Erwinase for Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL) (IND 104224)

Significance

1. Substitution of Erwinase after E.coli asparaginase allergy has been standard practice
despite the paucity of evidence regarding its efficacy and uncertainty about dose.
Definition of an appropriate dose and schedule of Erwinase that provides reliable
asparagine depletion may be useful for patients with clinical allergy to E. coli
asparaginase, both in first remission or after relapse.

2. Patients in relapse may have a different level of asparagine synthesis than patients
maintaining remission and require different asparaginase dosing.5

3. Intravenous administration provides more rapid and predictable asparagine depletion with
less discomfort and danger of bleeding for often thrombocytopenic patients than
intramuscular administration.

4. Vincristine, doxorubicin, asparaginase, and dexamethasone with dexrazoxane is clinically
relevant for a population with first marrow relapse.

5. Vincristine, doxorubicin, asparaginase, and dexamethasone with dexrazoxane is clinically
relevant for a population with second marrow relapse, if the duration of CR2 > 18 months
year.

Inclusion Criteria The eligibility criteria listed below are interpreted literally and
cannot be waived.

1. Age Patients must be >1 and < 21 years of age when enrolled onto this study.

2. Diagnosis Patients must have relapsed or refractory ALL with a M3 marrow (marrow
blasts >25%) who have had no more than two prior therapeutic attempts. Patients with
CNS 1, 2, or 3 or testicular disease are eligible. (See section 11.3 for CNS
definitions)

3. E. coli Asparaginase Allergy Patients must have a history of prior systemic allergic
reaction to E. coli asparaginase (native or pegylated), such as urticaria, wheezing,
or anaphylaxis. Local reactions are not sufficient.

4. Performance Level Karnofsky > 50% for patients > 10 years of age and Lansky > 50% for
patients < 10 years of age.

5. Prior Therapy Patients must have fully recovered from the acute toxic effects of all
prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

1. Patients may be in first or second relapse and should not have received more than
2 induction attempts (including frontline therapy).

2. Prior anthracycline exposure: Patients must have less than 400mg/m2 lifetime
exposure of anthracycline chemotherapy.

3. Stem Cell Transplant (SCT): Patients are eligible after allogeneic stem cell
transplant as long as patients are not actively being treated for
graft-versus-host-disease (GvHD).

4. Patients may have received previous therapy using intramuscular (IM) Erwinase.
Patients who have received Erwinase intravenously will be excluded.

6. Reproductive Function

1. Female patients of childbearing potential must have a negative urine or serum
pregnancy test confirmed prior to enrollment.

2. Female patients with infants must agree not to breastfeed their infants while on
this study.

3. Male and female patients of child-bearing potential must agree to use an
effective method of contraception approved by the investigator during the study.

Exclusion Criteria

1. Prior Stroke Patients with a prior history of asparaginase associated stroke are
excluded. Patients with a history of other asparaginase related deep-venous thromboses
(including intra-cranial thromboses without evidence of stroke or hemorrhage) are
eligible.

2. Down Syndrome Patients with Down Syndrome will be excluded.

3. Prior Pancreatitis Patients with prior history of Grade 2 or greater
asparaginase-induced symptomatic pancreatitis will be excluded.

4. Renal Function Patients will be excluded if their serum creatinine is > 1.5 x the
upper limit of normal for age at the institution's laboratory.

5. Liver/Pancreatic Function

Patients will be excluded if their lab results are as follows:

1. Direct bilirubin > 1.5x the institutional ULN for age. A total bilirubin result
that is less than 1.5 times the institutional ULN for age may be used for
eligibility if a direct bilirubin result is not available.

2. SGPT (ALT) > 4 x institutional ULN

3. Amylase or Lipase > 2 x institutional ULN

6. Cardiac Function Patients will be excluded if their shortening fraction by
echocardiogram is less than the institutional normal for age or an ejection fraction
by MUGA is less than the institutional normal for age.

7. Infection Patients will be excluded if they have an active uncontrolled infection.

8. Patients planning on receiving other investigational agents while on this study. (An
investigational agent is defined as any drug not currently approved for use in
humans.)

9. Patients planning on receiving other anti-cancer therapies while on this study.

10. Patients who, in the opinion of the investigator, may not be able to comply with the
safety monitoring requirements of the study.

11. Patients who have started protocol therapy prior to enrollment. Patient may still
enroll if IT therapy was given within 72 hours of study enrollment as part of the
diagnostic lumbar procedure.