A Study of Children With Refractory or Relapsed ALL

St. Jude Children's Research Hospital

Status and phase: Completed; Phase 3

Conditions: Acute Lymphoblastic Leukemia

Treatments: Drug: idarubicin, etoposide, cytarbine, teniposide; Drug: E. coli Asparaginase, PEG-L-asparaginase; Drug: fludarabine, methotrexate, mercaptopurine; Drug: erwinia asparaginase; Procedure: chemotherapy, intrathecal chemotherapy, steroid therapy; Drug: Topotecan, dexamethasone, vincristine

Study type: Interventional

Funder types: Other

Identifiers

NCT00187083

ALLR16

Details and patient eligibility

About

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)

Full 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

Enrollment: 40 patients

Sex: All

Ages: Under 18 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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40 participants in 2 patient groups

1

Experimental group

Description:

Native asparaginase

Treatment:

Drug: fludarabine, methotrexate, mercaptopurine

Drug: erwinia asparaginase

Procedure: chemotherapy, intrathecal chemotherapy, steroid therapy

Drug: Topotecan, dexamethasone, vincristine

Drug: E. coli Asparaginase, PEG-L-asparaginase

Drug: idarubicin, etoposide, cytarbine, teniposide

2

Experimental group

Description:

PEG-asparaginase

Treatment:

Drug: fludarabine, methotrexate, mercaptopurine

Drug: erwinia asparaginase

Procedure: chemotherapy, intrathecal chemotherapy, steroid therapy

Drug: Topotecan, dexamethasone, vincristine

Drug: E. coli Asparaginase, PEG-L-asparaginase

Drug: idarubicin, etoposide, cytarbine, teniposide