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.
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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
11
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
Day 2 \& 3: 3g/m2 IV over 2 hours q12 X 4
Day 1-4; 11-14: 40 mg daily
OHSU Knight Cancer Institute
Portland, Oregon, United States
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.
Time frame: 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.
Time frame: The assessment of safety will be based mainly on the frequency of adverse events
2-year Progression-free Survival
Time frame: After completion of 8 cycles
Proportion of Patients Who Achieve Complete Response or Partial Response After Courses 1 and 2
Time frame: An interim analysis of safety is planned after the enrollment of 15 evaluable patients.
Overall Survival
Time frame: 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
Time frame: End of cycles 1A and 1B
Half-life of Pegaspargase
Time frame: 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.
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Day 4: 50 mg/m2 IV over 2 hours
600 mg/day
Day 1: 1g/ m2 (200 mg/ m2load IV over 2 hours plus 800 mg/ m2 over 22 hours as an infusion
Day 1-3: 50mg IV BID
Day 3/Day4: 2,500 IU/ m2 IV
Day 4 \& 11: 2 mg IV