Bortezomib and Combination Chemotherapy in Treating Young Patients With Relapsed Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma
Condition: B-cell Adult Acute Lymphoblastic Leukemia; B-cell Childhood Acute Lymphoblastic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Lymphoblastic Lymphoma; T-cell Adult Acute Lymphoblastic Leukemia; T-cell Childhood Acute Lymphoblastic Leukemia
MeSH terms: Lymphoma; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Lymphoma, Non-Hodgkin; Recurrence
Study type: Interventional
Phase: Phase 2

Summary: 
      This pilot, phase II trial studies 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. 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.
    

Detailed description: 
      PRIMARY OBJECTIVES:

      I. To estimate the toxicity, second complete response (CR2) rate at the end of Block 1
      therapy, and 4-month event-free survival (EFS) for pediatric and young adult patients with
      relapsed acute lymphoblastic leukemia (ALL) treated with bortezomib in combination with
      intensive re-induction chemotherapy.

      II. To evaluate bortezomib pharmacokinetics (PK) in patients receiving the combination
      regimen.

      SECONDARY OBJECTIVES:

      I. To assess minimal residual disease (MRD) in bone marrow following completion of each
      therapy block.

      II. To assess the feasibility of measuring leukemia initiating cells (LIC) in patient samples
      before and after chemotherapy.

      III. To discover biologic pathways associated with response and drug resistance using gene
      and protein expression profiles at baseline and following initial exposure to chemotherapy.

      IV. To determine if bortezomib inhibits lymphoblast nuclear factor (NF)-kappa (k)-B activity
      in leukemia patients.

      OUTLINE:

      REINDUCTION BLOCK 1: Patients receive cytarabine intrathecally (IT) on day 1; vincristine
      sulfate IV over 1 minute on days 1, 8, 15, and 22; doxorubicin hydrochloride IV over 15
      minutes on day 1; prednisone orally (PO) twice daily (BID) on days 1-28; bortezomib IV over
      3-5 seconds on days 1, 4, 8, and 11; and pegaspargase intramuscularly (IM) or IV over 1-2
      hours on days 2, 8, 15, and 22. Patients with central nervous system (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 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 cerebral spinal fluid (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 15-30 minutes on days 1-5; bortezomib IV over 3-5 seconds 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 over 24 hours on day 22;
      and leucovorin calcium PO 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 BID on days 1, 2, 8, and 9;
      L-asparaginase IM on days 2 and 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.
    

Intervention name(s): L-asparaginase; doxorubicin hydrochloride; therapeutic hydrocortisone; vincristine sulfate; cytarabine; prednisone; bortezomib; pegaspargase; methotrexate; etoposide phosphate; cyclophosphamide; filgrastim; leucovorin calcium; laboratory biomarker analysis; High Dose MTX
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Biological; Drug; Other; Drug
Intervention description(s): Given IM 6000 IU/m2/dose Days 2 and 9; Given IV 60 mg/m2/dose on Day 1; Given IT (8mg - 15mg) Age-based dosing Block 1: Days 8,15, 22 and 29 Block 2: Days 1 and 22; Given IV 1.5 mg/m2 (max 2 mg) on Days 1, 8, 15 and 22; Given IT or IV 3,000 mg/m2/dose on Days 1, 2, 8 and 9; Given PO or IV 40 mg/m2/day on Days 1-28; Given IV 1.3 mg/m2/dose Block 1: Days 1, 4, 8 and 11 Block 2: Days 1, 4 and 8; Given IM or IV (over 2 hours) 2500 IU/m2/dose on days 2, 8,15 and 22; Given IT (8mg - 15mg) Age-based dosing Block 1: Days 15 and 29 Block 2: Days 1 and 22; Given IV 100 mg/m2/dose on Days 1-5; Given IV 440 mg/m2/dose on Days 1-5; Given IV or SC 5 micrograms/kg/dose Only on Day 6; Given PO or IV 15mg/m2/dose q6h x 3 doses; Correlative studies; IV 5000 mg/m2/dose Block 2: Day 22
Other intervention name(s): ASNase; Colaspase; Crasnitin; Elspar; L-ASP; ADM; ADR; Adria; Aeroseb-HC; Barseb HC; Cetacort; Cort-Dome; Cortef; liposomal vincristine; Marqibo; vincristine liposomal; vincristine sulfate liposome injection; ARA-C; arabinofuranosylcytosine; arabinosylcytosine; Cytosar-U; cytosine arabinoside; DeCortin; Deltra; LDP 341; MLN341; VELCADE; L-asparaginase with polyethylene glycol; Oncaspar; PEG-ASP; PEG-L-asparaginase; amethopterin; Folex; methylaminopterin; Mexate; MTX; ETOP; Etopophos; CPM; CTX; Cytoxan; Endoxan; Endoxana; G-CSF; Neupogen; CF; CFR; LV; methotrexate; amethopterin; Folex; methylaminopterin; Mexate
Intervention MeSH terms: Leucovorin; Cytarabine; Prednisone; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Methotrexate; Etoposide; Vincristine; Bortezomib; Asparaginase; Pegaspargase; Etoposide phosphate; Levoleucovorin
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment