A Study in Adults With Untreated Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety and optimal dosing of L-asparaginase in adult patients with acute lymphoblastic leukemia (ALL) between the ages of 18 and 50 years.

Detailed Description
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This study has four treatment phases: 1) induction, 2) central nervous system therapy, 3) intensification, and 4) continuation. The induction phase lasts one month and eight drugs are used during this phase of treatment. The drugs are administered as follows: Prednisone; on days 1-28: Vincristine; on days 1, 8, 15, and 22: Doxorubicin; on days 1 and 2: Methotrexate; on day 3; Leucovorin; 36 hours after methotrexate: Asparaginase; on day 5: Intra-thecal Cytarabine; on days 1, 15, and 29: Intra-thecal Methotrexate/Hydrocortisone; on days 15 and 29 A bone marrow aspirate and biopsy will be obtained on day 15 and day 29 of induction therapy. If on day 29, the patients' bone marrow and peripheral blood counts are not in complete remission, then the patient may receive vincristine on days 29, 36 and 43. Bone marrow biopsy will be repeated weekly until complete remission is documented. If the patient does not achieve complete remission by day 49, they will be removed from the study. Central nervous system (CNS) therapy begins immediately after the end of the induction therapy. This phase of treatment should last 3 weeks. Treatment includes a series of spinal taps with the instillation of anti-leukemia drugs. Four spinal taps will be performed over a two week period. Anti-leukemia drugs will also be given orally. The drugs given are as follows: Vincristine; on day 1: Doxorubicin; on day 1: 6-mercaptopurine (6-MP); on days 1-14: Intra-thecal Methotrexate/Cytarabine; 4 times over 2 weeks. Radiation therapy (RT) will be delivered in 10 daily treatments during the CNS phase of therapy. The intensification phase begins as soon as the CNS phase ends and lasts approximately 30 weeks. It consists of cycles of chemotherapy repeated every 3 weeks, along with asparaginase administered weekly. The drugs given are as follows: Vincristine; day 1: Dexamethasone; days 1-5: 6-MP; days 1-14: Doxorubicin; day 1: Asparaginase; weekly: Methotrexate; weekly: Intra-thecal Hydrocortisone/Methotrexate/cytarabine; every 18 weeks. The continuation phase of treatment begins after the intensification phase. It consists of cycles of chemotherapy repeated every three weeks and will last until the patient is in remission for two years. The drugs given are: Vincristine; day 1 : Prednisone or Dexamethasone; days 1-5: 6-MP; days 1-14: Methotrexate; weekly: Intra-thecal Methotrexate/Cytarabine/Hydrocortisone: every 18 weeks. During this study, blood tests will be performed at the start of therapy, at day 29 post induction and at the time of each intra-thecal therapy (every 18 weeks). Bone marrow biopsy/aspirate will be done days 15 and 29 of induction, then every 6 months until completion.

Official Title
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A Multicenter Phase II Study in Adults With Untreated Acute Lymphoblastic Leukemia: Testing Pharmacokinetically Individualized Doses of L-Asparaginase Following the DFCI Pediatric Consortium Protocol

Conditions
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Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: prednisone
* Drug: doxorubicin
* Drug: vincristine
* Drug: methotrexate
* Drug: asparaginase
* Drug: dexamethasone
* Radiation: cranial radiation
* Drug: leucovorin
* Drug: cytarabine
* Drug: hydrocortisone
* Drug: 6-mercaptopurine (6-MP)
* Drug: e. coli L-asparaginase


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have pathologically documented acute lymphoblastic leukemia, excluding mature B-cell ALL. No prior therapy for leukemia with the following exceptions: up to one week of steroids; emergent leukapheresis; emergency treatment for hyperleukocytosis with hydroxyurea; cranial RT for CNS leukostasis (one dose only); emergent radiation therapy to the mediastinum. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2. Between the ages of 18 to 50 years. Exclusion Criteria: Uncontrolled active infection. Pregnancy or nursing mothers. Prior history of pancreatitis. Prior history of a cerebrovascular accident or hemorrhage. Evidence of infection with the human immunodeficiency virus. Active psychiatric or mental illness making informed consent or careful clinical follow-up unlikely. The treating physician should consider all relevant medical and other considerations when deciding whether this protocol is appropriate for a particular patient.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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 |
| --- | --- |
| Other: Only Arm for this study<br>Only Arm for this study | Drug: prednisone<br>* Induction Phase: Given orally on days 1-28<br>Drug: doxorubicin<br>* Induction Phaese: Given intravenously on day 1 and day 2 CNS Therapy: Given intravenously on day 1 Intensification: Given day 1 of each cycle<br>Drug: vincristine<br>* Induction: Given intravenously on days 1, 8, 15, and 22. If complete remission not acheived, will be given on days 29, 36 and 43. CNS Therapy: Given intravenously on day 1. Intensification: Given intravenously on day 1 of each cycle. Continuation: Given intravenously on day 1 of each cycle<br>Drug: methotrexate<br>* Induction: Given intravenously on day 3. CNS Therapy: Given intrathecally 4 times over two weeks Intensification: Given intrathecally every 18 weeks Continuation: Given intravenously weekly and intrathecally every 18 weeks<br>Drug: asparaginase<br>* Induction: Given into the muscle on day 5<br>Drug: dexamethasone<br>* Intensification: Given orally on days 1-5 of each cycle<br>Radiation: cranial radiation<br>* Given in 10 daily treatments during CNS therapy phase<br>Drug: leucovorin<br>* Induction: Given intravenously or orally 36 hours after methotrexate<br>Drug: cytarabine<br>* Induction: Given intrathecally days 1, 15, 29 CNS Therapy: Given intrathecally 4 times over 2 weeks Intensification: Given intrathecally every 18 weeks Continuation: Given intrathecally every 18 weeks<br>* Other names: Ara-C;Drug: hydrocortisone<br>* Induction: Given intrathecally on days 15 and 29. Intensification: Given intrathecally every 18 weeks. Continuation: Given intrathecally every 18 weeks.<br>Drug: 6-mercaptopurine (6-MP)<br>* CNS Therapy: Taken orally on days 1-14. Intensification: Taken orally on days 1-14. Continuation: Taken orally on days 1-14.<br>Drug: e. coli L-asparaginase<br>* Intensification: Given in to the muscle weekly.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the feasibility, safety and efficacy of the high-risk pediatric treatment regimen in adult patients between the ages of 18 and 50 years |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the safety and optimal dosing of L-asparaginase during the intensification period |  | 5 years | 
| to determine the effect of weekly E. coli L-asparaginase by evaluating serum asparaginase levels in all patients |  | 5 years | 
| to determine the safety of individualized dosing of E. coli L-asparaginase based upon asparaginase levels |  | 5 years | 
| to evaluate the outcome of patients based upon minimal residual disease status (MRD) after 28 days of multi-agent induction chemotherapy |  | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chemotherapy, ALL, acute lymphoblastic leukemia, asparaginase