. Determine the efficacy and CNS-related toxicity (acute and long-term) of the high-risk (HR) regimen in which a subset of HR patients are treated with intensive intrathecal (IT) chemotherapy and the remainder are treated with cranial radiation therapy (concurrent with IT chemotherapy).
13. Determine the efficacy and CNS-related toxicity (acute and long-term) of intensive IT therapy in standard-risk patients.
14. Correlate dietary antioxidant micronutrient intake (including ascorbic acid, vitamin E, vitamin A, beta carotene, and total carotenoids) with the rate of infections (episodes of bacteremia and disseminated fungal infections) during remission induction therapy and the consolidation IA phase.
15. Correlate dietary calcium intake with risk for development of fractures during the continuation phase of therapy.

Entry Criteria

Disease Characteristics:

• Diagnosis of acute lymphoblastic leukemia (ALL)
  • No known mature B-cell ALL, defined by the presence of any of the following:
    • Surface immunoglobulin
    • L3 morphology
    • t(8;14)(q24;q32)
    • t(8;22)
    • t(2;8)
  • T-cell surface markers and t(8;14)(q24;q11) allowed



• Meets criteria for 1 of the following risk groups:
  • Standard-risk (SR) disease, defined by the following criteria:
    • 1 to 9 years of age
    • Highest pretreatment WBC < 50,000/mm³
    • No evidence of CNS leukemia, defined by all of the following:
      • Diagnostic lumbar puncture without any cerebrospinal fluid (CSF) blast cells on cytospin (CNS-1) OR < 5 WBC/high-power field (hpf) in CSF with blast cells on cytospin (CNS-2)
      • CNS-1 CSF on days 18 and 32 of study treatment
      • Absence of cranial nerve palsy at diagnosis
    • Absence of T-cell markers on lymphoblasts
    • Absence of t(9;22), mixed-lineage leukemia (MLL) gene translocations, and hypodiploidy < 45 chromosomes by karyotype or fluorescent in situ hybridization (FISH)
    • Minimal residual disease (MRD) level < 0.001 at the end of study remission induction therapy (day 32) OR end-of-induction MRD status cannot be determined
  • High-risk (HR) disease, defined by any of the following criteria:
    • 10 to 17 years of age
    • Highest pretreatment WBC ≥ 50,000/mm³
    • Evidence of CNS leukemia, defined by any of the following:
      • Diagnostic lumbar puncture with ≥ 5 WBC/hpf and blast cells on cytospin (CNS-3)
      • CNS-2 CSF on day 18 or 32 of study treatment
      • CNS-3 CSF on day 18 of study treatment
      • Presence of cranial nerve palsy at diagnosis
    • Predominance of T-cell markers on lymphoblasts
    • Presence of t(9;22)
      • An allogeneic stem cell donor will be sought for transplantation
      • These patients will not receive CNS therapy during study treatment
    • B-lineage and MRD level < 0.001 at the end of study remission induction therapy (day 32) OR end-of-induction MRD status cannot be determined
  • Very high-risk (VHR) disease, defined by any of the following criteria:
    • Presence of MLL gene translocations (i.e., t[4;11]) by karyotype, FISH, or molecular analysis
    • Presence of hypodiploidy < 45 chromosomes by karyotype or FISH analysis
    • MRD level ≥ 0.001 at the end of study remission induction therapy (day 32)



• No secondary ALL

Prior/Concurrent Therapy:

• No prior therapy except steroids of ≤ 1 week in duration and/or emergent radiation therapy to the mediastinum
  • Patients treated with steroids within the past 7 days will not receive steroid prophase during study treatment

Patient Characteristics:

• No known HIV positivity
• Not pregnant or nursing
• Fertile patients must use effective contraception

Expected Enrollment

A total of 544 patients will be accrued for this study.

Outcomes

Toxicity of pegasparaginase vs E. coli asparaginase

Efficacy of pegasparaginase vs E. coli asparaginase
Prognostic significance of asparaginase antibody formation
Correlation of trough enzyme levels with outcome (toxicity and relapse)
Quality of life
Comparison of trough serum asparaginase enzyme levels, asparagine levels, and anti-asparaginase antibody levels
Rate of infections (episodes of bacteremia and disseminated fungal infections) during the remission induction phase of combination chemotherapy
Prognostic significance of response to remission induction chemotherapy as measured by morphology and minimal residual disease (MRD)
Outcome based on MRD status after 28 days of multiagent chemotherapy that intensifies treatment for B-lineage patients with MRD levels > 0.001 at the end of remission induction therapy
Outcome based on MRD status after 14 days of multiagent chemotherapy, every 18 weeks after achieving complete remission, and at the completion of all chemotherapy
Comparison of the outcome of patients (based on bone marrow morphology after 14 days of multiagent chemotherapy) with M2/M3 status vs M1 status or hypoplastic marrows
Efficacy of CNS-directed treatment
CNS-related toxicity of CNS-directed treatment
Relationship between dietary intake and rate of infections and risk of development of fractures during treatment

Outline

This is a randomized, multicenter, open-label study. Patients are stratified according to disease risk (standard-risk [SR] vs high-risk [HR] vs very high risk [VHR]).

• Steroid prophase*: Patients receive intrathecal (IT) cytarabine on day 1 and methylprednisolone IV every 8 hours on days 1-3. Patients then proceed to remission induction therapy.

  Patients with CNS leukemia (CNS-2, CNS-3, or traumatic lumbar puncture [LP] with blasts) on initial LP receive additional IT cytarabine twice weekly beginning on days 4-6 and continuing until cerebrospinal fluid (CSF) is clear, followed by 2 additional doses. Patients with cranial nerve palsy but no leukemia blasts in CSF or leukemic eye infiltrates also receive additional IT cytarabine as above.

   [Note: *Patients who received steroids within the past 7 days do not receive steroid prophase treatment; instead they proceed directly to remission induction therapy according to their risk group.]




• Remission induction therapy (SR patients): Patients receive oral prednisone or prednisolone 2-3 times daily OR methylprednisolone IV every 8 hours on days 4-32; vincristine IV on days 4, 11, 18, and 25; doxorubicin hydrochloride (DOX) IV over 15 minutes on days 4 and 5; methotrexate (MTX) IV on day 6; pegasparaginase IV over 1 hour on day 7; triple intrathecal therapy (TIT) comprising methotrexate, cytarabine, and hydrocortisone on day 18; and IT MTX on day 32.

   [Note: Patients who do not receive steroid prophase treatment also receive IT cytarabine on day 4.]




• Remission induction therapy (HR and VHR patients): Patients receive prednisone/prednisolone OR methylprednisolone; vincristine; DOX; MTX IV; pegasparaginase; TIT; and IT MTX as in the SR group. Patients also receive dexrazoxane hydrochloride IV over 15 minutes preceding the DOX infusions on days 4 and 5.

   [Note: Patients who do not receive steroid prophase treatment also receive IT cytarabine on day 4.]

  Patients who are in complete remission (CR) on day 32 proceed to consolidation I. Patients who are not in CR on day 32 receive vincristine IV weekly until CR is achieved. Patients with persistent marrow (greater than 5% leukemic blasts) or those who do not achieve CR by day 53 are removed from the study.

  Patients with CSF blasts on cytospin and at least 5 WBC/high-power field (hpf) in the CSF (CNS-3) after remission induction therapy are removed from the study. Patients with CSF blasts and less than 5 WBC/hpf in the CSF (CNS-2) receive 1 course of systemic chemotherapy comprising vincristine IV once a week for 4 weeks; dexrazoxane hydrochloride IV over 15 minutes followed by DOX IV over 15 minutes once a day for 2 days; and oral mercaptopurine once a day for 2 weeks. Patients with persistent CNS blasts at day 53 are removed from the study. Patients with no CNS blasts at day 53 proceed to consolidation I.




• Consolidation I (SR patients): Patients receive vincristine IV and IT MTX on day 1 and oral mercaptopurine once daily on days 1-14. Patients also receive high-dose MTX (HDM) IV continuously over 24 hours on day 1 and leucovorin calcium IV every 6 hours beginning 36 hours after the start of the HDM infusion and continuing until MTX levels are undetectable. Patients proceed to CNS therapy after day 21.



• Consolidation I (HR patients): Patients receive vincristine, IT MTX, and mercaptopurine as in the SR group. Patients also receive dexrazoxane hydrochloride IV over 15 minutes followed by DOX IV over 15 minutes on day 1 and HDM with leucovorin calcium support as in the SR group beginning 8-24 hours after the completion of the DOX infusion. Patients proceed to CNS therapy after day 21.



• Consolidation I (VHR patients): Patients receive consolidation therapy in 3 stages.
  • Stage IA: Patients receive vincristine, IT MTX, and mercaptopurine as in the SR group. Patients also receive dexrazoxane hydrochloride, DOX, HDM, and leucovorin calcium as in the HR group.
  
  
  
  • Stage IB: Patients receive cyclophosphamide IV over 1 hour and IT MTX on day 22; oral mercaptopurine once daily on days 22-35; and cytarabine IV on days 23-26 and 30-33.
  
  
  
  • Stage IC: Patients receive high-dose cytarabine IV over 3 hours every 12 hours on days 43 and 44; etoposide IV over 1 hour on days 45-47; and oral dexamethasone twice daily on days 43-47. Patients also receive E. coli asparaginase* intramuscularly (IM) weekly beginning on day 48 and continuing for up to 30 weeks OR pegasparaginase* IV over 1 hour every 2 weeks beginning on day 48 and continuing for up to 30 weeks. Patients proceed to CNS therapy after day 49.

     [Note: *Patients are either randomized to receive E. coli asparaginase or pegasparaginase OR are assigned to receive E. coli asparaginase. Patients continue to receive E. coli asparaginase or pegasparaginase during CNS therapy and consolidation II therapy.]

  
  
  



• CNS therapy (SR patients): Patients receive vincristine IV on day 1; oral mercaptopurine once daily on days 1-14; oral dexamethasone twice daily on days 1-5; and TIT twice weekly for 2 weeks. Patients also receive E. coli asparaginase* OR pegasparaginase* as above beginning on day 1 and continuing for up to 30 weeks. Patients proceed to consolidation II after day 21.

   [Note: *Patients are either randomized to receive E. coli asparaginase or pegasparaginase OR are assigned to receive E. coli asparaginase. Patients continue to receive E. coli asparaginase or pegasparaginase during consolidation II therapy.]




• CNS therapy (HR and VHR patients): Patients receive vincristine, mercaptopurine, dexamethasone, and TIT as in the SR group. Patients also receive dexrazoxane hydrochloride IV over 15 minutes followed by DOX IV over 15 minutes on day 1. HR patients also receive E. coli asparaginase OR pegasparaginase as above beginning on day 1 and continuing for up to 30 weeks. VHR patients continue to receive E. coli asparaginase OR pegasparaginase as per consolidation I treatment. Patients proceed to consolidation II after day 21.

  Patients with WBC > 100,000/mm³, T-cell disease, and/or CNS-3 at diagnosis or CNS-2 at end of remission induction therapy also undergo cranial radiation therapy daily for 8 or 10 days.




• Consolidation II (SR patients): Patients receive vincristine IV on day 1; oral dexamethasone twice daily on days 1-5; and oral mercaptopurine once daily on days 1-14. Treatment repeats every 21 days until E. coli asparaginase or pegasparaginase is completed. Patients also receive MTX IV or IM 1 day after each E. coli asparaginase or pegasparaginase dose and TIT every 9 weeks for 6 doses and then every 18 weeks thereafter.



• Consolidation II (HR and VHR patients): Patients receive vincristine, dexamethasone, and mercaptopurine as in the SR group. Patients also receive dexrazoxane hydrochloride IV over 15 minutes followed by DOX IV over 15 minutes on day 1. Treatment repeats every 21 days until E. coli asparaginase or pegasparaginase is completed. Patients also receive MTX IV or IM as in the SR group and TIT every 9 weeks for 6 doses and then every 18 weeks thereafter OR TIT every 18 weeks.



• Continuation therapy: After completion of all consolidation therapy, all patients receive vincristine IV on day 1; oral dexamethasone twice daily on days 1-5; oral mercaptopurine once daily on days 1-14; and MTX IV or IM on days 1, 8, and 15. Treatment repeats every 21 days for up to 2 years after achieving CR. Patients continue to receive TIT as in consolidation II for up to 2 years after achieving CR.

Patients complete dietary questionnaires at the time of diagnosis, at day 32, and 12 months after diagnosis.

Quality of life is assessed periodically.

After completion of study therapy, patients are followed periodically for 3 years and then annually thereafter.

Trial Contact Information

Trial Lead Organizations

Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute

Lewis Silverman, MD, Principal investigator		Ph: 617-632-6191; 866-790-4500

U.S.A.
Massachusetts
	Boston
	Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
		Lewis Silverman, MD	Ph:  617-632-6191 866-790-4500
New York
	Bronx
	Albert Einstein Cancer Center at Albert Einstein College of Medicine
		Clinical Trials Office - Albert Einstein Cancer Center at Albert Einstein College of Medicine	Ph:  718-904-2730
			Email: aecc@aecom.yu.edu
	New York
	Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center
		Clinical Trials Office - Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center	Ph:  212-305-8615
	Rochester
	James P. Wilmot Cancer Center at University of Rochester Medical Center
		Barbara Asselin, MD	Ph:  716-275-2981
Rhode Island
	Providence
	Hasbro Children's Hospital
		Clinical Trials Office - Hasbro Children's Hospital	Ph:  401-444-8945
Virginia
	Fairfax
	INOVA Fairfax Hospital
		Marshall Schorin, MD	Ph:  703-750-8800
Canada
Ontario
	Hamilton
	McMaster Children's Hospital at Hamilton Health Sciences
		Uma Athale, MD	Ph:  905-521-2000 ext. 73464
Quebec
	Montreal
	Hopital Sainte Justine
		Albert Moghrabi, MD	Ph:  514-345-4969
			Email: albert.moghrabi@umontreal.ca
	Sainte Foy
	Centre de Recherche du Centre Hospitalier de l'Universite Laval
		Bruno Michon, MD	Ph:  418-656-4141
Puerto Rico
	Santurce
	San Jorge Children's Hospital
		Luis Clavell, MD	Ph:  787-726-0316
			Email: luis.clavell@sjcms.com

Registry Information
Official Title		Treatment of Acute Lymphoblastic Leukemia in Children
Trial Start Date		2005-04-22
Trial Completion Date		2010-05-03 (estimated)
Registered in ClinicalTrials.gov		NCT00400946
Date Submitted to PDQ		2006-10-04
Information Last Verified		2009-06-07
NCI Grant/Contract Number		CA068484, CA06516

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