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

Study Overview
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Brief Summary
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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.

Detailed Description
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Significance 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. Patients in relapse may have a different level of asparagine synthesis than patients maintaining remission and require different asparaginase dosing.5 Intravenous administration provides more rapid and predictable asparagine depletion with less discomfort and danger of bleeding for often thrombocytopenic patients than intramuscular administration. Vincristine, doxorubicin, asparaginase, and dexamethasone with dexrazoxane is clinically relevant for a population with first marrow relapse. 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.

Official Title
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Intravenous Erwinase for Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia and Allergy to E. Coli Asparaginase (IND 104224)

Conditions
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Relapsed Acute Lymphoblastic Leukemia, Allergy to PEG e.Coli Asparaginase, Allergy to Native e.Coli Asparaginase

Intervention / Treatment
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* Drug: Erwinase
* Drug: Vincristine
* Drug: Dexamethasone
* Drug: Doxorubicin
* Drug: Cytarabine
* Drug: Methotrexate
* Drug: Triple Intrathecal Therapy
* Drug: Dexrazoxane


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria The eligibility criteria listed below are interpreted literally and cannot be waived. Age Patients must be >1 and < 21 years of age when enrolled onto this study. 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) 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. Performance Level Karnofsky > 50% for patients > 10 years of age and Lansky > 50% for patients < 10 years of age. Prior Therapy Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study. Patients may be in first or second relapse and should not have received more than 2 induction attempts (including frontline therapy). Prior anthracycline exposure: Patients must have less than 400mg/m2 lifetime exposure of anthracycline chemotherapy. 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). Patients may have received previous therapy using intramuscular (IM) Erwinase. Patients who have received Erwinase intravenously will be excluded. Reproductive Function Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed prior to enrollment. Female patients with infants must agree not to breastfeed their infants while on this study. 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 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. Down Syndrome Patients with Down Syndrome will be excluded. Prior Pancreatitis Patients with prior history of Grade 2 or greater asparaginase-induced symptomatic pancreatitis will be excluded. 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. Liver/Pancreatic Function Patients will be excluded if their lab results are as follows: 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. SGPT (ALT) > 4 x institutional ULN Amylase or Lipase > 2 x institutional ULN 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. Infection Patients will be excluded if they have an active uncontrolled infection. 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.) Patients planning on receiving other anti-cancer therapies while on this study. Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study. 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.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm<br>All patients receive Vincristine, Dexamethasone, Doxorubicin, and Cytarabine. Dexrazoxane optional on Day 1. Erwinase is started between Days 3-5 and is given every M-W-F for a total of 10 doses. Patients with CNS 1 or 2 receive Methotrexate intrathecally on Day 15. Patients with CNS 3 receive Triple Intrathecal Therapy (Methotrexate, Cytarabine and Hydrocortisone) on Days 8, 15, and 22. | Drug: Erwinase<br>* 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.<br>* Other names: Erwinia L-Asparaginase;Drug: Vincristine<br>* 1.5 mg/m2/dose IV push (maximum single dose 2 mg) on Days 1, 8, 15 and 22<br>* Other names: VCR;Drug: Dexamethasone<br>* 10 mg/m2/day divided BID. Give by mouth days 1-14.<br>* Other names: Dexamethasone acetate;Drug: Doxorubicin<br>* 60 mg/m2/day IV over 15 minutes on day 1<br>* Other names: Rubex;Drug: Cytarabine<br>* 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<br>* Other names: Arabinosylcytosine;Drug: Methotrexate<br>* 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<br>* Other names: MTX;Drug: Triple Intrathecal Therapy<br>* 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.<br>Drug: Dexrazoxane<br>* 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).<br>* Other names: Zinecard;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of a Dose-Limiting Toxicity | The MTD in each stratum will be the highest dose at which 1 or fewer of six patients experience DLT during cycle 1 of therapy. | Beginning with the first dose of investigational product until 30 days following the last dose of Erwinase | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate and Minimum Residual Disease | Disease response evaluated by examination and labs. MRD evaluated from marrow samples. | After completion of treatment course | 
| Asparaginase Activity | Activity levels assessed from PK sampling | PK samples to be collected Pre-Tx, and and Erwinase Doses 3, 6 and 9 and Day 29 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed, Allergy, Erwinia, Acute, Lymphoblastic, Leukemia