Erwinase for Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL) (IND 104224)
Condition: Relapsed Acute Lymphoblastic Leukemia; Allergy to PEG e.Coli Asparaginase; Allergy to Native e.Coli Asparaginase
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Hypersensitivity
Intervention: Erwinase; Vincristine; Dexamethasone; Doxorubicin; Cytarabine; Methotrexate; Triple Intrathecal Therapy; Dexrazoxane
Intervention description: The dose of Erwinase will be assigned at study entry. The first dose of Erwinase wil be given between Days 3-5 and will continue on a M-W-F schedule for a total of 10 doses.
Erwinase will be administered as a 2-hour intravenous infusion.; 1.5 mg/m2/dose IV push (maximum single dose 2 mg) on Days 1, 8, 15 and 22; 10 mg/m2/day divided BID. Give by mouth days 1-14.; 60 mg/m2/day IV over 15 minutes on day 1; Given Intrathecally at the dose defined by age on day 1. 30 mg for age 1-1.99 50 mg for age 2-2.99 70 mg for age 3 and older; Given Intrathecally to all patients who are CNS 1 or 2 at study entry. Dose defined by age. Given on day 15 8mg for age 1-1.99 10 mg for age 2-2.99 12 mg for age 3-8.99 15 mg for age 9 and older; Methotrexate, Cytarabine and Hydrocortisone given Intrathecally on day 8, 15 and 22 for patients who are CNS 3 at study entry. Doses determined by age.; Due to the limited availability of Dexrazoxane (Zinecard®), treatment will be at the discretion of the treating physician. Dose should be 600 mg/m2 as a IV push immediately prior to anthracycline dose (the elapsed time from the beginning of the dexrazoxane dose to the end of the anthracycline infusion should be 30 minutes or less).
Intervention MeSH terms: Cytarabine; Dexamethasone; Dexamethasone acetate; Doxorubicin; Methotrexate; Vincristine; Asparaginase; Dexrazoxane; Razoxane; Dexamethasone 21-phosphate; BB 1101
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 1.0
Sex: All
Minimum age: 1 Year
Maximum age: 21 Years
Healthy volunteers: No
Keywords: Relapsed; Allergy; Erwinia; Acute; Lymphoblastic; Leukemia

Summary:

      This is a phase I study using the Erwinia form of asparaginase in place of the E. coli form
      using a standard re-induction regimen (Vincristine, Dexamethasone, Doxorubicin) for patients
      with relapsed ALL who have developed an allergy to the E. coli formulation. This study will
      administer the drug intravenously instead of the usual intramuscular route. The dose of
      Erwinia will be escalated in the absence of dose limiting toxicity. Patients must have first
      or second relapse ALL with a history of prior systemic reaction to E. coli asparaginase.
    

Eligibility criteria:

        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.