Clinical trial NCT00873093
Conditions: 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
Sponsor: National Cancer Institute (NCI)
Start date: 2009-03-01; Completion date: 2014-09-01
Enrollment: 148 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief 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.

Arms: arm 1: Re-Induction Block 1 patients receive vincristine sulfate, Prednisone, pegaspargase, Doxorubicin hydrochloride. Re-Induction Block 2 patients receive Cyclophosphamide, Etoposide phosphate, and Methotrexate. Re-Induction Block 3 patients receive Cytarabine. arm 2: Re-Induction Block 1 patients receive vincristine sulfate, Prednisone, pegaspargase, Doxorubicin hydrochloride. Re-Induction Block 2 patients receive Cyclophosphamide, Etoposide phosphate, and Methotrexate. Re-Induction Block 3 patients receive Cytarabine. arm 3: Re-Induction Block 1 patients receive vincristine sulfate, Prednisone, pegaspargase, Doxorubicin hydrochloride. Re-Induction Block 2 patients receive Cyclophosphamide, Etoposide phosphate, and Methotrexate. Re-Induction Block 3 patients receive Cytarabine. arm 4: Re-Induction Block 1 patients receive vincristine sulfate, Prednisone, pegaspargase, Doxorubicin hydrochloride. Re-Induction Block 2 patients receive Cyclophosphamide, Etoposide phosphate, and Methotrexate. Re-Induction Block 3 patients receive Cytarabine. arm 5: Re-Induction Block 1 patients receive vincristine sulfate, Prednisone, pegaspargase, Doxorubicin hydrochloride. Re-Induction Block 2 patients receive Cyclophosphamide, Etoposide phosphate, and Methotrexate. Re-Induction Block 3 patients receive Cytarabine.
Interventions: intervention 1: L-asparaginase intervention 2: doxorubicin hydrochloride intervention 3: therapeutic hydrocortisone intervention 4: vincristine sulfate intervention 5: cytarabine intervention 6: prednisone intervention 7: bortezomib intervention 8: pegaspargase intervention 9: methotrexate intervention 10: etoposide phosphate intervention 11: cyclophosphamide intervention 12: filgrastim intervention 13: leucovorin calcium intervention 14: laboratory biomarker analysis intervention 15: High Dose MTX
Intervention descriptions: intervention 1: Given IM 6000 IU/m2/dose Days 2 and 9 intervention 2: Given IV 60 mg/m2/dose on Day 1 intervention 3: Given IT (8mg - 15mg) Age-based dosing Block 1: Days 8,15, 22 and 29 Block 2: Days 1 and 22 intervention 4: Given IV 1.5 mg/m2 (max 2 mg) on Days 1, 8, 15 and 22 intervention 5: Given IT or IV 3,000 mg/m2/dose on Days 1, 2, 8 and 9 intervention 6: Given PO or IV 40 mg/m2/day on Days 1-28 intervention 7: Given IV 1.3 mg/m2/dose Block 1: Days 1, 4, 8 and 11 Block 2: Days 1, 4 and 8 intervention 8: Given IM or IV (over 2 hours) 2500 IU/m2/dose on days 2, 8,15 and 22 intervention 9: Given IT (8mg - 15mg) Age-based dosing Block 1: Days 15 and 29 Block 2: Days 1 and 22 intervention 10: Given IV 100 mg/m2/dose on Days 1-5 intervention 11: Given IV 440 mg/m2/dose on Days 1-5 intervention 12: Given IV or SC 5 micrograms/kg/dose Only on Day 6 intervention 13: Given PO or IV 15mg/m2/dose q6h x 3 doses intervention 14: Correlative studies intervention 15: IV 5000 mg/m2/dose Block 2: Day 22

Protocol documents: