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Clinical Trials (PDQ®)

Phase III Randomized Comparison of E. coli vs Erwinia vs PEG L-ASP "Investigational Window" Chemotherapy and of High-Dose vs Standard-Dose MTX Early in Induction Chemotherapy in Children with Previously Untreated Murphy's Stage III/IV Lymphoblastic Lymphoma

Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Related Publications
Trial Contact Information

Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IIITreatmentCompleted1 day to 18 yearsNCIDFCI-87001
NCI-T87-0107D, T87-0107

Objectives

I.  Compare, in a randomized Phase III study, the anti-leukemic efficacy, 
acute toxicity, and biochemical pharmacology of E. coli, Erwinia, and 
PEG-modified L-asparaginase administered on day 1 of a 4-day "investigational 
window" period at the outset of induction chemotherapy in children with 
previously untreated ALL or AUL (study closed to leukemia patients as of 8/91).
II.  Determine whether there is any difference in event-free survival and 
leukemia-free survival among patients treated early in their therapeutic 
regimen with standard-dose methotrexate vs. high-dose methotrexate with 
citrovorum rescue (study closed to leukemia patients as of 8/91).
III.  Compare the control of CNS leukemia and therapy-related toxicity of 
high-risk and very-high-risk patients randomized to one of the following two 
regimens of CNS prophylaxis:  conventionally fractionated radiotherapy vs. 
hyperfractionated irradiation, each of which is administered with concomitant 
intrathecal methotrexate/cytosine arabinoside (study closed to leukemia 
patients as of 8/91).

Entry Criteria

Disease Characteristics:

See General Eligibility Criteria

Patient Characteristics:

See General Eligibility Criteria

General Eligibility Criteria:

Previously untreated patients aged 1 
day to 18 years with a diagnosis of ALL, AUL, or Murphy's Stage III/IV 
lymphoblastic lymphoma; as of 8/91, the study is closed to patients with acute 
leukemia but remains open to those with lymphoblastic lymphoma.  Those 
patients found to have mature B-cell ALL, as indicated by surface 
immunoglobulin and/or translocation t8,14, will be removed from study.  
Patients with presumptive systemic infection are eligible for initiation of 
chemotherapy as soon as appropriate diagnostic studies have been completed and 
antimicrobial therapy started.  The following patients are excluded from 
investigational window treatment and start formal Induction chemotherapy 
immediately:  those who are gravely ill (specifically, those with severe 
respiratory distress, those requiring endotracheal intubation, those with 
septic shock, and those who have had intracranial hemorrhage); and those who 
at diagnosis or after appropriate hydration and supportive care demonstrate 
evidence of severe hepatic or pancreatic dysfunction (bilirubin greater than 
3.0 mg/dl, PT and/or PTT more than twice the control levels; or serum amylase 
more than twice normal).

Expected Enrollment

It is anticipated that a total accrual of 350 patients within 4 years will be 
sufficient for the study.

Outline

Randomized study (randomized portion closed as of 8/91).  Patients with 
Murphy's Stage III/IV lymphoblastic lymphoma are nonrandomly assigned to 
Regimen D.  All eligible patients with ALL or AUL were initially randomized on 
Arms I, II, and III for treatment during the Investigational Window.  
Subsequent treatment for these patients was based on prognostic risk.  
Standard-risk patients satisfied all of the following criteria:  WBC less than 
20,000; age 24 months 1 day to 8 years 11 months; no CNS disease or 
mediastinal mass; absence of T-cell markers; remission induction within 33 
days; Philadelphia chromosome (+9;22)-negative; no evidence of biphenotypic 
leukemia.  High-risk patients demonstrated any or all of the following:  WBC 
20,001-100,000; age 366 days to 24 months or over 9 years; CNS disease 
present; mediastinal mass present; T-cell markers present; remission induction 
longer than 33 days; evidence of biphenotypic leukemia.  Very-high-risk 
patients were those with a WBC greater than 100,000 and/or age under 365 days 
and Philadelphia chromosome-positive.  Patients of all risk strata were 
randomized to standard-dose vs. high-dose methotrexate during Induction 
(patients who received high-dose MTX were screened for "third space" fluid 
accumulation, mucositis, or severe skin rash, and met the following laboratory 
requirements:  bilirubin less than 1.2 mg/dl; and serum creatinine less than 
0.6, less than 0.8, less than 1.0, and less than 1.2 mg/dl for patients aged 
0-5, 6-10, 10-15, and over 15 years, respectively).  Patients with Down's 
syndrome were not eligible for high-dose methotrexate and received the lower 
dose.  High-risk and very-high-risk patients were randomized to standard 
fractionation vs. hyperfractionation of craniocervical irradiation during CNS 
Prophylaxis except for patients treated at institutions that are unable to 
give ketamine twice a day were assigned to conventional fractionation.
Investigational Window (Arms closed as of 8/91).
Arm I:  Single-agent Chemotherapy.  E. coli L-Asparaginase, L-ASP, NSC-109229.
Arm II:  Single-agent Chemotherapy.  Erwinia L-ASP, NSC-106977.
Arm III:  Single-agent Chemotherapy.  PEG-modified L-ASP.
Regimen A (Standard-Risk Patients)(Regimen closed as of 8/91).
Induction:  4-Drug Combination Systemic Chemotherapy with Leukovorin Rescue 
(only for patients receiving high-dose MTX) plus Single-agent Intrathecal 
Chemotherapy.  Vincristine, VCR, NSC-67574; Prednisone, PRED, NSC-10023; 
Methotrexate (Standard Dose or High Dose, depending on randomization), MTX, 
NSC-740; Adriamycin, ADR, NSC-123127; with Citrovorum Factor, CF, NSC-3590; 
plus Intrathecal Cytosine arabinoside, IT ARA-C, NSC-63878.
CNS Prophylaxis and Continuation:  5-Drug Combination Systemic Chemotherapy 
plus 2-Drug Combination Intrathecal Chemotherapy plus Bactrim Prophylaxis.  
VCR; PRED; 6-Mercaptopurine, 6-MP, NSC-755; E. coli L-ASP, NSC-109229; MTX; 
plus IT MTX; IT ARA-C; plus Bactrim.
Regimen B (High-Risk Patients)(Regimen closed as of 8/91).
Induction:  4-Drug Combination Systemic Chemotherapy with Leukovorin Rescue 
(only for patients receiving high-dose MTX) plus Single-agent Intrathecal 
Chemotherapy.  VCR; PRED; MTX (Standard Dose or High Dose, depending on 
randomization); ADR; with CF; plus IT ARA-C.
CNS Prophylaxis and Continuation:  6-Drug Combination Systemic Chemotherapy 
plus 2-Drug Combination Intrathecal Chemotherapy plus Radiotherapy plus 
Bactrim Prophylaxis.  VCR; PRED; E. coli L-ASP; ADR; 6-MP; MTX; plus IT MTX; 
IT ARA-C; plus craniospinal irradiation using linear accelerators of 4 or 6 
MeV; plus Bactrim.
Regimen C (Very-High-Risk Patients)(Regimen closed as of 8/91).
Induction:  4-Drug Combination Systemic Chemotherapy with Leukovorin Rescue 
(only for patients receiving high-dose MTX) plus Single-agent Intrathecal 
Chemotherapy.  VCR; PRED; MTX (Standard Dose or High Dose, depending on 
randomization); ADR; with CF; plus IT ARA-C.
Intensification:  5-Drug Combination Systemic Chemotherapy with Leukovorin 
Rescue plus Single-agent Intrathecal Chemotherapy.  VCR; E. coli L-ASP; 6-MP; 
High-Dose MTX; High-Dose ARA-C; with CF; plus IT MTX.
CNS Prophylaxis and Continuation:  6-Drug Combination Systemic Chemotherapy 
plus 2-Drug Combination Intrathecal Chemotherapy plus Radiotherapy plus 
Bactrim Prophylaxis.  VCR; PRED; E. coli L-ASP; ADR; 6-MP; MTX; plus IT MTX; 
IT ARA-C; plus craniospinal irradiation (delivered by conventional 
fractionation vs. hyperfractionation according to randomization) using linear 
accelerators of 4 or 6 MeV; plus Bactrim.
Regimen D (Lymphoblastic Lymphoma Patients).
Induction:  4-Drug Combination Systemic Chemotherapy plus Single-agent 
Intrathecal Chemotherapy.  VCR; PRED; MTX; ADR; plus IT ARA-C. 
CNS Prophylaxis and Continuation:  6-Drug Combination Systemic Chemotherapy 
plus 2-Drug Combination Intrathecal Chemotherapy plus Radiotherapy plus 
Bactrim Prophylaxis.  VCR; PRED; E. coli L-ASP; ADR; 6-MP; MTX; plus IT MTX; 
IT ARA-C; plus craniospinal irradiation using linear accelerators of 4 or 6 
MeV; plus Bactrim.

Published Results

LeClerc JM, Billett AL, Gelber RD, et al.: Treatment of childhood acute lymphoblastic leukemia: results of Dana-Farber ALL Consortium Protocol 87-01. J Clin Oncol 20 (1): 237-46, 2002.[PUBMED Abstract]

Waber DP, Tarbell NJ, Fairclough D, et al.: Cognitive sequelae of treatment in childhood acute lymphoblastic leukemia: cranial radiation requires an accomplice. J Clin Oncol 13 (10): 2490-6, 1995.[PUBMED Abstract]

Related Publications

Silverman LB, Stevenson KE, O'Brien JE, et al.: Long-term results of Dana-Farber Cancer Institute ALL Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1985-2000). Leukemia 24 (2): 320-34, 2010.[PUBMED Abstract]

Waber DP, Silverman LB, Catania L, et al.: Outcomes of a randomized trial of hyperfractionated cranial radiation therapy for treatment of high-risk acute lymphoblastic leukemia: therapeutic efficacy and neurotoxicity. J Clin Oncol 22 (13): 2701-7, 2004.[PUBMED Abstract]

Silverman LB, Declerck L, Gelber RD, et al.: Results of Dana-Farber Cancer Institute Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1981-1995). Leukemia 14 (12): 2247-56, 2000.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

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

Stephen Sallan, MD, Protocol chair
Ph: 617-632-3316; 866-790-4500

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.

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