Trial Information

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

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