A Study of Children With Refractory or Relapsed ALL

Acute Lymphoblastic Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00187083
• Other study ID #: ALLR16
• Status: Completed
• Phase: Phase 3
• First received: September 12, 2005
• Last updated: June 3, 2008
• Start date: February 1997
• Est. completion date: December 2003

Study information

• Verified date: June 2008
• Source: St. Jude Children's Research Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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)

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

OR

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: December 2003
• Est. primary completion date: December 2003
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 18 Years

Eligibility

Inclusion Criteria

For patients treated on frontline protocols at St. Jude:

• ALL in isolated bone marrow relapse, or combined marrow and extramedullary relapse, during or after treatment with multi-agent chemotherapy (TOTAL XI, XII, XIIIA, XIIIB), or isolated extramedullary relapse after treatment on TOTXII.

• Patients with recurrent T-Cell non-Hodgkin's lymphoma who relapse in the bone marrow with >25% blasts

For patients not treated on front-line St. Jude protocols:

• ALL in isolated bone marrow relapse, or isolated extramedullary relapse, or combined marrow and extramedullary relapse.

All patients:

• First relapse after receiving primary therapy or during primary therapy

• Life expectance of at least 8 weeks

• ECOG score 0-2 Exclusion criteria

• Life expectancy < 8 weeks

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukemia
• Leukemia
• Leukemia, Lymphoid
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Drug:
• Topotecan, dexamethasone, vincristine
See Detailed Description section for details of treatment interventions.
• E. coli Asparaginase, PEG-L-asparaginase
See Detailed Description section for details of treatment interventions.
• erwinia asparaginase
See Detailed Description section for details of treatment interventions.
• fludarabine, methotrexate, mercaptopurine
See Detailed Description section for details of treatment interventions.
• 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.

Locations

Country	Name	City	State
United States	St. Jude Children's Research Hospital	Memphis	Tennessee

Sponsors (1)

Lead Sponsor	Collaborator
St. Jude Children's Research Hospital

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To compare in a randomized trial the depletion of asparagine in patients who receive the native form of asparaginase or PEG-asparaginase during induction therapy.		December 2003	Yes

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