Bortezomib and Combination Chemotherapy in Treating Young Patients With Relapsed Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma
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
Drug: doxorubicin hydrochloride
Drug: therapeutic hydrocortisone
Drug: liposomal vincristine sulfate
Drug: etoposide phosphate
Drug: leucovorin calcium
Other: laboratory biomarker analysis
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase II Pilot Trial of Bortezomib (PS-341, Velcade) in Combination With Intensive Re-Induction Therapy for Children With Relapsed Acute Lymphoblastic Leukemia (ALL) and Lymphoblastic Lymphoma (LL)|
- Second complete remission rate at the end of block 1 reinduction chemotherapy [ Time Frame: 29 days ] [ Designated as safety issue: No ]Descriptive statistics will be used to assess CR2 rates by stratum including calculation of 95% confidence intervals.
- PK of bortezomib in patients receiving multi-agent combination therapy [ Time Frame: Day 8 of blocks 1 and 2 ] [ Designated as safety issue: No ]
- Toxicity according to NCI Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
- Minimal residual disease [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]A one-sample Z-test of proportions (one-sided, alpha= 5%) will be used.
- NF-kB activity [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]NF-kB activity will be measured as a continuous variable (ng NF-kB/ug protein). Differences in NF-kB activity between time points will be assessed using summary statistics such as mean, standard deviation, and range.
- Expression of apoptotic and cell cycle proteins assessed by using gene and tissue microarrays and immunoblots [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]Characterized using descriptive statistics. If differences are noted between pre- and post-treatment protein expression, pairwise comparisons will be made using paired t-test or an equivalent nonparametric test. The normality assumption will be assessed on the log-transformed data prior to paired t-test evaluation.
- Change in stem cell percentage [ Time Frame: Baseline to post-treatment with bortezomib ] [ Designated as safety issue: No ]Will use descriptive statistics to assess mean +/- standard deviation for stem cell percentage before and after bortezomib treatment. If there appears to be a difference in responders vs. non-responders, stem cell percentage differences between responders and non-responders will be compared using a paired t-test or equivalent nonparametric test.
- Plasma concentration-time profiles [ Time Frame: Up to day 8 of block 2 ] [ Designated as safety issue: No ]Will be analyzed using descriptive statistics and will be graphically displayed by age group and stratum. PK data will be analyzed using methods such as nonlinear mixed effects modeling to estimate bortezomib clearance and volume of distribution (and the associated 95% confidence intervals) in each age group (2-11 years and 12-16 years of age).
|Study Start Date:||March 2009|
|Estimated Primary Completion Date:||September 2014 (Final data collection date for primary outcome measure)|
Experimental: Treatment (bortezomib and combination chemotherapy)
See Detailed Description
Other Names:Drug: doxorubicin hydrochloride
Other Names:Drug: therapeutic hydrocortisone
Other Names:Drug: liposomal vincristine sulfate
Other Names:Drug: cytarabine
Given IT or IV
Other Names:Drug: prednisone
Given PO or IV
Other Names:Drug: bortezomib
Other Names:Drug: pegaspargase
Other Names:Drug: methotrexate
Given IT or IV
Other Names:Drug: etoposide phosphate
Other Names:Drug: cyclophosphamide
Other Names:Biological: filgrastim
Given IV or SC
Other Names:Drug: leucovorin calcium
Given PO or IV
Other Names:Other: laboratory biomarker analysis
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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.
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.
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00873093
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|Principal Investigator:||Terzah Horton||Children's Oncology Group|