A Study of Children With Refractory or Relapsed ALL

Sponsor

St. Jude Children's Research Hospital (Other)

Overall Status

Completed

CT.gov ID

NCT00187083

Collaborator

(none)

Enrollment

Location

Arms

81.9

Duration (Months)

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The main purpose of this study is to find out which form of asparaginase (the native E. coli/Erwinia) or PEG-asparaginase) is more effective during induction treatment for children with acute lymphoblastic leukemia that has come back after treatment (relapsed) or is resistant to treatment (refractory)

Condition or Disease	Intervention/Treatment	Phase
Acute Lymphoblastic Leukemia	Drug: Topotecan, dexamethasone, vincristine Drug: E. coli Asparaginase, PEG-L-asparaginase Drug: erwinia asparaginase Drug: fludarabine, methotrexate, mercaptopurine Drug: idarubicin, etoposide, cytarbine, teniposide Procedure: chemotherapy, intrathecal chemotherapy, steroid therapy	Phase 3

Detailed Description

The present protocol will compare the biologic effects of PEG-asparaginase vs native-forms of asparaginase in a randomized trial using the same dosages and schedules used in the POG 9411 study. Comprehensive studies, including the measurement of antibodies and asparagine levels as well as the pharmacokinetics of L-asparaginase, will be performed. This protocol will also study the changes in topoisomerase I and topoisomerase II levels and the fractions of topoisomerase I/II translocations in malignant lymphoblasts after upfront window topotecan therapy, and correlate oncolytic response with these changes.

Secondary objectives include:

To compare changes in asparagine levels 28 days after initiation of treatment with asparaginase between the two groups.
To estimate the pharmacokinetics of L-asparaginase, compare the pharmacokinetics between the two groups of patients, and correlate the pharmacokinetics with the development of antibody to asparaginase and depletion of asparagine.
To measure the pharmacokinetics and pharmacodynamics of topotecan in patients with recurrent acute lymphoblastic leukemia
To determine whether the frequency of recombinogenesis in lymphocytes is increased during or after etoposide therapy relative to the pre-therapy level, and to explore whether etoposide pharmacokinetics are related to the Day 7 or post-therapy level of recombinogenesis.

Detailed Description of Treatment Plan

WINDOW Topotecan 2.4 mg/m2 ; IV over 30 min in 5 doses Days 1-5

STANDARD INDUCTION Dexamethasone 6 mg/m2/day orally Days 8-35 Vincristine 1.5 mg/m2 (max 2.0 mg) days 8, 15, 22, 29

RANDOMIZE E. coli asparaginase 10,000 U/m2/day IM (or Erwinia if previous allergy to E. coli) Days 8, 11, 13, 15, 18, 20, 22, 25, 27, 29, 32, 34

PEG-Asparaginase 2500 U/m2/day IM Days 8, 15, 22, 29

ITHMA Days 8, 22, 36

CONSOLIDATION

Fludarabine: 15 mg/m2 IV over 30 min; days 1,2,3,4 Ara-C: 2 g/m2 IV days 1,2,3,4

Patients who achieve remission on R16 induction or consolidation may be eligible for either a matched sibling or a fully matched/one-antigen-mismatched unrelated donor transplant

For patients not undergoing bone marrow transplant:

SECONDARY CONSOLIDATION

VP 16: 50 mg/m2 PO qd for 14 days. Vincristine: 1.5 mg/m2 (max 2.0 mg) IV; days 1, 8. IT MHA day 1

CONTINUATION CHEMOTHERAPY

Cycle 1:

Cyclophosphamide 1 g/m2 IV on days 1 and 2 Vincristine 1.5 mg/m2 IV on day 1 (max 2.0 mg)

Cycle 2:

VP-16 50 mg/m2 day PO daily x 14 days Decadron 6 mg/m2 PO daily ) TID x 14 days Vincristine 1.5 mg/m2 IV (max 2 mg) on days 1 and 8.

Cycle 3:

HD MTX 5 gm/m2 continuous infusion over 24 hrs E. coli Asparaginase 10,000 U/m2/dose IM qod x3 or PEG Asparaginase 2500 U/m2/dose IM x 1 (maintain same randomization for Asparaginase preparation as during induction)

Cycle 4:

High Dose Ara-C 2 g/m2/dose IV over 2 hrs q 12 hrs x 3 doses.[Total dose 6 gm/m2] Idarubicin 12 mg/m2 IV over 30 min X 1 [after completion of first dose of Ara-C] IT MHA on day 1 prior to the HDARA-C (dose of ITMHA is age adjusted as outlined in section 7.3)

STANDARD CONTINUATION CHEMOTHERAPY

Patients will receive 4-week rotational cycles of chemotherapy with the following pairs of drugs for total treatment duration of 17 months.

Week #1 Cyclophosphamide (300 mg/m2 IV) + VCR (1.5 mg/m2 IV; max 2 mg). Week #2 VM26 (200 mg/m2 IV) + Ara C (300 mg/m2 IV). Week #3 MTX (MTX should be given IM or as a 2 hr IV infusion if the patient has had previous cranial iradiation) (40 mg/m2 IV/IM) + 6 MP (75 mg/m2 PO q HS x 7) Week #4 MTX (MTX should be given IM or as a 2 hr IV infusion if the patient has had previous cranial irradiation)(40 mg/m2 IV/IM) + 6 MP (75 mg/m2 PO q HS x 7)

IT MHA: Given every 8 weeks throughout standard continuation chemotherapy for patients with CNS 1 status Given every 4 weeks for patients with CNS 2/3 status who will receive CSI at the end of chemotherapy

Study Design

Study Type:

Interventional

Actual Enrollment :

40 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Study of Children With Refractory or Relapsed Acute Lymphoblastic Leukemia (ALLR16)

Study Start Date :

Feb 1, 1997

Actual Primary Completion Date :

Dec 1, 2003

Actual Study Completion Date :

Dec 1, 2003

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Native asparaginase	Drug: Topotecan, dexamethasone, vincristine See Detailed Description section for details of treatment interventions. Drug: E. coli Asparaginase, PEG-L-asparaginase See Detailed Description section for details of treatment interventions. Drug: erwinia asparaginase See Detailed Description section for details of treatment interventions. Drug: fludarabine, methotrexate, mercaptopurine See Detailed Description section for details of treatment interventions. Drug: idarubicin, etoposide, cytarbine, teniposide See Detailed Description section for details of treatment interventions. Procedure: chemotherapy, intrathecal chemotherapy, steroid therapy See Detailed Description section for details of treatment interventions.
Experimental: 2 PEG-asparaginase	Drug: Topotecan, dexamethasone, vincristine See Detailed Description section for details of treatment interventions. Drug: E. coli Asparaginase, PEG-L-asparaginase See Detailed Description section for details of treatment interventions. Drug: erwinia asparaginase See Detailed Description section for details of treatment interventions. Drug: fludarabine, methotrexate, mercaptopurine See Detailed Description section for details of treatment interventions. Drug: idarubicin, etoposide, cytarbine, teniposide See Detailed Description section for details of treatment interventions. Procedure: chemotherapy, intrathecal chemotherapy, steroid therapy See Detailed Description section for details of treatment interventions.

Arm

Intervention/Treatment

Experimental: 1

Native asparaginase

Drug: Topotecan, dexamethasone, vincristine