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
Conditions
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.
Interventions
DRUGL-asparaginase
Given IM 6000 IU/m2/dose Days 2 and 9
DRUGdoxorubicin hydrochloride
Given IV 60 mg/m2/dose on Day 1
DRUGtherapeutic hydrocortisone
Given IT (8mg - 15mg) Age-based dosing Block 1: Days 8,15, 22 and 29 Block 2: Days 1 and 22
DRUGvincristine sulfate
Given IV 1.5 mg/m2 (max 2 mg) on Days 1, 8, 15 and 22
DRUGcytarabine
Given IT or IV 3,000 mg/m2/dose on Days 1, 2, 8 and 9
DRUGprednisone
Given PO or IV 40 mg/m2/day on Days 1-28
DRUGbortezomib
Given IV 1.3 mg/m2/dose Block 1: Days 1, 4, 8 and 11 Block 2: Days 1, 4 and 8
DRUGpegaspargase
Given IM or IV (over 2 hours) 2500 IU/m2/dose on days 2, 8,15 and 22
DRUGmethotrexate
Given IT (8mg - 15mg) Age-based dosing Block 1: Days 15 and 29 Block 2: Days 1 and 22
DRUGetoposide phosphate
Given IV 100 mg/m2/dose on Days 1-5
DRUGcyclophosphamide
Given IV 440 mg/m2/dose on Days 1-5
BIOLOGICALfilgrastim
Given IV or SC 5 micrograms/kg/dose Only on Day 6
DRUGleucovorin calcium
Given PO or IV 15mg/m2/dose q6h x 3 doses
OTHERlaboratory biomarker analysis
Correlative studies
DRUGHigh Dose MTX
IV 5000 mg/m2/dose Block 2: Day 22
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 31 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis * Pre-B ALL in first early (\< 36 months from diagnosis) isolated bone marrow (BM) or combined BM/extramedullary relapse; or * T-cell ALL in first isolated BM or combined relapse; or * T-LL in first relapse * Patients with leukemia must have had histologic verification of the malignancy at relapse, including immunophenotyping to confirm diagnosis * Patients with lymphoblastic lymphoma must have measurable disease documented by clinical, radiographic, or histologic criteria; patients must have relapsed or become refractory to conventional therapy * Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2; use Karnofsky for patients \> 16 years of age and Lansky for patients =\< 16 years of age * Patients who relapse while receiving standard ALL maintenance chemotherapy will not be required to have a waiting period before entry onto this study * Patients who relapse on therapy other than standard ALL maintenance therapy must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study * At least 14 days since the completion of cytotoxic therapy with the exception of hydroxyurea, which is permitted up to 24 hours prior to the start of protocol therapy * At least 7 days since the completion of therapy with a biologic agent or donor lymphocyte infusions (DLI); for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur * No evidence of active graft-vs-host disease (GVHD) and \>= 4 months must have elapsed; must not be receiving GVHD prophylaxis * Creatinine clearance or radioisotope glomerular filtration rate (GFR) \>= 70 mL/min/1.73 m\^2 or a serum creatinine based on age/gender as follows: * 1 month to \< 6 months (0.4 male, 0.4 female) * 6 months to \< 1 year (0.5 male, 0.5 female) * 1 to \< 2 years (0.6 male, 0.6 female) * 2 to \< 6 years (0.8 male, 0.8 female) * 6 to \< 10 years (1 male, 1 female) * 10 to \< 13 years (1.2 male, 1.2 female) * 13 to \< 16 years (1.5 male, 1.4 female) * \>= 16 years (1.7 male, 1.4 female) * Total bilirubin =\< 1.5 x upper limit of normal (ULN) for age * Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) \< 3 x ULN for age, unless elevation due to leukemia infiltration * Shortening fraction of \>= 27% by echocardiogram, or * Ejection fraction of \>= 50% by gated radionuclide study * No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry \>= 94% at sea level (\> 90% if at high altitude) * No evidence of acute pulmonary infiltrates on chest radiograph * Patients with seizure disorder may be enrolled if on allowed anticonvulsants and well controlled; benzodiazepines and gabapentin are acceptable * Central nervous system (CNS) toxicity =\< grade 2 * Peripheral nervous system (PNS) toxicity \< grade 3 * All patients and/or their parents or legal guardians must sign a written informed consent * All institutional, FDA, and National Cancer Institute (NCI) requirements for human studies must be met
Exclusion criteria
* Patients with Philadelphia chromosome positive ALL are not eligible unless refractory to at least one tyrosine kinase inhibitor (TKI) therapy; patients that are unable to tolerate TKI therapy due to toxicity are eligible * Patients with mature B-cell ALL, ie, leukemia with B-cell (soluble immunoglobulin \[sIg\] positive and kappa or lambda restricted positivity) ALL, with French-American-British (FAB) L3 morphology and/or a myc translocation, are not eligible * Extramedullary disease status: patients with isolated CNS disease or isolated testicular disease are not eligible * Patients with known optic nerve and/or retinal involvement are not eligible; patients presenting with visual disturbances should have an ophthalmological exam and, if indicated, an magnetic resonance imaging (MRI) to determine optic nerve or retinal involvement * Patients with concomitant genetic syndrome: patients with Down syndrome, Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome are not eligible * Cumulative prior anthracycline exposure must not exceed 400 mg/m\^2 * Patients taking anticonvulsants known to activate the cytochrome p450 system, in particular anticonvulsants such as phenytoin, carbamazepine, and phenobarbital, are not eligible; benzodiazepines and gabapentin are acceptable * Patients who have previously received bortezomib or other proteasome inhibitors are not eligible * Patients who have a known allergy to doxorubicin, cytarabine, both etoposide and etopophos, boron, mannitol or bortezomib are not eligible * Patients who cannot receive any asparaginase products (E. Coli, PEG-asparaginase, or Erwinia asparaginase) on this study (eg, due to prior severe pancreatitis, stroke or other toxicity) are not eligible; patients who initially receive asparaginase, but must discontinue due to toxicity, remain eligible; patients with clinically significant prior allergies to pegaspargase are eligible if Erwinia L-asparaginase can be substituted * Patients who are pregnant or breast-feeding are not eligible for this study; negative pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective birth control method * Patients must not have received any prior re-induction attempts and must not have received treatment for prior extramedullary relapse; patients with primary induction failure are not eligible
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Second Complete Remission Rate at the End of Block 1 Reinduction Chemotherapy | The outcome is measured the end of Block 1 (Day 36 of Block 1) of re-induction therapy. | The percentage of eligible and evaluable patients who have achieved complete response at the end Block 1 of re-induction therapy. |
| Severe Adverse Events (SAE) Rate. | 4 months | The proportion of SAE rate among all eligible patients |
| Toxic Death Rate | 4 months | The proportion of toxic death rate among all eligible patients. |
| Event Free Survival | 4 months after enrollment | Percentage of patients who were event free at 4 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 2 | End of Block 2 (Day 36 of Block 2) of re-induction therapy | Percentage of eligible and evaluable patients with MRD \< 0.01% among those who had successful MRD determination at the end of Block 2. |
| Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 1 | End of Block 1 (Day 36 of Block 1) of re-induction therapy | Percentage of eligible and evaluable patients with MRD \< 0.01% among those who had successful MRD determination at the end of Block 1. |
| Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 3 | End of Block 3 (Day 36 of Block 3) of re-induction therapy | Percentage of eligible and evaluable patients with MRD \< 0.01% among those who had successful MRD determination at the end of Block 3. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Expression of Apoptotic and Cell Cycle Proteins Assessed by Using Gene and Tissue Microarrays and Immunoblots | Up to 5 years | 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. |
| Pharmacokinetics (PK) of Bortezomib in Patients Receiving Multi-agent Combination Therapy. | Day 8 of blocks 1 and 2 | This outcome measure cannot be reported due to the data used for analysis was not collected. |
| Plasma Concentration-time Profiles | Up to day 8 of block 2 | 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). |
| Change in Stem Cell Percentage | Baseline to post-treatment with bortezomib | 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. |
| NF-kB Activity | Up to 5 years | 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. |
Countries
Australia, Canada, Puerto Rico, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pre-B ALL Relapse < 36 Mths From Dx (Chemotherapy) Age >21 Yrs 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. | 4 |
| Pre-B ALL Relapse 18-36 Mths From Dx (Chemotherapy)Age<=21 Yrs 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. | 62 |
| Pre-B ALL Relapse <18 Mths From Dx (Chemotherapy) Age <=21 Yrs 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. | 49 |
| T-cell ALL (Chemotherapy) 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. | 23 |
| T-cell Lymphoblastic Lymphoma (LL) (Chemotherapy) 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. | 10 |
| Total | 148 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 | 0 | 0 | 0 |
| Overall Study | Death | 0 | 3 | 2 | 0 | 0 |
| Overall Study | Ineligible | 0 | 1 | 0 | 1 | 0 |
| Overall Study | Physician Decision | 0 | 17 | 10 | 10 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 4 | 4 | 0 | 0 |
Baseline characteristics
| Characteristic | 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 <=18 years | 0 Participants | 53 Participants | 45 Participants | 20 Participants | 8 Participants | 126 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 9 Participants | 4 Participants | 3 Participants | 2 Participants | 22 Participants |
| Age, Continuous | 23.14 years STANDARD_DEVIATION 0.57 | 10.16 years STANDARD_DEVIATION 5.77 | 9.27 years STANDARD_DEVIATION 6.06 | 13.00 years STANDARD_DEVIATION 5.28 | 13.79 years STANDARD_DEVIATION 6.27 | 10.91 years STANDARD_DEVIATION 6.23 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 15 Participants | 18 Participants | 4 Participants | 0 Participants | 38 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 44 Participants | 31 Participants | 19 Participants | 10 Participants | 107 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants |
| Gender Female | 2 Participants | 29 Participants | 21 Participants | 6 Participants | 5 Participants | 63 Participants |
| Gender Male | 2 Participants | 33 Participants | 28 Participants | 17 Participants | 5 Participants | 85 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 3 Participants | 1 Participants | 1 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 9 Participants | 8 Participants | 4 Participants | 1 Participants | 22 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 5 Participants | 5 Participants | 1 Participants | 0 Participants | 12 Participants |
| Race (NIH/OMB) White | 2 Participants | 44 Participants | 34 Participants | 16 Participants | 8 Participants | 104 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 4 | 58 / 61 | 44 / 49 | 21 / 22 | 9 / 10 |
| serious Total, serious adverse events | 2 / 4 | 47 / 61 | 40 / 49 | 18 / 22 | 7 / 10 |
Outcome results
Primary
Event Free Survival
Percentage of patients who were event free at 4 months
Time frame: 4 months after enrollment
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pre-B ALL Relapse 18-36 Mths From Dx (Chemotherapy)Age<=21 Yrs | Event Free Survival | 68.5 Percentage of participants |
| Pre-B ALL Relapse <18 Mths From Dx (Chemotherapy) Age <=21 Yrs | Event Free Survival | 37.8 Percentage of participants |
Primary
Second Complete Remission Rate at the End of Block 1 Reinduction Chemotherapy
The percentage of eligible and evaluable patients who have achieved complete response at the end Block 1 of re-induction therapy.
Time frame: The outcome is measured the end of Block 1 (Day 36 of Block 1) of re-induction therapy.
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pre-B ALL Relapse 18-36 Mths From Dx (Chemotherapy)Age<=21 Yrs | Second Complete Remission Rate at the End of Block 1 Reinduction Chemotherapy | 72.2 Percentage of participants |
| Pre-B ALL Relapse <18 Mths From Dx (Chemotherapy) Age <=21 Yrs | Second Complete Remission Rate at the End of Block 1 Reinduction Chemotherapy | 63 Percentage of participants |
Primary
Severe Adverse Events (SAE) Rate.
The proportion of SAE rate among all eligible patients
Time frame: 4 months
Population: The SAE event was monitored for all eligible patients. It was not compared between subgroups per protocol 9.3.2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pre-B ALL Relapse < 36 Mths From Dx (Chemotherapy) Age >21 Yrs | Severe Adverse Events (SAE) Rate. | 8.2 percentage of participants |
Primary
Toxic Death Rate
The proportion of toxic death rate among all eligible patients.
Time frame: 4 months
Population: The toxic death was monitored for all eligible patients. It was not compared between subgroups per protocol 9.3.2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pre-B ALL Relapse < 36 Mths From Dx (Chemotherapy) Age >21 Yrs | Toxic Death Rate | 2.1 percentage of participants |
Secondary
Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 1
Percentage of eligible and evaluable patients with MRD \< 0.01% among those who had successful MRD determination at the end of Block 1.
Time frame: End of Block 1 (Day 36 of Block 1) of re-induction therapy
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pre-B ALL Relapse 18-36 Mths From Dx (Chemotherapy)Age<=21 Yrs | Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 1 | 35.4 percentage of participants |
| Pre-B ALL Relapse <18 Mths From Dx (Chemotherapy) Age <=21 Yrs | Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 1 | 25 percentage of participants |
Secondary
Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 2
Percentage of eligible and evaluable patients with MRD \< 0.01% among those who had successful MRD determination at the end of Block 2.
Time frame: End of Block 2 (Day 36 of Block 2) of re-induction therapy
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pre-B ALL Relapse 18-36 Mths From Dx (Chemotherapy)Age<=21 Yrs | Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 2 | 66.7 percentage of participants |
| Pre-B ALL Relapse <18 Mths From Dx (Chemotherapy) Age <=21 Yrs | Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 2 | 42.1 percentage of participants |
Secondary
Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 3
Percentage of eligible and evaluable patients with MRD \< 0.01% among those who had successful MRD determination at the end of Block 3.
Time frame: End of Block 3 (Day 36 of Block 3) of re-induction therapy
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pre-B ALL Relapse 18-36 Mths From Dx (Chemotherapy)Age<=21 Yrs | Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 3 | 80 Percentage of participants |
| Pre-B ALL Relapse <18 Mths From Dx (Chemotherapy) Age <=21 Yrs | Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 3 | 63.6 Percentage of participants |
Other Pre-specified
Change in Stem Cell Percentage
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.
Time frame: Baseline to post-treatment with bortezomib
Population: These were for correlative biology studies and the data were not collected in COG database.
Other Pre-specified
Expression of Apoptotic and Cell Cycle Proteins Assessed by Using Gene and Tissue Microarrays and Immunoblots
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.
Time frame: Up to 5 years
Population: These were for correlative biology studies and the data were not collected in COG database.
Other Pre-specified
NF-kB Activity
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.
Time frame: Up to 5 years
Population: These were for correlative biology studies and the data were not collected in COG database.
Other Pre-specified
Pharmacokinetics (PK) of Bortezomib in Patients Receiving Multi-agent Combination Therapy.
This outcome measure cannot be reported due to the data used for analysis was not collected.
Time frame: Day 8 of blocks 1 and 2
Other Pre-specified
Plasma Concentration-time Profiles
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).
Time frame: Up to day 8 of block 2
Population: These were for correlative biology studies and the data were not collected in COG database.