Pegaspargase and Combination Chemotherapy in Treating Patients With Newly Diagnosed Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells. PURPOSE: This phase II trial is studying the side effects of giving pegaspargase together with combination chemotherapy and to see how well it works in treating patients with newly diagnosed acute lymphoblastic leukemia.

Detailed Description
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OBJECTIVES: Primary To estimate the complete response rate in patients with newly diagnosed acute lymphoblastic leukemia treated with pegaspargase in combination with hyper-CVAD regimen comprising cyclophosphamide, dexamethasone, vincristine sulfate, doxorubicin hydrochloride, methotrexate, and cytarabine. To determine the safety and tolerability of this regimen in these patients. Secondary To evaluate the progression-free survival and overall survival of patients treated with this regimen. To determine the half-life of pegaspargase when administered in combination with hyper-CVAD regimen. To monitor the development of neutralizing antibodies to pegaspargase when administered in combination with hyper-CVAD regimen. To assess minimal residual disease by flow cytometry at the end of courses 1A and 1B. OUTLINE: This is a multicenter study. Hyper-CVAD regimen (courses 1, 3, 5, and 7): Patients receive cyclophosphamide IV over 2-3 hours twice daily on days 1-3, dexamethasone IV on days 1-4 and 11-14, methotrexate intrathecally (IT) on day 2, doxorubicin hydrochloride IV over 2 hours and pegaspargase IV over 1-2 hours on day 4, vincristine sulfate IV on days 4 and 11, and cytarabine IT on day 8. High-dose methotrexate/cytarabine regimen (courses 2, 4, 6, and 8): Patients receive methotrexate IV continuously over 24 hours on day 1, methylprednisolone IV twice daily on days 1-3, methotrexate IT on day 2, cytarabine IV over 2 hours twice daily on days 2 and 3, pegaspargase IV over 1-2 hours on day 3, and cytarabine IT on day 8. Treatment repeats every 3-4 weeks for 8 courses in the absence of disease progression or unacceptable toxicity. Patients with Philadelphia chromosome-positive disease also receive oral imatinib mesylate daily beginning at diagnosis. Patients who complete 8 courses of chemotherapy and are not candidates for hematopoietic stem cell transplantation receive maintenance therapy off study. Blood samples are collected at baseline and periodically during study for pharmacokinetics and neutralizing antibody assays. After completion of study therapy, patients are followed up every 6 months.

Official Title
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Phase II Trial of the Addition of PEG-Asparaginase to the Hyper-CVAD Regimen in Adult Newly-Diagnosed Acute Lymphoblastic Leukemia

Conditions
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Leukemia

Intervention / Treatment
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* Drug: cyclophosphamide
* Drug: cytarabine
* Drug: dexamethasone
* Drug: doxorubicin hydrochloride
* Drug: imatinib mesylate
* Drug: methotrexate
* Drug: methylprednisolone
* Drug: pegaspargase
* Drug: vincristine sulfate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be newly diagnosed (untreated) with Acute Lymphoblastic Leukemia based on a bone marrow examination unless there is a contraindication to having the test performed. This includes precursor-B ALL, precursor-T ALL, and Philadelphia chromosome positive ALL. For reference, see criteria by Center for International Blood and Marrow Transplant Research (CIBMTR).> 20% blasts on a bone marrow aspirate OR If a bone marrow aspirate is not obtained, the diagnosis of acute leukemia can be established by a pathologic diagnosis of acute leukemia on a bone marrow biopsy OR A complete blood count documenting the presence of at least 10,000 white blood cells (WBC)/μl and at least 20% circulating blasts Adults, 18 to 60 years of age. Women of child bearing potential (WOCBP) must be willing to use adequate contraception to avoid pregnancy for the duration of study participation. Eastern Cooperative Oncology Group (ECOG) performance status < 2 Adequate renal function defined as: Serum creatinine ≤ 2.0 x upper limit normal (ULN) for institution Adequate hepatic function defined as:Total bilirubin ≤ 2.0 x ULN for institution Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.0 x ULN for institution Patient must have the ability to understand and the willingness to sign a written informed consent document. The patient and/or the patient's legally authorized guardian must acknowledge consent for treatment as a human subject on this study. Exclusion Criteria: Mature B (Burkitt's) ALL will be excluded. An active malignancy other than ALL (with the exception of basal and/or squamous cell skin cancers and curatively treated carcinoma of the cervix) within 5 past years of study entry. Documented central nervous system (CNS) involvement with leukemia will be excluded. A diagnostic lumbar puncture will not be part of screening procedures. Severe pulmonary, renal, or hepatic disease not related to the patient's ALL will be excluded. Cardiac dysfunction as defined by:Myocardial infarction within the last 6 months of study entry, or Reduced left ventricular function with an ejection fraction ≤50% as measured by Multigated Acquisition (MUGA) scan or echocardiogram at study entry, Unstable angina, Unstable cardiac arrhythmias, New York Heart Association (NYHA) Class III or IV heart failure, Electrocardiographic evidence of acute ischemia or active conduction system abnormalities Known or suspected human immunodeficiency virus (HIV)-positive patients are excluded from the study because of possible risk of lethal infection when treated with marrow suppressive therapy. Any concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, etc.) or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol. Patients who have had chemotherapy or radiotherapy for ALL prior to entering the study will be excluded. Hydroxyurea and one dose of intravenous vincristine are allowed prior to registration for patient convenience. Prior steroid therapy is allowable, ≤5 days prior to the start of the regimen. Patients may not have received any other investigational agents within the last 30 days. WOCBP who are unwilling or unable to use an acceptable method of contraception for the entire study period. Pregnant or lactating women are excluded from this study because of possible risk to the fetus or infant. Women with a positive serum pregnancy test on enrollment or prior to study drug administration will be excluded. Men whose sexual partners are WOCBP, who are unwilling or unable to use an acceptable contraceptive method to avoid pregnancy of his partner for the entire study period.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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: Group 1<br>Drug:cyclophosphamide Day 1- 3: 300 m g/m2 IV over 2-3 hours every 12 hours for 6 doses plus mesna 600 mg/ m2 /day continuous infusion Days 1-3 Drug:cytarabine Day 2 & 3: 3g/m2 IV over 2 hours q12 X 4 Drug:dexamethasone Day 1-4; 11-14: 40 mg daily Drug:doxorubicin hydrochloride Day 4: 50 mg/m2 IV over 2 hours Drug:imatinib mesylate 600 mg/day Drug:methotrexate Day 1: 1g/ m2 (200 mg/ m2load IV over 2 hours plus 800 mg/ m2 over 22 hours as an infusion Drug: methylprednisolone Day 1-3: 50mg IV BID Drug: pegaspargase Day 3/Day4: 2,500 IU/ m2 IV Drug: vincristine sulfate Day 4 & 11: 2 mg IV | Drug: cyclophosphamide<br>* Day 1- 3: 300 m g/m2 IV over 2-3 hours every 12 hours for 6 doses plus mesna 600 mg/ m2 /day continuous infusion Days 1-3<br>* Other names: Cytoxan, Neosar, CTX;Drug: cytarabine<br>* Day 2 & 3: 3g/m2 IV over 2 hours q12 X 4<br>* Other names: Cytosar-U, Ara-C, Arabinosylcytosine;Drug: dexamethasone<br>* Day 1-4; 11-14: 40 mg daily<br>* Other names: Decadron, DexPak, dex;Drug: doxorubicin hydrochloride<br>* Day 4: 50 mg/m2 IV over 2 hours<br>* Other names: Adriamycin RDF, Adriamycin PFS;Drug: imatinib mesylate<br>* 600 mg/day<br>* Other names: Gleevec, Glivec;Drug: methotrexate<br>* Day 1: 1g/ m2 (200 mg/ m2load IV over 2 hours plus 800 mg/ m2 over 22 hours as an infusion<br>* Other names: Trexall, Rheumatrex, MTX;Drug: methylprednisolone<br>* Day 1-3: 50mg IV BID<br>* Other names: Medrol, Depo-Medrol, Solu-Medrol;Drug: pegaspargase<br>* Day 3/Day4: 2,500 IU/ m2 IV<br>* Other names: Onscapar, PEG-L-asparaginase;Drug: vincristine sulfate<br>* Day 4 & 11: 2 mg IV<br>* Other names: Marqibo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response Rate After Course 1 of Pegaspargase When Administered in Combination With Hyper-CVAD Regimen | The complete response rate after 1A cycle of a PEG-Asparaginase and hyper-CVAD combination regimen will be estimated, and an exact 95% confidence interval will be computed using a binomial distribution. | After day 4 of treatment | 
| Grade 3 and 4 Toxicity Associated With the Combination of Peg-Asparaginase and Hyper-CVAD Which Include: Allergic Reactions, Elevated Liver Enzymes, Hyperbilirubinemia, Hyperglycemia, Central Nervous System (CNS) Thrombosis, and Pancreatitis. |  | The assessment of safety will be based mainly on the frequency of adverse events | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2-year Progression-free Survival |  | After completion of 8 cycles | 
| Proportion of Patients Who Achieve Complete Response or Partial Response After Courses 1 and 2 |  | An interim analysis of safety is planned after the enrollment of 15 evaluable patients. | 
| Overall Survival |  | At least every 6 months until death. | 
| Rate of Minimal Residual Disease | Cycle 1A: Days 1 through 14 Cycle 1B: Days 1 through 8, after the first 14 days of cycle 1A | End of cycles 1A and 1B | 
| Half-life of Pegaspargase |  | The approximate t½ in adult patients is 5.73 days. The half-life is independent of the dose administered, disease status, renal or hepatic function, age, or gender. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adults, Philadelphia chromosome precursor ALL,, T-cell ALL, untreated ALL