AALL07P1 Millennium Pharmaceuticals A Phase II Pilot Trial of Bortezomib in Combo iwth Intensive Re-Induction Therapy

Confidential Human Clinical Trial Sponsor: Children's Oncology Group Collaborator: National Cancer Institute (NCI) Funding: Millennium Official Title: A Phase II Pilot Trial of Bortezomib (PS-341, Velcade®, IND #58,443) in Combination With Intensive Re-Induction Therapy for Children With Relapsed Acute Lymphoblastic Leukemia (ALL) and Lymphoblastic Lymphoma (LL) Purpose RATIONALE: Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. 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 bortezomib together with combination chemotherapy may kill more cancer cells. PURPOSE: This phase II trial is studying the side effects of giving bortezomib together with combination chemotherapy and to see how well it works in treating young patients with relapsed acute lymphoblastic leukemia or lymphoblastic lymphoma. Detailed Description: OBJECTIVES: Primary •To estimate the toxicity of bortezomib in combination with intensive reinduction chemotherapy in young patients with relapsed acute lymphoblastic leukemia or lymphoblastic lymphoma. •To estimate the second complete remission rate at the end of block 1 reinduction chemotherapy and the 4-month event-free survival of these patients. Secondary •To assess minimal residual disease in bone marrow following completion of each block of reinduction chemotherapy. OUTLINE: This is a multicenter study. •Reinduction block 1: Patients receive cytarabine intrathecally (IT) on day 1; vincristine sulfate IV on days 1, 8, 15, and 22; doxorubicin hydrochloride IV over 15 minutes on day 1; oral prednisone twice daily on days 1-29; bortezomib IV on days 1, 4, 8, and 11; and pegaspargase intramuscularly (IM) on days 2, 8, 15, and 22. Patients with CNS-negative disease (CNS1 or CNS2) also receive methotrexate IT on days 15 and 29; patients with CNS-positive disease (CNS3) receive triple intrathecal therapy (TIT) comprising methotrexate, hydrocortisone, and cytarabine IT on days 8, 15, 22, and 29. After completion of reinduction block 1, patients with acute lymphoblastic leukemia (ALL) and M2 or M3 bone marrow proceed directly to reinduction block 2. Patients with ALL and M1 bone marrow or lymphoblastic lymphoma proceed to reinduction block 2 after blood counts recover. Patients with persistent CSF blasts after 6 doses of TIT or patients with progressive lymphoblastic lymphoma are removed from the study. •Reinduction block 2: Patients receive etoposide phosphate IV over 1-2 hours on days 1-5; cyclophosphamide IV over 1 hour on days 1-5; bortezomib IV on days 1, 4, and 8; filgrastim (G-CSF) subcutaneously (SC) or IV daily beginning on day 6 and continuing until blood counts recover*; high-dose methotrexate IV on day 22; and leucovorin calcium orally or IV every 6 hours on days 23 and 24. Patients with CNS-negative disease also receive methotrexate IT on days 1 and 22; patients with CNS-positive disease receive TIT on days 1 and 22. After completion of reinduction block 2, patients proceed to reinduction block 3 immediately or when blood counts recover. Patients with disease progression are removed from the study. NOTE: *Patients do not receive G-CSF on day 8. •Reinduction block 3: Patients receive cytarabine IV over 3 hours twice daily on days 1, 2, 8, and 9; L-asparaginase IM on days 2 and 9 (or a single dose of PEG-asparaginase IM or IV on day 9); and G-CSF SC or IV daily beginning on day 10 and continuing until blood counts recover. After completion of study treatment, patients are followed every 6 months for 3 years and then annually for 2 years.