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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.

L-asparaginase

doxorubicin hydrochloride

Given IT (8mg - 15mg) Age-based dosing Block 1: Days 8,15, 22 and 29 Block 2: Days 1 and 22

therapeutic hydrocortisone

Given IV 1.5 mg/m2 (max 2 mg) on Days 1, 8, 15 and 22

vincristine sulfate

Given IT or IV 3,000 mg/m2/dose on Days 1, 2, 8 and 9

cytarabine

prednisone

Given IV 1.3 mg/m2/dose Block 1: Days 1, 4, 8 and 11 Block 2: Days 1, 4 and 8

bortezomib

Given IM or IV (over 2 hours) 2500 IU/m2/dose on days 2, 8,15 and 22

pegaspargase

Given IT (8mg - 15mg) Age-based dosing Block 1: Days 15 and 29 Block 2: Days 1 and 22

methotrexate

etoposide phosphate

cyclophosphamide

Given IV or SC 5 micrograms/kg/dose Only on Day 6

filgrastim

Given PO or IV 15mg/m2/dose q6h x 3 doses

leucovorin calcium

laboratory biomarker analysis

High Dose MTX

Terzah Horton, MD PhD

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.

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.

Bortezomib and Combination Chemotherapy in Treating Young Patients With Relapsed Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma

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)

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.

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.

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.

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).

This outcome measure cannot be reported due to the data used for analysis was not collected.

The percentage of eligible and evaluable patients who have achieved complete response at the end Block 1 of re-induction therapy.

Percentage of patients who were event free at 4 months

The proportion of toxic death rate among all eligible patients.

The proportion of SAE rate among all eligible patients

Percentage of eligible and evaluable patients with MRD \< 0.01% among those who had successful MRD determination at the end of Block 1.

Percentage of eligible and evaluable patients with MRD \< 0.01% among those who had successful MRD determination at the end of Block 2.

Percentage of eligible and evaluable patients with MRD \< 0.01% among those who had successful MRD determination at the end of Block 3.

National Cancer Institute (NCI)

SAE field contains NCI CTCAEs submitted via expedited reporting (NCI AdEERs/CAeRs). AE field contains grade 3 \& higher CTCAEs reported on study excluding reported SAEs. Analyses on outcomes was based on eligible \& evaluable patients. Reported AEs should be enrolled eligible patient based, so numbers of participants in the two AE tables are larger.

Re-Induction Block 1 patients receive liposomal vincristine sulfate , Prednisone, pegaspargase and Doxorubicin hydrochloride. Re-Induction Block 2 patients receive Cyclophosphamide, Etoposide phosphate, and Methotrexate. Re-Induction Block 3 patients receive Cytarabine and L-Asparaginase. Patients receive Bortezomib on days 1, 4, 8 \& 11 of Block 1 and days 1, 4, \& 8 of Block 2.

Pre-B ALL Relapse < 36 Mths From Dx (Chemotherapy) Age >21 Yrs

Pre-B ALL Relapse 18-36 Mths From Dx (Chemotherapy)Age<=21 Yrs

Pre-B ALL Relapse <18 Mths From Dx (Chemotherapy) Age <=21 Yrs

T-cell ALL (Chemotherapy)

T-cell Lymphoblastic Lymphoma (LL) (Chemotherapy)

Total

Age, Categorical

Age, Continuous

Gender

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Results Reporting Coordinator

The analysis on this primary outcome is limited to pre-B ALL with age \<= 21 years who relapsed \< 36 months only (stratum 1 \& 2) per protocol section 9.2.1.

Second Complete Remission Rate at the End of Block 1 Reinduction Chemotherapy

Event Free Survival

Overall

The toxic death was monitored for all eligible patients. It was not compared between subgroups per protocol 9.3.2.

Toxic Death Rate

The SAE event was monitored for all eligible patients. It was not compared between subgroups per protocol 9.3.2.

Severe Adverse Events (SAE) Rate.

The MRD analysis is limited to eligible and evaluable pre-B ALL with age \<= 21 years who relapsed \< 36 months only (stratum 1 \& 2) and have successful MRD determination at the end of Block 1per protocol section 9.3.3.

Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 1

The MRD analysis is limited to eligible and evaluable pre-B ALL with age \<= 21 years who relapsed \< 36 months only (stratum 1 \& 2) and have successful MRD determination at the end of Block 2per protocol section 9.3.3.

Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 2

The MRD analysis is limited to eligible and evaluable pre-B ALL with age \<= 21 years who relapsed \< 36 months only (stratum 1 \& 2) and have successful MRD determination at the end of Block 3per protocol section 9.3.3.

Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 3

Re-Induction Block 1 patients receive vincristine sulfate, Prednisone, pegaspargase, Doxorubicin hydrochloride. Re-Induction Block 2 patients receive Cyclophosphamide, Etoposide phosphate, and MTX. Re-Induction Block 3 patients receive Cytarabine.

L-asparaginase: Given IM 6000 IU/m2/dose Days 2 and 9

doxorubicin hydrochloride: Given IV 60 mg/m2/dose on Day 1

therapeutic hydrocortisone: Given IT (8mg - 15mg) Age-based dosing Block 1: Days 8,15, 22 \& 29 Block 2: Days 1 \& 22

vincristine sulfate: Given IV 1.5 mg/m2 (max 2 mg) on Days 1, 8, 15 and 22

cytarabine: Given IT or IV 3,000 mg/m2/dose on Days 1, 2, 8 \& 9

prednisone: Given PO or IV 40 mg/m2/day on Days 1-28

bortezomib: Given IV 1.3 mg/m2/dose Block 1: Days 1, 4, 8 \& 11 Block 2: Days 1, 4 \& 8

pegaspargase: Given IM or IV (over 2 hours) 2500 IU/m2/dose on days 2, 8,15 \& 22

MTX: Given IT (8mg - 15mg) Age-based dosing Block 1: Days 15 \& 29 Block 2: Days 1 \& 22

etopo

Re-Induction Block 1 patients receive vincristine sulfate, Prednisone, pegaspargase, Doxorubicin hydrochloride. Re-Induction Block 2 patients receive Cyclophosphamide, Etoposide phosphate, and MTX. Re-Induction Block 3 patients receive Cytarabine.

L-asparaginase: Given IM 6000 IU/m2/dose Days 2 \& 9

doxorubicin hydrochloride: Given IV 60 mg/m2/dose on Day 1

therapeutic hydrocortisone: Given IT (8mg - 15mg) Age-based dosing Block 1: Days 8,15, 22 \& 29 Block 2: Days 1 \& 22

vincristine sulfate: Given IV 1.5 mg/m2 (max 2 mg) on Days 1, 8, 15 \& 22

cytarabine: Given IT or IV 3,000 mg/m2/dose on Days 1, 2, 8 \& 9

prednisone: Given PO or IV 40 mg/m2/day on Days 1-28

bortezomib: Given IV 1.3 mg/m2/dose Block 1: Days 1, 4, 8 \& 11 Block 2: Days 1, 4 \& 8

pegaspargase: Given IM or IV (over 2 hours) 2500 IU/m2/dose on days 2, 8,15 \& 22

MTX: Given IT (8mg - 15mg) Age-based dosing Block 1: Days 15 \& 29 Block 2: Days 1 \& 22

etopo

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.

L-asparaginase: Given IM 6000 IU/m2/dose Days 2 \& 9

doxorubicin hydrochloride: Given IV 60 mg/m2/dose on Day 1

therapeutic hydrocortisone: Given IT (8mg - 15mg) Age-based dosing Block 1: Days 8,15, 22 \& 29 Block 2: Days 1 \& 22

vincristine sulfate: Given IV 1.5 mg/m2 (max 2 mg) on Days 1, 8, 15 \& 22

cytarabine: Given IT or IV 3,000 mg/m2/dose on Days 1, 2, 8 \& 9

prednisone: Given PO or IV 40 mg/m2/day on Days 1-28

bortezomib: Given IV 1.3 mg/m2/dose Block 1: Days 1, 4, 8 \& 11 Block 2: Days 1, 4 \& 8

pegaspargase: Given IM or IV (over 2 hours) 2500 IU/m2/dose on days 2, 8,15 \& 22

MTX: Given IT (8mg - 15mg) Age-based dosing Block 1: Days 15 \& 29 Block 2: Days 1 \& 22

etopo

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.

L-asparaginase: Given IM 6000 IU/m2/dose Days 2 \& 9

doxorubicin hydrochloride: Given IV 60 mg/m2/dose on Day 1

therapeutic hydrocortisone: Given IT (8mg - 15mg) Age-based dosing Block 1: Days 8,15, 22 \& 29 Block 2: Days 1 \& 22

vincristine sulfate: Given IV 1.5 mg/m2 (max 2 mg) on Days 1, 8, 15 \& 22

cytarabine: Given IT or IV 3,000 mg/m2/dose on Days 1, 2, 8 \& 9

prednisone: Given PO or IV 40 mg/m2/day on Days 1-28

bortezomib: Given IV 1.3 mg/m2/dose Block 1: Days 1, 4, 8 \& 11 Block 2: Days 1, 4 \& 8

pegaspargase: Given IM or IV (over 2 hours) 2500 IU/m2/dose on days 2, 8,15 \& 22

methotrexate: Given IT (8mg - 15mg) Age-based dosing Block 1: Days 15 \& 29 Block 2: Days 1 \& 22

etopo

These were for correlative biology studies and the data were not collected in COG database.

NF-kB Activity

Re-Induction Block 1 patients receive vincristine sulfate, Prednisone, pegaspargase, Doxorubicin hydrochloride. Re-Induction Block 2 patients receive Cyclophosphamide, Etoposide phosphate and MTX. Re-Induction Block 3 patients receive Cytarabine.

L-asparaginase: Given IM 6000 IU/m2/dose Days 2 and 9

doxorubicin hydrochloride: Given IV 60 mg/m2/dose on Day 1

therapeutic hydrocortisone: Given IT (8mg - 15mg) Age-based dosing Block 1: Days 8,15, 22 \& 29 Block 2: Days 1 \& 22

vincristine sulfate: Given IV 1.5 mg/m2 (max 2 mg) on Days 1, 8, 15 and 22

cytarabine: Given IT or IV 3,000 mg/m2/dose on Days 1, 2, 8 \& 9

prednisone: Given PO or IV 40 mg/m2/day on Days 1-28

bortezomib: Given IV 1.3 mg/m2/dose Block 1: Days 1, 4, 8 \& 11 Block 2: Days 1, 4 \& 8

pegaspargase: Given IM or IV (over 2 hours) 2500 IU/m2/dose on days 2, 8,15 \& 22

MTX: Given IT (8mg - 15mg) Age-based dosing Block 1: Days 15 \& 29 Block 2: Days 1 \& 22

etopo

Re-Induction Block 1 patients receive vincristine sulfate, Prednisone, pegaspargase, Doxorubicin hydrochloride. Re-Induction Block 2 patients receive Cyclophosphamide, Etoposide phosphate and MTX. Re-Induction Block 3 patients receive Cytarabine.

L-asparaginase: Given IM 6000 IU/m2/dose Days 2 \& 9

doxorubicin hydrochloride: Given IV 60 mg/m2/dose on Day 1

therapeutic hydrocortisone: Given IT (8mg - 15mg) Age-based dosing Block 1: Days 8,15, 22 \& 29 Block 2: Days 1 \& 22

vincristine sulfate: Given IV 1.5 mg/m2 (max 2 mg) on Days 1, 8, 15 \& 22

cytarabine: Given IT or IV 3,000 mg/m2/dose on Days 1, 2, 8 \& 9

prednisone: Given PO or IV 40 mg/m2/day on Days 1-28

bortezomib: Given IV 1.3 mg/m2/dose Block 1: Days 1, 4, 8 \& 11 Block 2: Days 1, 4 \& 8

pegaspargase: Given IM or IV (over 2 hours) 2500 IU/m2/dose on days 2, 8,15 \& 22

MTX: Given IT (8mg - 15mg) Age-based dosing Block 1: Days 15 \& 29 Block 2: Days 1 \& 22

etopo

Re-Induction Block 1 patients receive vincristine sulfate, Prednisone, pegaspargase, Doxorubicin hydrochloride. Re-Induction Block 2 patients receive Cyclophosphamide, Etoposide phosphate, and MTX. Re-Induction Block 3 patients receive Cytarabine.

L-asparaginase: Given IM 6000 IU/m2/dose Days 2 \& 9

doxorubicin hydrochloride: Given IV 60 mg/m2/dose on Day 1

therapeutic hydrocortisone: Given IT (8mg - 15mg) Age-based dosing Block 1: Days 8,15, 22 \& 29 Block 2: Days 1 \& 22

vincristine sulfate: Given IV 1.5 mg/m2 (max 2 mg) on Days 1, 8, 15 \& 22

cytarabine: Given IT or IV 3,000 mg/m2/dose on Days 1, 2, 8 \& 9

prednisone: Given PO or IV 40 mg/m2/day on Days 1-28

bortezomib: Given IV 1.3 mg/m2/dose Block 1: Days 1, 4, 8 \& 11 Block 2: Days 1, 4 \& 8

pegaspargase: Given IM or IV (over 2 hours) 2500 IU/m2/dose on days 2, 8,15 \& 22

methotrexate: Given IT (8mg - 15mg) Age-based dosing Block 1: Days 15 \& 29 Block 2: Days 1 \& 22

etopo

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Bortezomib and Combination Chemotherapy in Treating Young Patients With Relapsed Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma	NCT00873093	B-cell Adult Ac... B-cell Childhoo... Recurrent Adult... Recurrent Adult... Recurrent Child... Recurrent Child... T-cell Adult Ac... T-cell Childhoo...	L-asparaginase doxorubicin hyd... therapeutic hyd... vincristine sul... cytarabine prednisone bortezomib pegaspargase methotrexate etoposide phosp... cyclophosphamid... filgrastim leucovorin calc... laboratory biom... High Dose MTX	1 Year - 31 Years	National Cancer Institute (NCI)
Bortezomib and Combination Chemotherapy in Treating Young Patients With Relapsed Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma	NCT00873093	B-cell Adult Ac... B-cell Childhoo... Recurrent Adult... Recurrent Adult... Recurrent Child... Recurrent Child... T-cell Adult Ac... T-cell Childhoo...	L-asparaginase doxorubicin hyd... therapeutic hyd... vincristine sul... cytarabine prednisone bortezomib pegaspargase methotrexate etoposide phosp... cyclophosphamid... filgrastim leucovorin calc... laboratory biom... High Dose MTX	1 Year - 31 Years	National Cancer Institute (NCI)

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