Clinical trial NCT02535806
Conditions: Acute Lymphoblastic Leukemia Lymphoblastic Lymphoma
Keywords: Relapsed, Refractory
Sponsor: Children's Mercy Hospital Kansas City
Start date: 2015-07-01; Completion date: 2017-05-25
Enrollment: 2 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a phase II study designed to investigate the combination of bortezomib with the mitoxantrone reinduction regimen used in the ALL R3 trial. The study will enroll patients with high risk ALL relapse including early bone marrow relapse and second or greater relapse of any kind. Patients with relapsed LL will also be eligible. Bone marrow evaluation will be performed after blood counts recover to assess the rate of CR (\<5% bone marrow blasts) and MRD status in children following this regimen. Further treatment with or without HSCT will be at the discretion of the primary physician.

Detailed description:
1.0 GOALS AND OBJECTIVES (SCIENTIFIC AIMS)

1.1 Primary Aims

1.1.1 To evaluate the feasibility and toxicity of using bortezomib in combination with the ALL R3 re-induction regimen in pediatric patients with relapsed or refractory ALL or LL.

1.1.2 To determine the rate of complete response and negative minimal residual disease status following bortezomib combined with R3 reinduction.

2.0 BACKGROUND

Despite the progress that has been made in the treatment of ALL in children, relapse of disease remains a significant treatment problem. By itself, the number of patients with relapsed ALL would be the 4th most common childhood malignancy and overall survival in these patients is poor. Using conventional treatments, second remission rates after bone marrow relapse in ALL are 81-93% and long-term event free survival (EFS) is only 27-50%. Initial standard therapy for children following relapse includes a four drug reinduction strategy, typically using prednisone, vincristine, PEG-asparaginase, and doxorubicin. For children with first marrow relapse of ALL less than 36 months from diagnosis, this four drug reinduction strategy results in a CR rate of 68%. However, 75% of patients in CR2 had minimal residual disease (MRD) that was positive (\>0.01%) at the end of reinduction. The presence of MRD in relapsed ALL is strongly associated with worse long term outcomes. For children with ALL that relapsed following a second (CR2) remission, outcomes are dismal with 5 year disease free survival of 15%.

In 2010, results were published of the ALL R3 trial from the Children's Cancer and Leukemia Group in the United Kingdom and Ireland. This trial randomized children with first relapse of ALL to receive a four drug reinduction using either mitoxantrone or idarubicin as the anthracycline. The study was closed early due to a statistically significant improvement in survival for children randomized to mitoxantrone. Children who received mitoxantrone had a 3 year disease free survival of 64.6% compared to 35.9% in the idarubicin group. Toxicities in this study were not excessive, and children randomized to receive mitoxantrone had significantly less toxicity than those in the idarubicin group. Based on the results of this trial, the Children's Oncology Group (COG) has begun using this reinduction regimen as the backbone for new clinical trials for children with relapsed ALL.

Despite the improvement in outcomes for the children with relapsed ALL treated with mitoxantrone on the R3 study, there is still a need for continued efforts to improve outcomes in patients with ALL and LL that experience a relapse. This is particularly true for high risk groups such as those who have an early bone marrow relapse (\<36 months from diagnosis), second or greater relapse or relapsed LL where long term survival remains less than 50% Bortezomib is a proteasome inhibitor that has demonstrated activity in a number of cancer types including acute leukemias. Bortezomib acts by inhibiting the ubiquitin-proteasome pathway resulting in the blockade of NF-κB activation and the stabilization of multiple proapoptotic proteins including p53, p21, p27, and Bax. Collectively, these effects induce apoptosis and enhance the cytotoxic effects of chemotherapy. In the Pediatric Preclinical Testing Program (PPTP), bortezomib showed activity against a number of ALL cell lines. As a single agent, bortezomib was effective at inhibiting NF-κB but there was no clinical response in 9 heavily pretreated children with ALL. Proteasome inhibition is able to induce apoptosis, and may be best utilized in combination with other conventional chemotherapy drugs to help overcome resistance. Preclinical evaluation of bortezomib with a number of drugs commonly used in pediatric ALL therapy demonstrated synergy with dexamethasone and additive effects when given along with vincristine, asparaginase, and doxorubicin.

In a phase 1 study of children with relapsed ALL of bortezomib combined with a four drug reinduction using dexamethasone, vincristine, doxorubicin, PEG-asparaginase and intrathecal therapy, bortezomib at a dose of 1.3 mg/m2 given on days 1, 4, 8 and 11 was well tolerated. The phase 2 study of this regimen was able to produce a complete response or complete response without platelet recovery in 73% of patients. These results are encouraging as these were heavily pretreated patients treated with 2 or 3 previous regimens. Due to 3 deaths from infectious toxicities, the study was amended to require infectious prophylaxis with vancomycin, levofloxacin, and voriconazole. No further deaths were seen in children following this change. Other toxicities seen on this study include grade 3 peripheral neuropathy in 2 patients.

This is a phase II study designed to investigate the combination of bortezomib with the mitoxantrone reinduction regimen used in the ALL R3 trial. The study will enroll patients with high risk ALL relapse including early bone marrow relapse and second or greater relapse of any kind. Patients with relapsed LL will also be eligible. Bone marrow evaluation will be performed after blood counts recover to assess the rate of CR (\<5% bone marrow blasts) and MRD status in children following this regimen. Further treatment with or without HSCT will be at the discretion of the primary physician.

2.1 Bortezomib for Injection 2.1.1 Scientific Background Bortezomib for Injection is a small-molecule proteasome inhibitor developed by Millennium Pharmaceuticals, Inc., (Millennium) as a novel agent to treat human malignancies. Bortezomib is currently approved by the United States Food and Drug Administration (US FDA) for the treatment of patients with multiple myeloma (MM). It is also indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least 1 prior therapy. In the European Union (EU), bortezomib in combination with melphalan and prednisone is indicated for the treatment of patients with previously untreated MM who are not eligible for high-dose chemotherapy with bone marrow transplant. Bortezomib is indicated as monotherapy for the treatment of progressive MM in patients who have received at least 1 prior therapy and who have already undergone or are unsuitable for bone marrow transplantation.

By inhibiting a single molecular target, the proteasome, bortezomib affects multiple signaling pathways. The antineoplastic effect of bortezomib likely involves several distinct mechanisms, including inhibition of cell growth and survival pathways, induction of apoptosis, and inhibition of expression of genes that control cellular adhesion, migration, and angiogenesis. Thus, the mechanisms by which bortezomib elicits its antitumor activity may vary among tumor types, and the extent to which each affected pathway is critical to the inhibition of tumor growth could also differ. Bortezomib has a novel pattern of cytotoxicity in National Cancer Institute (NCI) in vitro and in vivo assays.(19) In addition, bortezomib has cytotoxic activity in a variety of xenograft tumor models, both as a single agent and in combination with chemotherapy and radiation. Notably, bortezomib induces apoptosis in cells that over express bcl-2, a genetic trait that confers unregulated growth and resistance to conventional chemotherapeutics.

The mechanisms of action leading up to apoptosis have been more clearly defined and include initiation of the unfolded protein response and direct/indirect effects on various molecular targets including cell cycle control proteins p27 and p21, cyclins, signal transduction molecules, transcription factors c-jun and HIF1-, tumor suppressor protein p53, angiogenesis factors, and many others. Bortezomib is thought to be efficacious in multiple myeloma via its inhibition of nuclear factor B (NF-B) activation, its attenuation of interleukin-6 (IL-6)-mediated cell growth, a direct apoptotic effect, and possibly anti-angiogenic and other effects.

Arms: arm 1: Velcade will be given IV push on days 1,4,8 and 11 at a dose of 1.3 mg/m2/dose. At least 72 hours must have relapsed between doses.

IT Methotrexate (CNS Negative patients only) on days 1 and 8; age based dosing IT Methotrexate/Hydrocortisone/AraC (CNS positive patients only) on days 1, 8, 15 and 22; age based dosing.

Dexamethasone: Days 1-5 and 15-19; 10mg/m2/dose PO BID. Mitoxantrone: Days 1 and 2; 10mg/m2/dose Vincristine: days 1, 8, 15, and 22 at 1.5 mg/m2 (Maximum dose 2 mg) PEG-asparaginase: Days 3 and 17, 2500 IU/m2/dose
Interventions: intervention 1: Velcade intervention 2: Methotrexate intervention 3: Methotrexate / Hydrocortisone / Cytarabine intervention 4: Dexamethasone intervention 5: Mitoxantrone intervention 6: Vincristine intervention 7: Pegaspargase
Intervention descriptions: intervention 1: 4 doses of study drug will be given. intervention 2: Intrathecal dose For CNS negative patients, Day 1 and Day 8 intervention 3: Intrathecal dose for CNS positive patients, Day 1, 8, 15, 22 intervention 4: Days 1-5 and 15-19 intervention 5: Days 1 and 2 intervention 6: Days 1, 8, 15, 22 intervention 7: Days 3 and 17

Protocol documents:
Prot_SAP_000.pdf: 
1 
 
 
 
 
 
 
 
MERCY01  
 
A Pilot Study of Mitoxantrone-Based Four Drug Reinduction in Combination with 
Bortezomib for Relapsed or Refractory Acute Lymphoblastic Leukemia or Lymphoblastic 
Lymphoma in Children and Young Adults (NCT02535806) 
Protocol Date: 01/25/2016 
 
Principal Investigator 
Keith August, M.D., M.S. 
Pediatric Hematology/Oncology 
Children’s Mercy Hospital and Clinics 
Kansas City, MO 64108 
(816) 3026808 
kjaugust@cmh.edu 
 
This is an investigator-initiated study. The principal investigator, Dr. Keith August, (who may 
also sometimes be referred to as the sponsor-investigator), is conducting the study and acting as 
the sponsor. Therefore, the legal/ethical obligations of the principal investigator include both 
those of a sponsor and those of an investigator. 
 
 


 
 
TABLE OF CONTENTS 
 
ABSTRACT  
 
 
 
 
 
 
 
 
 
 1 
 
EXPERIMETNAL DESIGN 
 
 
 
 
 
  
 
2 
 
1.0  
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
  
 
3 
 
2.0  
BACKGROUND 
 
 
 
 
 
 
  
 
3 
 
3.0  
PATIENT ELIGIBILITY CRITERIA 
 
 
 
 
 
 5 
 
4.0   
TREATMENT PROGRAM 
 
 
 
 
 
 
11 
 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
 
 
 
 
13 
 
6.0   
AGENT INFORMATION  
 
 
 
 
 
 
16 
 
7.0  
SUPPORTIVE CARE AND OTHER CONCOMMITANT THERAPY 
29 
 
8.0  
STUDY EVALUATIONS  
 
 
 
 
 
 
30 
 
9.0  
STATISTICAL CONSIDERATIONS 
 
 
 
 
 
31 
 
10.0 
EVALUATION CRITERIA 
 
 
 
 
 
 
31 
 
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES  
 
 
36 
 
APPENDIX II: CYP3A4 INDUCERS AND INHIBITORS 
 
 
 
37 
 
REFERENCES  
 
 
 
 
 
 
 
 
 
38


1 
 
ABSTRACT 
 
This is a pilot study to determine the feasibility and safety of adding bortezomib (Velcade) to 
four drug reinduction therapy that includes mitoxantrone for patients with relapsed B-precursor 
cell acute lymphoblastic leukemia (ALL), relapsed T-cell ALL or relapsed lymphoblastic 
lymphoma (LL).  Relapsed ALL or LL in children is associated with a poor prognosis and new 
strategies for treatment are needed.  This study aims to improve outcomes in relapsed ALL and 
LL by combining bortezomib with the backbone chemotherapy regimen that includes 
mitoxantrone, which has demonstrated the most success in this population. 
 
The objectives of this protocol are to estimate the toxicity, remission rate, post-induction 
minimal residual disease, and 2 year event free survival of the above regimen.  
 
This is a pilot study for re-induction therapy only.  Upon completion of therapy, it is expected 
that patients will continue on to further consolidation therapy with either stem cell 
transplantation or further chemotherapy at the discretion of the treating physician. 
 
 
 


2 
 
EXPERIMENTAL DESIGN 
 
  
 
 
 
 
Day Vincristine Dexamethasone Mitoxantrone 
PEG-
Asparaginase 
Bortezomib Methotrexate 
(IT) 
1 
• 
Twice Daily 
• 
 
• 
• 
2 
 
 
• 
 
 
 
3 
 
 
 
• 
 
 
4 
 
 
 
 
• 
 
5 
 
 
 
 
 
 
8 
• 
 
 
 
• 
• 
10 
 
 
 
 
 
 
11 
 
 
 
 
• 
 
15 
• 
Twice Daily 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
• 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
22 
• 
 
 
 
 
 
 
 
 
 
 
 
 


3 
 
1.0 GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 Primary Aims 
 
4.1.1 To evaluate the feasibility and toxicity of using bortezomib in combination 
with the ALL R3 re-induction regimen in pediatric patients with relapsed 
or refractory ALL or LL. 
 
4.1.2 To determine the rate of complete response and negative minimal residual  
disease status following bortezomib combined with R3 reinduction. 
 
 
2.0 BACKGROUND 
 
Despite the progress that has been made in the treatment of ALL in children, relapse of disease 
remains a significant treatment problem.  By itself, the number of patients with relapsed ALL 
would be the 4th most common childhood malignancy and overall survival in these patients is 
poor.  Using conventional treatments, second remission rates after bone marrow relapse in ALL 
are 81-93%(1-6) and long-term event free survival (EFS) is only 27-50%.(2-4, 6-8)  Initial 
standard therapy for children following relapse includes a four drug reinduction strategy, 
typically using prednisone, vincristine, PEG-asparaginase, and doxorubicin.(5, 9)  For children 
with first marrow relapse of ALL less than 36 months from diagnosis, this four drug reinduction 
strategy results in a CR rate of 68%.(5)  However, 75% of patients in CR2 had minimal residual 
disease (MRD) that was positive (>0.01%) at the end of reinduction.  The presence of MRD in 
relapsed ALL is strongly associated with worse long term outcomes(5, 10).  For children with 
ALL that relapsed following a second (CR2) remission, outcomes are dismal with 5 year disease 
free survival of 15%.(2) 
 
In 2010, results were published of the ALL R3 trial from the Children’s Cancer and Leukemia 
Group in the United Kingdom and Ireland.  This trial randomized children with first relapse of 
ALL to receive a four drug reinduction using either mitoxantrone or idarubicin as the 
anthracycline.(8)  The study was closed early due to a statistically significant improvement in 
survival for children randomized to mitoxantrone.  Children who received mitoxantrone had a 3 
year disease free survival of 64.6% compared to 35.9% in the idarubicin group.  Toxicities in this 
study were not excessive, and children randomized to receive mitoxantrone had significantly less 
toxicity than those in the idarubicin group.  Based on the results of this trial, the Children’s 
Oncology Group (COG) has begun using this reinduction regimen as the backbone for new 
clinical trials for children with relapsed ALL. 
 
Despite the improvement in outcomes for the children with relapsed ALL treated with 
mitoxantrone on the R3 study, there is still a need for continued efforts to improve outcomes in 
patients with ALL and LL that experience a relapse.  This is particularly true for high risk groups 
such as those who have an early bone marrow relapse (<36 months from diagnosis), second or 
greater relapse or relapsed LL where long term survival remains less than 50%.(2, 5)  
 
Bortezomib is a proteasome inhibitor that has demonstrated activity in a number of cancer types 
including acute leukemias. Bortezomib acts by inhibiting the ubiquitin-proteasome pathway 


4 
 
resulting in the blockade of NF-κB activation and the stabilization of multiple proapoptotic 
proteins including p53, p21, p27, and Bax. Collectively, these effects induce apoptosis and 
enhance the cytotoxic effects of chemotherapy.(11-13)  In the Pediatric Preclinical Testing 
Program (PPTP), bortezomib showed activity against a number of ALL cell lines.(14)  As a 
single agent, bortezomib was effective at inhibiting NF-κB but there was no clinical response in 
9 heavily pretreated children with ALL.(15)  Proteasome inhibition is able to induce apoptosis, 
and may be best utilized in combination with other conventional chemotherapy drugs to help 
overcome resistance. Preclinical evaluation of bortezomib with a number of drugs commonly 
used in pediatric ALL therapy demonstrated synergy with dexamethasone and additive effects 
when given along with vincristine, asparaginase, and doxorubicin.(16) 
 
In a phase 1 study of children with relapsed ALL of bortezomib combined with a four drug 
reinduction using dexamethasone, vincristine, doxorubicin, PEG-asparaginase and intrathecal 
therapy, bortezomib at a dose of 1.3 mg/m2 given on days 1, 4, 8 and 11 was well tolerated.(17)  
The phase 2 study of this regimen was able to produce a complete response or complete response 
without platelet recovery in 73% of patients.(18)  These results are encouraging as these were 
heavily pretreated patients treated with 2 or 3 previous regimens.  Due to 3 deaths from 
infectious toxicities, the study was amended to require infectious prophylaxis with vancomycin, 
levofloxacin, and voriconazole.  No further deaths were seen in children following this change.  
Other toxicities seen on this study include grade 3 peripheral neuropathy in 2 patients.   
This is a phase II study designed to investigate the combination of bortezomib with the 
mitoxantrone reinduction regimen used in the ALL R3 trial.  The study will enroll children with 
high risk ALL relapse including early bone marrow relapse and second or greater relapse of any 
kind.  Patients with relapsed LL will also be eligible.  Bone marrow evaluation will be performed 
after blood counts recover to assess the rate of CR (<5% bone marrow blasts) and MRD status in 
children following this regimen.  Further treatment with or without HSCT will be at the 
discretion of the primary physician.  
2.1 Bortezomib for Injection 
2.1.1 Scientific Background 
Bortezomib for Injection is a small-molecule proteasome inhibitor developed by Millennium 
Pharmaceuticals, Inc., (Millennium) as a novel agent to treat human malignancies.  Bortezomib 
is currently approved by the United States Food and Drug Administration (US FDA) for the 
treatment of patients with multiple myeloma (MM).  It is also indicated for the treatment of 
patients with mantle cell lymphoma (MCL) who have received at least 1 prior therapy.  In the 
European Union (EU), bortezomib in combination with melphalan and prednisone is indicated 
for the treatment of patients with previously untreated MM who are not eligible for high-dose 
chemotherapy with bone marrow transplant.  Bortezomib is indicated as monotherapy for the 
treatment of progressive MM in patients who have received at least 1 prior therapy and who have 
already undergone or are unsuitable for bone marrow transplantation. 


5 
 
By inhibiting a single molecular target, the proteasome, bortezomib affects multiple signaling 
pathways.  The antineoplastic effect of bortezomib likely involves several distinct mechanisms, 
including inhibition of cell growth and survival pathways, induction of apoptosis, and inhibition 
of expression of genes that control cellular adhesion, migration, and angiogenesis.  Thus, the 
mechanisms by which bortezomib elicits its antitumor activity may vary among tumor types, and 
the extent to which each affected pathway is critical to the inhibition of tumor growth could also 
differ.  Bortezomib has a novel pattern of cytotoxicity in National Cancer Institute (NCI) in vitro 
and in vivo assays.(19)  In addition, bortezomib has cytotoxic activity in a variety of xenograft 
tumor models, both as a single agent and in combination with chemotherapy and radiation.(12, 
20-31)   Notably, bortezomib induces apoptosis in cells that over express bcl-2, a genetic trait 
that confers unregulated growth and resistance to conventional chemotherapeutics.(32) 
The mechanisms of action leading up to apoptosis have been more clearly defined and include 
initiation of the unfolded protein response and direct/indirect effects on various molecular targets 
including cell cycle control proteins p27 and p21, cyclins, signal transduction molecules, 
transcription factors c-jun and HIF1-, tumor suppressor protein p53, angiogenesis factors, and 
many others.  Bortezomib is thought to be efficacious in multiple myeloma via its inhibition of 
nuclear factor B (NF-B) activation, its attenuation of interleukin-6 (IL-6)-mediated cell 
growth, a direct apoptotic effect, and possibly anti-angiogenic and other effects.(33-40) 
2.1.2 
Clinical Experience 
To date, more than 436,000 patients have been treated with bortezomib, including patients 
treated through Millennium-sponsored clinical trials, Investigator-Initiated Studies, the US NCI 
Cancer Therapy Evaluation Program (CTEP), and with commercially available drug.  
Bortezomib has been commercially available since 13 May 2003. 
The overall goal of the Millennium phase 1 program was to determine the MTD and dose-
limiting toxicity (DLT) of bortezomib in a number of therapeutic settings involving subjects with 
various advanced malignancies.  In a phase 1 trial in patients with refractory hematologic 
malignancies, the MTD for a twice weekly dosing for 4 weeks of a 42-day cycle was 
1.04 mg/m2/dose, with DLTs of thrombocytopenia, hyponatremia, hypokalemia, fatigue, and 
malaise.(41)  The toxicity was greatest during the third and fourth weeks of therapy.  In the 3-
week schedule of bortezomib monotherapy (4 doses, given on Days 1, 4, 8, and 11 of a 21-day 
treatment cycle), the DLT occurred at 1.56 mg/m2/dose (3 subjects with Grade 3 diarrhea and 1 
with peripheral sensory neuropathy).  Therefore, the MTD at this schedule was 1.3 mg/m2/dose.  


6 
 
In a 35-day treatment cycle with 4 weekly doses of bortezomib monotherapy, the MTD was 1.6 
mg/m2/dose and DLT included hypotension, tachycardia, diarrhea, and syncope. 
In phase 1 clinical studies, antitumor activity was reported in subjects with Non-Hodgkin’s 
Lymphoma (NHL), MM, Waldenström’s Macroglobulinemia, squamous cell carcinoma of the 
nasopharynx, bronchoalveolar carcinoma of the lung, renal cell carcinoma, and prostate 
cancer.(41-44)   
The safety and efficacy of bortezomib in subjects with MM were investigated in two phase 2 
clinical studies, studies M34100-024 (subjects with first relapse)(45) and M34100-025 (subjects 
with second or greater relapse and refractory to their last prior therapy).(46)  In M34100-025, 
202 heavily pretreated subjects with refractory MM after at least 2 previous treatments received 
bortezomib, 1.3 mg/m2 on Days 1, 4, 8, and 11 of a 21-day treatment cycle.  The European 
Group for Blood and Marrow Transplant (EBMT) response criteria, as described by Blade(47) 
were utilized to determine disease response.  Complete responses (CRs) were observed in 4% of 
subjects, with an additional 6% of patients meeting all criteria for CR but having a positive 
immunofixation test.  Partial response (PR) or better was observed in 27% of subjects, and the 
overall response rate (CR, PR, and minor response [MR] combined) was 35%.  Seventy percent 
of subjects experienced stable disease or better. 
The phase 3 study (M34101-039)(48), also referred to as the APEX study, was designed to 
determine whether bortezomib provided benefit (time to progression [TTP], response rate, and 
survival) to patients with relapsed or refractory MM relative to treatment with high-dose 
dexamethasone.  The study was also designed to determine the safety and tolerability of 
bortezomib relative to high-dose dexamethasone, and whether treatment with bortezomib was 
associated with superior clinical benefit and quality of life relative to high-dose dexamethasone.  
A total of 669 patients were enrolled and 663 patients received study drug (bortezomib:  331; 
dexamethasone:  332).  Patients randomized to bortezomib received 1.3 mg/m2 IV push twice 
weekly on Days 1, 4, 8, and 11 of a 3-week cycle for up to 8 treatment cycles as induction 
therapy, followed by 1.3-mg/m2 bortezomib weekly on Days 1, 8, 15, and 22 of a 5-week cycle 
for 3 cycles as maintenance therapy.  Patients randomized to dexamethasone received oral 
dexamethasone 40 mg once daily on Days 1 to 4, 9 to 12, and 17 to 20 of a 5-week cycle for up 
to 4 treatment cycles as induction therapy, followed by dexamethasone 40 mg once daily on 
Days 1 to 4 of a 4-week cycle for 5 cycles as maintenance therapy.  The EBMT response criteria 
were utilized to determine disease response.  There was a 78% increase in TTP for the 
bortezomib arm.  Median TTP was 6.2 months for the bortezomib arm and 3.5 months for the 
dexamethasone arm (p < 0.0001).  CR + PR was 38% with bortezomib versus 18% with 


7 
 
dexamethasone (p  0.0001).  CR was 6% with bortezomib versus  1% with dexamethasone (p 
< 0.0001).  The CR + nCR (near CR) rate was 13% with bortezomib versus 2% with 
dexamethasone.  In patients who had received only 1 prior line of treatment (bortezomib:  132; 
dexamethasone:  119), CR + PR was 45% with bortezomib vs 26% with dexamethasone (p = 
0.0035).  With a median 8.3 months of follow-up, overall survival was significantly longer (p = 
0.0013) for patients on the bortezomib arm versus patients on the dexamethasone arm.  The 
probability of survival at 1 year was 80% for the bortezomib arm versus 66% for the 
dexamethasone arm, which represented a 41% decreased relative risk of death in the first year 
with bortezomib (p = 0.0005).  In patients who had received only 1 prior line of treatment, the 
probability of survival at 1 year was 89% for the bortezomib arm versus 72% for the 
dexamethasone arm, which represented a 61% decreased relative risk of death in the first year 
with bortezomib (p = 0.0098).  Updated response rates and survival data were reported for 
M34101-039.(49)  The updated CR + PR rate was 43% with bortezomib.  The CR + nCR rate 
was 16% with bortezomib.  With a median 22 months of follow-up, overall survival was 
significantly longer for patients on the bortezomib arm versus patients on the dexamethasone 
arm.  The median overall survival was 29.8 months (95% CI:  23.2, not estimable) for the 
bortezomib arm vs 23.7 months (95% CI:  18.7, 29.1) for the dexamethasone arm (hazard ratio = 
0.77, p = 0.0272).  The probability of survival at 1 year was 80% for the bortezomib arm versus 
67% for the dexamethasone arm (p = 0.0002). 
The safety and efficacy of bortezomib in relapsed or refractory mantle cell lymphoma (MCL) 
were investigated in an international, phase 2, multicenter study M34103-053, also referred to as 
the PINNACLE study.(50)  The single-arm study was designed to evaluate the response rates, 
duration of response (DOR), TTP, overall survival (OS), and safety of bortezomib treatment in 
patients with relapsed or refractory mantle cell lymphoma.  For 141 evaluable patients, the 
response rate was 31% (8% CR/unconfirmed CR [Cru]).  Median time to response was 40 days 
(range 31-204 days).  The median number of cycles administered across all patients was 4; in 
responding patients, the median number of cycles was 8.  The median DOR by algorithm was 9.2 
months and 13.5 months in patients with CR/CRu.  Median TTP for both groups was 6.2 months.  
With a median follow-up of 13.4 months, overall survival had not been reached.  The most 
commonly reported adverse events (AEs) were fatigue, peripheral neuropathy, and 
gastrointestinal events.  A time-to-event update to the PINNACLE studyi was reported after a 
median follow-up of 26.4 months.  TTP was 6.7 months for all patients, 12.4 months in all 
responders.  The median DOR was 9.2 months in all responders and had not been reached in 
patients achieving CR/Cru.  Overall survival was 23.5 months in all patients and 36 months in 
patients with CR/Cru.  Survival at 12 months was 69% overall and 91% in responding patients. 


8 
 
The phase 3 study (MMY 3002) known as the VISTA study, evaluated the safety and efficacy of 
the combination of bortezomib, melphalan, and prednisone in previously untreated multiple 
myeloma patients who were not candidates for stem cell transplant.(51)  The study was designed 
to determine the benefit of adding bortezomib to MP (melphalan and prednisone) as assessed by 
TTP.  Patients (682) were randomized to receive nine 6-week cycles of melphalan 9mg/m2 and 
prednisone 60 mg/m2 on Days 1 to 4, alone or in combination with bortezomib 1.3 mg/m2 by IV 
bolus on Days 1, 4, 8, 11, 22, 25, 29, and 32 during Cycles 1 to 4, and on Days 1, 8, 22, and 29 
during Cycles 5 to 9.  Response was evaluated every 3 weeks using the EBMT criteria.  At a 
preplanned interim analysis, the independent data monitoring committee recommended that the 
study be stopped since the prespecified statistical boundary end point of TTP had been crossed.  
Response rates were 30% with 4% CR.  The rates of partial response or better were 71% in the 
bortezomib (VMP) group compared to 34% in the MP group (p = 0.001).  With follow-up of 
16.3 months, the TTP for the VMP group was 24 months compared to 16.6 months in the MP 
group (p = 0.000001) and was associated with a 52% reduced time to progression.  The median 
DOR was 19.9 months in the VMP group and 13.1 months in the MP group.  Overall survival 
had not been reached in either group.  Hematologic toxicity was similar in both groups.  The 
incidence of peripheral sensory neuropathy and gastrointestinal symptoms was higher in the 
VMP group.  The incidence of herpes zoster was 3% in patients in the VMP group who received 
antiviral prophylaxis.  Fifteen percent of patients in the VMP group discontinued therapy due to 
AEs compared to 14% in the MP group. 
The VISTA study update after extended follow-up of 25.9 months,(51) confirmed a survival 
benefit for the VMP group.  Overall survival was not reached in either group:  VMP group (75) 
deaths, 3 year OS 72%; MP group (111) deaths, 3 year OS 59% (p = 0.0032).  Patients on VMP 
were less likely to start second-line therapy (VMP 38% vs MP 57% at the time of data cut-off) 
with a longer time to next therapy (TNT) and treatment free interval (TFI).  Of the MP patients 
who received subsequent therapy, 43% went on to receive bortezomib. 
Based on investigator-reported best responses to subsequent therapies, patients relapsing after 
therapy with a novel agent were not intrinsically more resistant than after receiving a traditional 
agent. 
In the VISTA study, VMP was associated with prolonged TTP, TNT, TFI, and OS.  Patients 
were successfully treated with subsequent IMiD-based therapy and retreated with bortezomib.  
After 36.7 months follow-up, OS continued to be superior for VMP.  The OS for VMP had not 
yet been reached compared to MP (43.1 months).(52)  In an updated analysis of overall survival 
based on 387 deaths (median follow-up 60.1 months), the median overall survival for VMP was 


9 
 
56.4 months and the MP was 43.1 months, with a hazard ration of 0.695 (95% CI: 0.57, 
0.85).(53) 
2.1.3    
Potential Risks of Bortezomib  
To date, more than 436,000 patients have been treated with bortezomib in both clinical trials 
investigating its use in hematological malignancies and solid tumors, and in patients who were 
treated with commercially available bortezomib. 
Prescribing physicians and health care practitioners are referred to their locally approved product 
label for bortezomib regarding Indications and Usage, Contraindications, Warnings, and 
Precautions. 
The known anticipated risks of bortezomib therapy are presented in Table 1-1  and Table 1-2.  
These risks are grouped according to the combined frequency observed in an integrated analysis 
of AEs in sponsored clinical studies of single-agent bortezomib dosed at 1.3 mg/m2 twice weekly 
on a 21-day schedule, in patients with multiple myeloma and mantle cell lymphoma. 


10 
 
Table 1-1    
Known Anticipated Risks of Bortezomib by MedDRA System Organ 
Class, Observed Incidence, and Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
Blood and Lymphatic System Disorders 
Most common 
Thrombocytopenia*, anaemia* 
Very common  
Neutropenia* 
Common  
Lymphopenia, pancytopenia*, leukopenia*, febrile 
neutropenia 
Cardiac Disorders 
Common  
Tachycardia, atrial fibrillation, palpitations, cardiac 
failure congestive* 
Uncommon 
Cardiogenic shock*, atrial flutter, cardiac tamponade*, 
bradycardia, atrioventricular block complete, arrhythmia, 
cardiac arrest, cardiac failure, arrhythmia, pericardial 
effusion, pericarditis, pericardial disease, 
cardiopulmonary failure 
Ear and Labyrinth Disorders 
Uncommon 
Deafness, hearing impaired 
Eye Disorders 
Common  
Blurred vision, conjunctivitis, conjunctival haemorrhage  
Gastrointestinal Disorders 
Most common 
Constipation, diarrhoea*, nausea, vomiting* 
Very common  
abdominal pain (excluding oral and throat) 
Common  
Dyspepsia, pharyngolaryngeal pain, gastroesophageal 
reflux, abdominal distension, gastritis, stomatitis, mouth 
ulceration, dysphagia, gastrointestinal haemorrhage*, 
lower gastrointestinal haemorrhage*± rectal 
haemorrhage 
Uncommon 
Eructation, gastrointestinal pain, tongue ulceration, 
retching, upper gastrointestinal haemorrhage*, 
haematemesis*, oral mucosal petechiae, ileus paralytic*, 
ileus, odynophagia, enteritis, colitis, oesophagitis, 
enterocolitis, diarrhoea haemorrhagic, acute 
pancreatitis*, intestinal obstruction 
General Disorders and Administration Site Conditions 
Most common 
Fatigue, pyrexia 
Very common  
Chills, oedema peripheral, asthenia 
Common  
Neuralgia, lethargy, malaise, chest pain, mucosal 
inflammation* 
Uncommon 
Injection site pain, injection site irritation, injection site 
phlebitis, general physical health deterioration*, 
catheter-related complication 
Hepatobiliary Disorders 
Uncommon 
Hyperbilirubinaemia, hepatitis* 


11 
 
Table 1-1    
Known Anticipated Risks of Bortezomib by MedDRA System Organ 
Class, Observed Incidence, and Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
Immune System Disorders 
Uncommon 
Drug hypersensitivity, angioedema 
Infections and Infestations 
Very common  
Upper respiratory tract infection, nasopharyngitis, 
pneumonia*, Herpes zoster* 
Common  
Lower respiratory tract infection*, sinusitis, pharyngitis, 
oral candidiasis, urinary tract infection*, sepsis, 
bactaeremia*, cellulitis, Herpes simplex, bronchitis, 
gastroenteritis*, infection 
Uncommon 
Septic shock*, catheter-related infection*, skin 
infection*, Herpes zoster disseminated*, lung infection, 
infusion site cellulitis, catheter site cellulitis, infusion 
site infection, urosepsis*, Aspergillosis*, tinea infection, 
Herpes zoster ophthalmic, Herpes simplex ophthalmic, 
meningoencephalitis herpetic, varicella, empyema, 
fungal oesophagitis 
Injury, Poisoning, and Procedural Complications  
Common 
Fall 
Uncommon 
Subdural haematoma 
Investigations 
Common  
Weight decreased, alanine aminotransferase (ALT) 
increased, aspartate aminotransferase (AST) increased, 
blood alkaline phosphatase increased, liver function test 
abnormal, blood creatinine increased* 
Uncommon 
Gamma-glutamyltransferase (GGT) increased, oxygen 
saturation decreased*, blood albumin decreased, ejection 
fraction decreased* 
Metabolism and Nutritional Disorders 
Very common  
Decreased appetite, anorexia, dehydration* 
Common  
Hyperglycaemia, hypoglycaemia, hyponatraemia, 
hypokalaemia, hypercalcaemia* 
Musculoskeletal and Connective Tissue Disorders 
Very common  
Bone pain, myalgia, arthralgia, back pain 
Common 
Muscular weakness 
Uncommon 
Limb discomfort 
Neoplasms, Benign, Malignant, and Unspecified (including cysts and polyps) 
Uncommon 
Tumour lysis syndrome* 


12 
 
Table 1-1    
Known Anticipated Risks of Bortezomib by MedDRA System Organ 
Class, Observed Incidence, and Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
Nervous System Disorders 
Most common 
Peripheral neuropathy (including all preferred terms 
under the MedDRA High-level term Peripheral 
neuropathy NEC) 
Very common  
Paresthesia, dizziness excluding vertigo, headache 
Common  
Polyneuropathy, syncope, dysesthesia, dysgeusia, 
postherpetic neuralgia 
Uncommon 
Convulsion, loss of consciousness, ageusia, 
encephalopathy, paralysis*,autonomic neuropathy, 
reversible posterior leukoencephalopathy syndrome, 
posterior reversible encephalopathy syndrome  
Psychiatric Disorders 
Very common 
Anxiety, insomnia  
Common 
Confusional state  
Uncommon 
Delirium 
Renal and Urinary Disorders 
Common 
Renal impairment*, renal failure*, haematuria 
Uncommon 
Micturition disorder 
Respiratory, Thoracic, and Mediastinal Disorders 
Very common 
Cough, dyspnoea  
Common 
Epistaxis, dyspnoea exertional, pleural effusion*, 
rhinorrhea, hypoxia*, pulmonary oedema 
Uncommon 
Hemoptysis*, acute respiratory distress syndrome*, 
respiratory failure*, pneumonitis*, lung infiltration, 
pulmonary alveolar haemorrhage*, interstitial lung 
disease*, pulmonary hypertension*, pleurisy, pleuritic 
pain 
Skin and Subcutaneous Tissue Disorders 
Very common 
Rash 
Common 
Rash pruritic, rash erythematous, urticaria, petechiae 
Uncommon 
Cutaneous vasculitis, leukocytoclastic vasculitis  
Vascular Disorders 
Common 
Hypotension*, orthostatic hypotension 
Uncommon 
Cerebral haemorrhage* 
Source:  VELCADE® (bortezomib) for Injection Investigator’s Brochure Edition 17. 
Most common =  30%, Very common = 10% to 29%, Common = 1% to 9%, Uncommon = < 1%. 
* Fatal outcomes have been reported. 
 Indicates a Preferred term not listed in the source table, however the event is deemed medically important 
and so is included. 


13 
 
Table 1-1    
Known Anticipated Risks of Bortezomib by MedDRA System Organ 
Class, Observed Incidence, and Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
  Effective MedDRA update to version 14.0, the term ‘reversible posterior leukoencephalopathy syndrome’ 
updated to ‘posterior reversible encephalopathy syndrome (PRES)’. 
 
 
 


14 
 
Table 1-2    
Reports of Adverse Reactions From Postmarketing Experience 
System Organ Class 
 
Preferred Term 
Observed 
Incidencea 
Blood and lymphatic system disorders 
 
 
Disseminated intravascular coagulation  
Rare 
Cardiac Disorders 
 
 
Atrioventricular block complete 
Rare 
 
Cardiac tamponade 
Rare 
Ear and labyrinth disorders 
 
 
Deafness bilateral 
Rare 
Eye Disorders 
 
 
Ophthalmic herpes 
Rare 
              Optic neuropathy 
Rare 
              Blindness 
Rare  
Gastrointestinal Disorders 
 
 
Acute pancreatitis  
Rare 
 
Ischemic colitis 
Rare 
Hepatobiliary disorders 
 
 
Hepatitis 
Uncommon 
 
Liver failure 
Unknown 
Infections and infestations 
 
 
Herpes meningoencephalitis 
Rare 
 
Septic shock 
Rare 
Progressive multifocal leukoencephalopathy 
Very rare 
Immune System Disorders 
 
 
Angioedema 
Rare 
Nervous System Disorders 
 
 
Autonomic neuropathy 
Rare 
 
Dysautonomia 
Unknown 
 
Encephalopathy 
Rare 
Respiratory, thoracic and mediastinal disorders: 
 
 
Acute diffuse infiltrative pulmonary diseaseb  
Rare 
 
Acute respiratory distress syndrome (ARDS) 
Rare 
 
Interstitial pneumonia 
Rare 
 
Lung infiltration 
Rare 
 
Pneumonitis 
Rare 
 
Pulmonary hypertension 
Rare 


15 
 
Table 1-2    
Reports of Adverse Reactions From Postmarketing Experience 
System Organ Class 
 
Preferred Term 
Observed 
Incidencea 
Skin and subcutaneous system disorders 
 
 
Acute febrile neutrophilic dermatosis 
Unknown 
 
Toxic epidermal necrolysis 
Unknown 
Source:  VELCADE® (bortezomib) for Injection Investigator’s Brochure Edition 17. 
a Incidence is assigned using the following convention:  very common ( 1/10); common ( 1/100 and 
 1/10); uncommon ( 1/1000 and  1/100); rare ( 1/10,000 and  1/1000 ); very rare ( 1/10,000, 
including isolated reports). 
b Acute diffuse infiltrative pulmonary disease is a MedDRA Lower Level Term which corresponds to a 
Preferred Term of Interstitial lung disease. 
 
Other medical events of interest that are considered not causally related to bortezomib include 
hepatic failure and QT prolongation.  Fatal outcomes have been reported. 
Women of childbearing potential should avoid becoming pregnant while being treated with 
bortezomib.  Genotoxicity testing has shown that bortezomib is negative in the in vitro Ames 
assay and in the in vivo micronucleus assay, but it is a clastogen in the in vitro chromosomal 
aberration assay. 
Additional details on the potential risks of bortezomib may be found in the current Investigator’s 
Brochure. 
 


16 
 
3 
PATIENT ELIGIBILITY CRITERIA 
 
3.1 The total number of patients to be enrolled in this study is 10. 
 
3.1 Inclusion Eligibility Criteria 
 
The eligibility criteria below are interpreted literally and cannot be waived. Each patient must 
meet all of the following inclusion criteria to be enrolled in the study.  Study procedures must 
occur within seven days of starting therapy. 
 
3.1.2 
Age 
Patients must be > 1 month old and < 40 years of age at the time of enrollment 
 
3.1.3 
Diagnosis 
– Precursor B-cell ALL with bone marrow (BM) or combined BM/extramedullary 
relapse; 
– T-cell ALL with relapsed disease 
– LL with relapsed disease 
– ALL(T or pre-B) or LL with primary refractory disease after at least two regimens 
 
3.1.4 Performance Score 
Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for patients ≤ 16 years 
of age. (See Appendix I for Performance Scales) 
3.1.4   Prior Therapy 
3.1.4.1  
Patients who relapse while receiving standard ALL maintenance chemotherapy will not be 
required to have a waiting period before entry onto this study.  
 
3.1.4.2  
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. In addition, the following requirements must be 
met: 
   
a. Cytotoxic therapy: 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.  
 
b. Biologic (anti-neoplastic) agent: 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.  
 


17 
 
c. Stem cell transplant or rescue: No evidence of active graft-vs-host disease (GVHD) 
and ≥ 4 months must have elapsed from time of transplant. Must not be receiving GVHD 
prophylaxis.  
 
3.1.5 Organ Function Requirements 
 
All patients must have:  
 
3.1.5.1 Adequate Renal Function Defined As:  
 
- Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m2 
 
 or 
 
- A serum creatinine based on age/gender as follows:  
 
Age 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 to < 2 years 
0.6 
0.6 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the Schwartz 
formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child 
length and stature data published by the CDC. 
 
3.1.5.2 Adequate Liver Function Defined As: 
 
- Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age, and  
 
- SGPT (ALT) < 3 x upper limit of normal (ULN) for age, unless elevation due to 
leukemia infiltration.  
 
3.1.5.3 Adequate Cardiac Function Defined As: 
  
- Shortening fraction of ≥ 27% by echocardiogram, or  
 
- Ejection fraction of ≥ 50% by gated radionuclide study.  
 
- Please see Section 3.2.6 for prior anthracycline restrictions. 
  
3.1.5.4 Adequate Pulmonary Function Defined As: 
  


18 
 
- 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. 
  
3.1.5.5 Central Nervous System Function Defined As: 
  
- Patients with seizure disorder may be enrolled if on allowed anticonvulsants (see 
Appendix II) and well controlled. Benzodiazepines and gabapentin are acceptable.  
 
- CNS toxicity < Grade 3. 
  
3.1.5.6 Peripheral Nervous System (PNS) Function Defined As:  
 
- PNS toxicity ≤Grade 2.  
 
3.1.5.7 Reproductive Function 
 
– Female patients of childbearing potential must have a negative urine or serum 
   pregnancy test confirmed within 2 weeks prior to enrollment. 
 
– Female patients with infants must agree not to breastfeed their infants while on this 
study. 
 
– Male and female patients of child-bearing potential must agree to use 2 effective 
methods of contraception approved by the investigator, at the same time, from the time 
of signing the informed consent form and for a minimum of 6 months after study 
treatment, or agree to completely abstain from heterosexual intercourse. 
 
3.2 Exclusion Eligibility Criteria 
 
Patients will be excluded if they meet any of the following criteria 
 
3.2.1 Patients will be excluded if they have a known allergy to any of the drugs on the study 
with the exception of PEG-asparaginase (see below). 
3.2.2 Patients with isolated CNS or isolated testicular disease will be excluded. 
3.2.3 Patients will be excluded if they have a systemic fungal, bacterial, viral or other infection 
that is exhibiting ongoing signs/symptoms related to the infection without improvement 
despite appropriate antibiotics or other treatment. The patient needs to be off pressors and 
have negative blood cultures for 48 hours. 
3.2.4 Patients with known optic nerve and/or retinal involvement (because it may not be 
possible to safely delay irradiation) are not eligible. Patients presenting with visual 
disturbances should have an ophthalmological exam and, if indicated, an MRI to 
determine optic nerve or retinal involvement. 


19 
 
3.2.5 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. 
3.2.6 Cumulative prior anthracycline exposure must not exceed 400 mg/m2 
(each 10 mg/m2 of idarubicin should be calculated as the isotoxic equivalent of 30 
mg/m2of daunorubicin or doxorubicin). 
 
3.2.7 Patients who have previously received bortezomib or other proteasome inhibitors are not 
eligible. 
 
3.2.8 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 (see Appendix II). Please see 
Appendix II for a list of drugs known to be potent inducers/inhibitors of the cytochrome 
p450 system. 
 
3.2.9 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 PEG-asparaginase are eligible if Erwinia L-asparaginase can be substituted. 
 
3.2.10 Pregnancy and Breast Feeding: patients who are pregnant or breast-feeding are not 
eligible for this study as there is as yet no available information regarding human fetal or 
teratogenic toxicities. Negative pregnancy tests must be obtained in girls who are post-
menarchal.  
 
3.2.11 Patients will be excluded if there is a plan to administer non-protocol chemotherapy, 
radiation therapy, or immunotherapy during the study period. 
 
3.2.12 Patients will be excluded if they have significant concurrent disease, illness, psychiatric 
disorder or social issue that would compromise patient safety or compliance with the 
protocol treatment or procedures, interfere with consent, study participation, follow up, or 
interpretation of study results. 
 
3.2.13  Patients with Down syndrome will be excluded. 
 
3.2.14 All patients and/or their parents or legal guardians must voluntarily sign a written 
informed consent before performance of any study-related procedure not part of normal 
medical care, with the understanding that consent may be withdrawn by the subject at any 
time without prejudice to future medical care. Assent from children will be obtained per 
institutional guidance. 
 
3.2.15 For lymphoma patients with <5% marrow blasts, the platelet count must be ≥ 25,000/mm3  
within 7 days before enrollment. 
 


20 
 
3.2.16  For lymphoma patients with <5% marrow blasts, the absolute neutrophil count must be ≥  
500 cell/mm3 within 7 days before enrollment. 
 
3.2.17 Patient had myocardial infarction within 6 months prior to enrollment or has New York  
Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe 
uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia 
or active conduction system abnormalities. Prior to study entry, any ECG abnormality at 
screening must be documented by the investigator as not medically relevant. 
 
3.2.18 Diagnosed or treated for another malignancy within 2 years of enrollment, with the  
exception of complete resection of basal cell carcinoma or squamous cell carcinoma of 
the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy. 
 
3.2.19 Participation in clinical trials with other investigational agents not included in this trial,  
within 14 days of the start of this trial and throughout the duration of this trial. 
 
3.2.20 Radiation therapy within 3 weeks before randomization. Enrollment of subjects who  
require concurrent radiotherapy (which must be localized in its field size) should be 
deferred until the radiotherapy is completed and 3 weeks have elapsed since the last date 
of therapy. 
 
 
3.3    Definitions 
 
Bone marrow status: 
M1  
< 5%      lymphoblasts   
M2 
 5 - 25%  lymphoblasts  
M3  
> 25%     lymphoblasts  
 
Leukemia Relapse: 
 
Isolated Bone Marrow Relapse: M3 marrow confirmed by bone marrow aspirate or biopsy.  
 
Isolated CNS Relapse: Positive cytomorphology and WBC ≥ 5/µL OR positive 
cytomorphology with CSF WBC 0-4/µL on 2 successive occasions 1 month apart.  
 
Isolated Testicular Relapse: Confirmation by testicular biopsy preferred but not required. 
  
Combined Relapse: Documented extramedullary relapse and an M2 or M3 bone marrow. 
  
Lymphoblastic Lymphoma Relapse: 
 
Patients must have histologic verification of lymphoblastic lymphoma at diagnosis or at the time 
of relapse. Patients must have measurable disease. Measurable disease is defined as any nodal 
mass with longest transverse diameter > 2 cm, or any measurable, focal mass lesion of a visceral 


21 
 
organ (such as liver, spleen, kidney). Measurable lesions in a visceral organ are lesions that can 
be accurately measured in 2 axial dimensions by CT. 
  
Central nervous system (CNS) leukemia at relapse diagnosis: 
 
CNS 1: In cerebral spinal fluid (CSF), absence of blasts on cytospin preparation, 
regardless of the number of WBCs. 
  
CNS 2: In CSF, presence < 5/µL WBCs and cytospin positive for blasts, or ≥ 5/µL 
WBCs but negative by Steinherz/Bleyer algorithm:  
 
– CNS 2a: < 10/µL red blood cells (RBCs); < 5/µL WBCs and cytospin 
positive for blasts;  
– CNS 2b:  ≥ 10/µL RBCs; < 5/µL WBCs and cytospin positive for blasts; 
and  
– CNS 2c:  ≥ 10/µL RBCs; ≥ 5/µL WBCs and cytospin positive for blasts 
but negative by Steinherz/Bleyer algorithm (see below); 
 
CNS 3: In CSF, presence of ≥ 5/µL WBCs and cytospin positive for blasts and/or clinical 
signs of CNS leukemia:  
 
– CNS 3a: < 10/µL RBCs; ≥ 5/µL WBCs and cytospin positive for blasts;  
– CNS 3b:  ≥ 10/µL RBCs, ≥ 5/µL WBCs and positive by Steinherz/Bleyer 
algorithm 
(see below);   
– CNS 3c: Clinical signs of CNS leukemia (such as facial nerve palsy, 
brain/eye involvement or hypothalamic syndrome).  
 
Method of evaluating initial traumatic lumbar punctures (LPs): 
If the patient has leukemic cells in the peripheral blood and the lumbar puncture is traumatic and 
contains ≥ 5 WBC/µL and blasts, the following Steinherz/Bleyer algorithm should be used to 
distinguish between CNS2 and CNS3 disease:  
 
CSF WBC > 2X   Blood WBC 
CSF RBC             Blood RBC  
 
A patient with CSF WBC ≥ 5/µL blasts, whose CSF WBC/RBC ratio is 2X greater than the 
blood WBC/RBC ratio, has CNS disease at diagnosis.  
 
 
 


22 
 
4.0 TREATMENT PROGRAM 
 
Bortezomib Administration  
 
Drug will be administered only to eligible patients under the supervision of the investigator 
or identified subinvestigator(s). Patients may be treated on an outpatient basis, if possible. 
The drug will be prepared under the supervision of a pharmacist, or appropriately qualified 
and trained personnel. The amount (in mg) of drug to be administered will be determined 
based on body surface area. Body surface area is to be calculated based on body weight using 
a standard nomogram or calculation .The dose should be calculated on Day 1 of each cycle; 
the dose administered should remain the same throughout each cycle but should be 
recalculated at the start of the next cycle. If a patient experiences a notable change in weight 
within a cycle, as determined by an unscheduled weight assessment, then the patient’s dose 
should be recalculated at that time based on clinical judgment. 
The appropriate amount of bortezomib will be drawn from the injection vial and 
administered as an IV push over 3 to 5 seconds followed by a standard saline flush or 
through a running IV line.  Vials are for single-use administration. 
There must be at least 72 hours between each dose of bortezomib. 
 
 
 
It is strongly recommended that all patients remain inpatient until adequate count recovery due to 
the risk of serious infection.  Antifungal prophylaxis is required (see Section 7.3.1 for 
appropriate medications) and antibacterial prophylaxis with ciprofloxacin +/- vancomycin is 
recommended. 
 
Dose calculations should be based on actual BSA.  There is no maximum dosing with the 
exception of vincristine which is capped at a maximum dose of 2 mg. 
 
• Check O2 saturation within 12 hours prior to each dose of bortezomib. In the absence of 
congestive heart failure or other known cause of hypoxia, O2 saturation must be ≥ 94% 
at sea level (> 90% at high altitude) prior to bortezomib administration. (Please see 
Section 5.1 if patient develops drug-induced pulmonary toxicity.)  
• Vigorous hydration without potassium should be instituted prior to starting therapy.  
Allopurinol or urate oxidase may be used as necessary for hyperuricemia.  
• No other cytotoxic therapy may be given during this therapy.  
• Antiemetics should be given during each chemotherapy course, individualized to the 
patient’s best response. Dexamethasone and aprepitant should not be used as antiemetics.  
• Bortezomib has been associated with hypophosphatemia. Phosphorus should be 
evaluated prestudy. If the level is < 1.5 mg/dL, correct the  level to 2 mg/dL or above 


23 
 
prior to beginning chemotherapy. Maintain phosphorus level above 2 mg/dL during the 
first two weeks of therapy. 
• Bortezomib-related hyponatremia has been associated with seizures. Sodium should be 
monitored and kept > 130 mEq/L during the first two weeks of therapy. 
 
Treatment Plan 
 
Methotrexate: IT - for CNS-negative (CNS1/CNS2) patients only.  
Days 1 and 8 (day 1 IT may be given up to 72 hours prior to starting therapy):  
Aged – based dosing:  
Age (years) 
Dose 
1 - 1.99 
8 mg 
2 - 2.99 
10 mg 
3 – 8.99 
12 mg 
≥ 9 
15 mg 
 
Triple Intrathecal Therapy (ITT): IT – for CNS-positive (CNS3) patients only.  
Days 1, 8, 15, and 22 (day 1 TIT may be given up to 72 hours prior to starting therapy): 
Weekly TIT will be continued if necessary beyond the required 4 doses until 2  
successive LPs are free of lymphoblasts (up to a maximum of 6 doses ITT). Note that all CNS-
positive patients should receive 4 doses of ITT, even if CSF is clear of lymphoblasts prior to Day 
15. 
 
Age (years) 
Dose (methotrexate (MTX), hydrocortisone 
(HC), cytarabine (ARAC)) 
1 - 1.99 
MTX: 8 mg; HC: 8 mg; ARAC: 16 mg 
2 - 2.99 
MTX: 10 mg; HC: 10 mg; ARAC: 20 mg 
3 – 8.99 
MTX: 12 mg; HC: 12 mg; ARAC: 24 mg 
≥ 9 
MTX: 15 mg; HC: 15 mg; ARAC: 30 mg 
 
 
Dexamethasone: PO   
Days 1-5 and 15-19  
Dose: 10 mg/m2/dose PO BID (ie, 20 mg/m2/day PO, divided BID)   
 
Mitoxantrone: IV over 15-30 minutes  
Days 1 and 2.  
Dose: 10 mg/m2/dose.  
 
Administer through the tubing of a rapidly infusing solution of D5W or 0.9% NaCl. Avoid  
extravasation; the use of a central line is suggested. 
 
Bortezomib: IV push over 3-5 seconds followed by a standard saline flush or through a 
running IV line. Vials are for single-use administration. 
Days: 1, 4, 8 and 11. Note: at least 72 hours must have elapsed between doses.  
Dose: 1.3 mg/m2/dose. 


24 
 
 
Vincristine: IV push over 1 minute  
Days 1, 8, 15 and 22 
Dose: 1.5 mg/m2/dose (maximum dose 2 mg).  
 
Special precautions: FOR INTRAVENOUS USE ONLY.    
The container or the syringe containing vincristine must be enclosed in an overwrap bearing the 
statement “Do not remove covering until moment of injection. For intravenous use only - Fatal if 
given by other routes.”  
 
PEG-asparaginase:  IV over 1 hours 
Days 3 and 17.  
Dose: 2500 International units/m2/dose. 
 
Suggested monitoring during administration: Because PEG-asparaginase is long acting, 
hypersensitivity reactions may not appear for hours after drug administration. Monitor vital 
signs, for fever, chills, and acute allergic reactions including anaphylaxis. Have medications to 
treat hypersensitivity reactions readily available at each administration (eg, epinephrine, IV 
corticosteroids, antihistamines). May prescribe an EpiPen® for home use. 
 
 
If allergic to PEG-asparaginase then use Asparaginase Erwinia Chrysanthemi  
20,000 IU/m2 IM x 6 doses on a Monday/Wednesday/Friday schedule as a replacement 
for each scheduled dose of PEG- asparaginase 2,500 IU/ m2/dose. 
 
 


25 
 
5.0 DOSE MODIFICATIONS FOR TOXICITIES 
 
Before each drug dose, the patient will be evaluated for possible toxicities that may have 
occurred after the previous dose(s). The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for 
grading and reporting adverse events. 
 
All previously established or new toxicities observed any time are to be managed as described in 
5-1.  Neuropathic pain and peripheral sensory neuropathy are to be managed as described in table 
5-2. 
 


26 
 
Table 5-1    
Toxicity Management 
Toxicity 
Grade 
Action 
Lymphopenia 
Any 
None 
Nonhematological toxicity 
3 
Hold bortezomib therapy 
Hematological Toxicity 
4 
Hold bortezomib therapy 
 
5.1  Bortezomib  
 
For nonhematologic toxicities, bortezomib is to be held for up to 2 weeks until the toxicity 
returns to Grade 1 or better. 
Once bortezomib is reduced for any toxicity, the dose may not be re-escalated. 
If after bortezomib has been held, the toxicity does not resolve, then bortezomib must be 
discontinued. 
If the toxicity resolves, as described above, bortezomib may be restarted at the same schedule the 
patient was on prior to holding therapy, and the dose must be reduced by approximately 25% as 
follows: 
• If the patient was receiving 1.3 mg/m2, reduce the dose to 1 mg/m2. 
• If the patient was receiving 1 mg/m2, reduce the dose to 0.7 mg/m2. 
If the patient was receiving 0.7 mg/m2, discontinue drug unless patient is responding, in which 
case, this should be discussed with the principal investigator. 
Patients who experience bortezomib-related neuropathic pain or peripheral sensory neuropathy 
are to be managed as presented in 5-1.  Once the dose is reduced for peripheral neuropathy, the 
dose may not be re-escalated. 
 
 
Peripheral Neuropathy: 
 
For grade 3 peripheral neuropathy, hold bortezomib until symptoms have resolved to ≤ grade 
1.  Do not make up missed doses.  When toxicity resolves, resume bortezomib at 1 
mg/m2/dose. 
 
For grade 4 peripheral neuropathy, discontinue bortezomib. 
 


27 
 
Table 5-2    
Management of Patients With VELCADE-Related Neuropathic Pain 
and/or Peripheral Sensory or Motor Neuropathy  
Severity of Peripheral Neuropathy Signs and 
Symptomsa  
Modification of Dose and Regimen 
Grade 1 (asymptomatic; loss of deep tendon 
reflexes or parasthesias) without pain or loss of 
function 
No action 
Grade 1 with pain or Grade 2 (moderate 
symptoms; limiting instrumental Activities or 
Daily Living [ADL]b) 
Reduce VELCADE to 1.0 mg/m2 
Grade 2 with pain or Grade 3 (severe symptoms; 
limiting self care ADLc) 
Withhold VELCADE therapy until toxicity resolves. 
When toxicity resolves reinitiate with a reduced dose of 
VELCADE at 0.7 mg/m2 once per week. 
Grade 4 (life-threatening consequence; urgent 
intervention indicated) 
Discontinue VELCADE 
Source:  VELCADE USPI issued January 2012. 
Abbreviations: ADL = activities of daily living 
a   Grading based on NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0. 
b   Instrumental ADL: refers to preparing meals, shopping for groceries or clothes, using telephone, 
managing money, etc 
c   Self care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
 
Patients with mild hepatic impairment (bilirubin ≤ 1.5  ULN) do not require a starting dose 
adjustment.  Please note that patients with bilirubin levels > 1.5 ULN are excluded from 
enrollment in this protocol.  If a patient develops moderate or severe hepatic impairment with 
bilirubin ≥ Grade 2 (> 1.5 -3.0 X ULN) while on study, the investigator should hold Bortezomib 
until the toxicity returns to < Grade 2. Restarting Bortezomib at the next lower dosed level could 
be considered at the Investigator’s discretion and following exclusion of  Bortezomib-induced 
liver impairment and careful consideration of liver disease due to other causes, such as, but not 
limited to, active infection and multiple myeloma-related liver disease. 
 
Pulmonary Toxicity: 
 
Pulmonary toxicity from bortezomib has been reported including pneumonitis, pneumonia, 
infiltrates and acute respiratory distress syndrome.  All patients should have a CXR prior to 
starting therapy.  Pulse oximetry should be performed prior to each dose of bortezomib. 
 
For grade 3 pulmonary toxicity, hold bortezomib until symptoms have resolved to ≤ grade 1.  
Do not make up missed doses.  When toxicity resolves, resume bortezomib at 1 mg/m2/dose. 
 
For grade 4 pulmonary toxicity, discontinue bortezomib. 
 


28 
 
For patients that develop hypoxia (oxygen saturation ≤ 90%) and/or pulmonary infiltrates in 
the absence of other identifiable causes, steroid treatment is recommended.  
 
5.2 Mitoxantrone 
 
Dose adjustment for hyperbilirubinemia: 
 
Direct bilirubin: 
< 2.0 mg/dL 
 
Full dose 
2.1-- 3.0 mg/dL 
 
50%  
3.1 – 5.0 mg/dL 
 
25% of calculated dose 
> 5.0 mg/dL 
Hold dose and administer subsequent doses if toxicity has 
resolved.  Do not make up missed doses. 
 
Left Ventricular Systolic Dysfunction: 
 
Hold mitoxantrone for shortening fraction ≤ 27%. 
 
Extravasation: 
 
In the event of an extravasation, discontinue the IV administration of the drug and institute 
appropriate measures to prevent further extravasation and damage according to institutional 
guidelines. 
 
5.3 Asparaginase 
 
Allergy: 
 
Continue asparaginase for grade 1 reaction (localized reaction) 
 
Discontinue asparaginase infusion if ≥ grade 2 reaction occurs including anaphylaxis. 
 
For patients that have had a previous allergic reaction to E. Coli or PEG-asparaginase, or 
who react to the first dose on this protocol then Erwinia asparaginase should be substituted 
for each dose at a schedule of 20,000 IU/m2 on a Monday/Wednesday/Friday schedule for 2 
weeks (6 doses).   
 
Coagulopathy: 
 
If symptomatic, hold asparaginase until symptoms resolve, then resume with the next 
scheduled dose. Consider factor replacement (FFP, cryoprecipitate, factor VIIa). Do not 
withhold dose for abnormal laboratory findings without clinical symptoms. 
 
Hyperglycemia and/or hyperlipidemia: 
 
Do not modify dose. Treat hyperglycemia as medically indicated. 


29 
 
 
Ketoacidosis: 
 
Hold asparaginase until blood glucose can be regulated with insulin. 
 
Pancreatitis: 
 
Discontinue asparaginase in the presence of hemorrhagic pancreatitis or severe pancreatitis 
(grades 3 and 4). In the case of mild pancreatitis, asparaginase should be held until symptoms 
and signs subside, and amylase levels return to normal and then resumed. Severe pancreatitis 
is a contraindication to additional asparaginase administration. 
 
Thrombosis: 
 
Withhold asparaginase until resolved, and treat with appropriate antithrombotic therapy, as 
indicated. Upon resolution of symptoms consider resuming asparaginase, while continuing 
LMWH or antithrombotic therapy. Do not withhold dose for abnormal laboratory findings 
without clinical correlate. For significant thrombosis, not line related, consider evaluation for 
inherited predisposition to thrombosis.  CNS Events (bleed, thrombosis or infarction): Hold 
asparaginase. Treat with FFP, factors or anticoagulation as appropriate. Resume at full dose 
when all symptoms have resolved (and evidence of recanalization in case of thrombosis by 
CT/MRI). Consider evaluation for inherited predisposition to thrombosis. 
 
5.4 Dexamethasone 
 
Hypertension:  
 
Dose should not be reduced. Sodium restriction and anti-hypertensives should be 
used in an effort to control hypertension. Avoid calcium channel blockers due to their 
potential prohemorrhagic effect. 
 
Hyperglycemia:  
 
Dose should not be reduced for hyperglycemia. Rather, insulin therapy should be employed 
to control the blood glucose level. 
 
Pancreatitis:  
 
Do not modify dose for asymptomatic elevations of amylase and/or lipase. Discontinue 
steroids, except for stress doses, in the presence of hemorrhagic pancreatitis or severe 
pancreatitis. 
 
Infection: 
 
Do not hold steroids for infection unless the infection is life-threatening and discontinuing 
steroids is thought to provide potential benefit. 


30 
 
 
Severe Psychosis:  
 
Do not hold steroids for behavioral issues unless they are severe.  May reduce dose by 50% if 
necessary. 
 
5.5 Intrathecal Methotrexate 
 
Neurologic Toxicity 
 
For patients that have ≥ grade 3 neurological toxicity from methotrexate, options include 
substituting intrathecal cytarabine for future treatments or to treat with leucovorin rescue at a 
dose of 5 mg/m2 q 12 hrs x 2 doses beginning 48 hours after the LP.   
 
CNS Infection: 
 
For patients with active CNS infection, do not administer intrathecal treatments. 
 
 
 


31 
 
6.0     AGENT INFORMATION 
 
6.1 PEG-Asparaginase 
 
Source and Pharmacology: 
PEG-asparaginase is a modified version of the enzyme L-asparaginase. L-asparaginase is 
modified by covalently conjugating units of monomethoxypolyethylene glycol (PEG), molecular 
weight of 5000, to the enzyme, forming the active ingredient PEG-L-asparaginase. The L-
asparaginase (L-asparagine amidohydrolase, type EC-2, EC 3.5.1.1) used in the manufacture of 
PEG-asparaginase is derived from Escherichia coli which is purchased in bulk from Merck, 
Sharp and Dohme. L-asparagine is a nonessential amino acid synthesized by the transamination 
of L-aspartic acid by a reaction catalyzed by the enzyme L-asparagine synthetase. The ability to 
synthesize asparagine is notably lacking in malignancies of lymphoid origin. Asparaginase 
depletes L-asparagine from leukemic cells (especially lymphoblasts) by catalyzing the 
conversion of L-asparagine to aspartic acid and ammonia. In predominately L-asparaginase naive 
adult patients with leukemia and lymphoma, initial plasma levels of L-asparaginase following 
intravenous administration of PEG-asparaginase were determined. Apparent volume of 
distribution was equal to estimated plasma volume. L-asparaginase was measurable for at least 
15 days following the initial treatment with PEG-asparaginase. The approximate t½ in adult 
patients is 5.73 days. The enzyme could not be detected in the urine.  The half-life is independent 
of the dose administered, disease status, renal or hepatic function, age, or gender. In a study of 
newly diagnosed pediatric patients with ALL who received either a single intramuscular 
injection of PEG-asparaginase (2500 IU/m2), E. coli L-asparaginase (25000 IU/m2), or Erwinia 
(25000 IU/m2), the plasma half-lives for the three forms of L-asparaginase were: 5.73 ± 3.24 
days, 1.24 ± 0.17 days, and 0.65 ± 0.13 days respectively. The plasma half-life of PEG-
asparaginase is shortened in patients who are previously hypersensitive to native L-asparaginase 
as compared to non-hypersensitive patients. L-asparaginase is cleared by the reticuloendothelial 
system and very little is excreted in the urine or bile. Cerebrospinal fluid levels are < 1% of 
plasma levels. 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children 
out of every 100 
Immediate: 
Within 1-2 days 
of receiving drug 
Allergic reactions (total 
likelihood of local and/or 
systemic reaction), pain at 
injection site 
Rash  
 
Tachycardia, periorbital 
edema, chills, fever, 
dizziness, dyspnea, 
bronchospasm, lip edema, 
arthralgia, myalgia, 
urticaria, mild 
nausea/vomiting, 
abdominal pain, 
flatulence, somnolence, 
lethargy, headache, 
seizures (L), 
hyperuricemia  


32 
 
Prompt: 
Within 2-3 
weeks, prior to 
the next course 
Hyperammonemia (L), 
coagulation abnormalities 
with prolonged PTT, PT 
and bleeding times 
(secondary to decreased 
synthesis of fibrinogen, 
AT-III & other clotting 
factors) (L)  
 
Hyperglycemia, abnormal 
liver function tests, 
pancreatitis (L), increased 
serum lipase/amylase  
 
Pancreatitis (L), 
hemorrhage (L), DIC, 
thrombosis, anorexia, 
CNS 
ischemic attacks, edema, 
azotemia and decreased 
renal function, mild 
leukopenia and 
thrombocytopenia, coma 
and stupor, 
hypertriglyceridemia, 
hyperlipidemia, 
Parkinson-like syndrome 
with tremor and increase 
in muscular tone, CNS 
changes 
including irritability, 
depression, 
confusion, EEG changes, 
hallucinations 
Delayed: 
Any time later during 
therapy, excluding the 
above conditions 
 
 
Renal failure, urinary 
frequency, hemorrhagic 
cystitis, elevated 
creatinine and BUN, fatty 
liver deposits, 
hepatomegaly, liver 
failure  
Unknown 
Frequency and 
Timing: 
Animal reproduction studies have not been conducted with PEG-asparaginase. It is 
not known whether PEG-asparaginase can cause fetal harm when administered to a 
pregnant woman or can affect reproduction capacity. However, fetal toxicities and 
teratogenic effects of asparaginase have been noted in animals. It is unknown 
whether the drug is excreted in breast milk.  
(L) Toxicity may also occur later. 
 
Formulation and Stability: 
Each milliliter of PEG-asparaginase contains: PEG-L-asparaginase 750 IU ± 20%, monobasic 
sodium phosphate, USP 1.20 mg ± 5% dibasic sodium phosphate, USP 5.58 mg ± 5%, sodium 
chloride, USP 8.50 mg ± 5% , Water for Injection, USP qs to 1 mL. The specific activity of 
PEG-asparaginase is at least 85 IU per milligram protein. Available in 5 mL vials as Sterile 
Solution for Injection in ready to use single-use vials, preservative free. Keep refrigerated at 2°-
8°C (36°-46°F). Do not use if stored at room temperature for more than 48 hours. DO NOT 
FREEZE. Do not use product if it is known to have been frozen. Freezing destroys activity, 
which cannot be detected visually. 
 
Guidelines for Administration:  
See Treatment and Dose Modifications sections of the protocol (Section 4.0 and Section 5.0). 
 
For IV administration: dilute PEG-asparaginase contains in 100 mL of 0.9% sodium chloride 
injection (NS) or 5% dextrose injection (D5W) and infuse over 1 to 2 hours through a NS or 
D5W running infusion line. PEG-asparaginase admixed in 100 mL of NS or D5W is stable for 
48 hours at room temperature. PEG-asparaginase diluted in 100 mL of NS is stable for up to 72 


33 
 
hours refrigerated (4ºC [39°F]) (refrigerated stability data on file with Sigma-Tau). Avoid 
excessive agitation. DO NOT SHAKE. Do not use if cloudy of if precipitate is present.  
Have available during and after the infusion: antihistamine, epinephrine, oxygen, and IV 
corticosteroids. Observe patient for ONE hour after administration for signs of hypersensitivity 
reactions. 
 
6.2 Dexamethasone 
 
Source and Pharmacology: 
Dexamethasone is a synthetic fluorinated glucocorticoid devoid of mineralocorticoid effects. 
Dexamethasone, 0.75 mg, has potent anti-inflammatory activity equivalent to approximately 5 
mg of prednisone. Glucocorticoids produce widespread and diverse physiologic effects on 
carbohydrate, protein, and lipid metabolism, electrolyte and water balance, functions of the 
cardiovascular system, kidney, skeletal muscle, and the nervous systems. Glucocorticoids reduce 
the concentration of thymus-dependent lymphocytes (T-lymphocytes), monocytes, and 
eosinophils. Glucocorticoids selectively bind to the cortisol receptors on human lymphoid cells 
which are found in larger numbers on leukemic lymphoblasts. They also decrease binding of 
immunoglobulin to cell surface receptors and inhibit the synthesis and/or release of interleukins, 
thereby decreasing T-lymphocyte blastogenesis and reducing expansion of the primary immune 
response. The specific cellular mechanisms that act to halt DNA synthesis are thought to be 
related to inhibition of glucose transport or phosphorylation, retardation of mitosis, and 
inhibition of protein synthesis. Elimination half-lives for the following age groups have been 
reported to be: infants and children under 2 years of age: 2.3 to 9.5 hours, 8 to 16 years: 2.82 to 
7.5 hours, and adults (age not specified): 3 to 6 hours. The biologic half-life is 36-72 hours. It is 
primarily metabolized in the liver and excreted by the kidneys. 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children 
out of every 100 
Immediate: 
Within 1-2 days 
of receiving drug 
Insomnia, hyperphagia  
 
Gastritis  
 
Hyperuricemia  
 
Prompt: 
Within 2-3 
weeks, prior to 
the next course 
Immunosuppression, 
personality changes 
(mood swings, euphoria, 
anxiety, depression), 
pituitary-adrenal axis 
suppression, acne (L)  
Hyperglycemia, facial 
erythema, poor wound 
healing, infections 
(bacterial, fungal, 
parasitic, viral), edema  
Pancreatitis (L), increased 
intraocular pressure (L), 
hypertension, psychosis, 
vertigo, headache  
Delayed: 
Any time later during 
therapy, excluding the 
above conditions 
Cushing’s syndrome 
(moon facies, truncal 
obesity)  
 
Striae and thinning of the 
skin, easy bruising, 
muscle weakness, 
osteopenia  
 
Spontaneous fractures 
(L), growth suppression, 
peptic ulcer and GI 
bleeding, pseudotumor 
cerebri (increased 
intracranial pressure with 
papilledema, headache), 
aseptic necrosis of the 


34 
 
femoral and humeral 
heads (L), urolithiasis (L)  
 
Late: 
Any time after 
completion of treatment  
 
 
Cataracts (which may be 
reversible on 
discontinuation of 
dexamethasone in 
children)  
 
Unknown 
Frequency and 
Timing: 
Fetal and teratogenic toxicities: dexamethasone crosses the placenta with 54% 
metabolized by enzymes in the placenta. In animal studies, large doses of cortisol 
administered early in pregnancy produced cleft palate, stillborn fetuses, and 
decreased fetal size. Chronic maternal ingestion during the first trimester has shown 
a 1% incidence of cleft palate in humans. There are no reports of dexamethasone 
excretion into breast milk in humans; however, it is expected due to its low 
molecular weight that it would partition into breast milk.  
(L) Toxicity may also occur later. 
 
Formulation and Stability: 
Oral: 
Available in 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 4 mg, and 6 mg tablets; liquid formulations 
are available in 0.5 mg/5 mL and 1 mg/1 mL concentrations. Inactive ingredients vary depending 
on manufacturer but tablet formulations may include: calcium or magnesium stearate, corn 
starch, lactose, and various dyes. Liquid formulations may include: 5%-30% alcohol, benzoic 
acid, sorbitol, sodium saccharin, glycerin, purified water, and various dyes. 
 
Injection: 
Dexamethasone Sodium Phosphate Solution for Injection is available as 4 mg/mL (1 mL, 5 mL, 
and 30 mL vials) and 10 mg/mL (1 mL and 10 mL vial sizes). Four milligrams of dexamethasone 
sodium phosphate is equivalent to 3.33 mg of dexamethasone. IV dexamethasone should be 
given as 1;1 replacement on study. Vials are available in multi-dose vials as well as unit of use 
vials and syringes. Inactive ingredients vary depending on manufacturer but include creatinine, 
sodium citrate, sodium hydroxide to adjust pH, Water for Injection, sodium sulfite, bisulfite and 
metabisulfite, methyl and propyl paraben, benzyl alcohol, and EDTA. 
 
Guidelines for Administration:  
See Treatment and Dose Modifications sections of the protocol (Section 4.0 and Section 5.0). 
 
Dexamethasone Sodium Phosphate for Injection may be given IV, or IM undiluted. For IV use, it 
may be further diluted in dextrose or saline containing solutions. Avoid using benzyl alcohol-
containing dexamethasone solutions in neonates. Diluted solutions that contain no preservatives 
should be used within 24 hours, but maintain stability for at least 14 days in PVC bags at room 
temperature protected from light. 
 
6.3 Vincristine 
 
Source and Pharmacology: 
Vincristine is an alkaloid isolated from Vinca rosea Linn (periwinkle). It binds to tubulin, 
disrupting microtubules and inducing metaphase arrest. Its serum decay pattern is triphasic. The 


35 
 
initial, middle, and terminal half-lives are 5 minutes, 2.3 hours, and 85 hours respectively; 
however, the range of the terminal half-life in humans is from 19 to 155 hours. The liver is the 
major excretory organ in humans and animals; about 80% of an injected dose of vincristine 
sulfate appears in the feces and 10% to 20% can be found in the urine. The p450 cytochrome 
involved with vincristine metabolism is CYP3A4. Within 15 to 30 minutes after injection, over 
90% of the drug is distributed from the blood into tissue, where it remains tightly, but not 
irreversibly bound. It is excreted in the bile and feces. There is poor CSF penetration.  
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children 
out of every 100 
Immediate: 
Within 1-2 days 
of receiving drug 
 
Jaw pain, headache  
 
Extravasation (rare) but if 
occurs = local ulceration, 
shortness of breath, and 
bronchospasm  
Prompt: 
Within 2-3 
weeks, prior to 
the next course 
Alopecia, constipation  
 
Weakness, abdominal 
pain, mild brief 
myelosuppression 
(leukopenia, 
thrombocytopenia, 
anemia)  
Paralytic ileus, ptosis, 
diplopia, night blindness, 
hoarseness, vocal cord 
paralysis, SIADH, 
seizure, defective 
sweating  
 
Delayed: 
Any time later during 
therapy, excluding the 
above conditions 
Loss of deep tendon 
reflexes  
 
Peripheral paresthesias 
including numbness, 
tingling and pain; 
clumsiness; wrist drop, 
foot drop, abnormal gait  
 
Difficulty walking or 
inability to walk; 
sinusoidal obstruction 
syndrome (SOS, formerly 
VOD) (in combination); 
blindness, optic atrophy; 
urinary tract disorders 
(including bladder atony, 
dysuria, polyuria, 
nocturia, and urinary 
retention); autonomic 
neuropathy with postural 
hypotension; 8th cranial 
nerve damage with 
dizziness, nystagmus, 
vertigo and hearing loss 
Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of vincristine (either alone or in combination 
with other antineoplastic agents) have been noted in humans. The toxicities include: 
chromosome abnormalities, malformation, pancytopenia, and low birth weight. It is 
unknown whether the drug is excreted in breast milk.  
(L) Toxicity may also occur later. 
 
Formulation and Stability: 
Vincristine is supplied in 1 mL and 2 mL vials in which each mL contains vincristine sulfate, 1 
mg (1.08 μmol), mannitol 100 mg, Sterile Water for Injection; acetic acid and sodium acetate are 
added for pH control. The pH of vincristine sulfate injection, USP ranges from 3.5 to 5.5. This 
product is a sterile, preservative free solution. Store refrigerated at 2˚-8˚C or 36˚-46˚F. Protect 
from light and retain in carton until time of use.  


36 
 
Do not mix with any IV solutions other than those containing dextrose or saline. 
 
Guidelines for Administration:  
See Treatment and Dose Modifications sections of the protocol (Section 4.0 and Section 5.0). 
 
Vincristine should NOT be delivered to the patient at the same time with any medications intended for 
central nervous system administration. Vincristine is fatal if given intrathecal.  
Injection of vincristine sulfate should be accomplished as per institutional policy. Vincristine sulfate must 
be administered via an intact, free-flowing intravenous needle or catheter. Care should be taken to ensure 
that the needle or catheter is securely within the vein to avoid extravasation during administration. The 
solution may be injected either directly into a vein or into the tubing of a running intravenous infusion.  
 
Special precautions: FOR INTRAVENOUS USE ONLY.  
The container or the syringe containing vinCRIStine must be enclosed in an overwrap bearing 
the statement: "Do not remove covering until moment of injection. For intravenous use only. 
Fatal if given by other routes." 
 
6.4 Mitoxantrone 
 
Source and Pharmacology: 
Mitoxantrone is a substituted alkylaminoanthraquinone and is a potent inhibitor of DNA and 
RNA synthesis in vitro and binds strongly to DNA. Mitoxantrone most likely acts through 
intercalation between base pairs of the DNA double helix causing crosslinks and strand breaks. 
In addition, it is a topoisomerase II inhibitor, an enzyme responsible for uncoiling and repairing 
damaged DNA. It has a cytocidal effect on both proliferating and non-proliferating cultured 
human cells, suggesting lack of cell cycle phase specificity. The drug disappears rapidly from 
plasma (drug found only in the 3-minute sample) and < 1% appears in the urine in 24 hours. The 
mean alpha half-life of mitoxantrone is 6 to 12 minutes, the mean beta half-life is 1.1 to 3.1 
hours and the mean gamma (terminal or elimination) half-life is 23 to 215 hours (median 
approximately 75 hours). Primary excretion is biliary with 25% appearing in the feces; renal 
excretion accounting for only 11% of the total dose. Mitoxantrone clearance is reduced by 
hepatic impairment. Patients with severe hepatic dysfunction (bilirubin > 3.4 mg/dL) have an 
AUC more than three times greater than that of patients with normal hepatic function receiving 
the same dose. Mitoxantrone is approximately 95% protein bound. 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children 
out of every 100 
Immediate: 
Within 1-2 days 
of receiving drug 
Nausea, vomiting, 
diarrhea, fever, anorexia, 
green blue discoloration 
of the urine and/or sclera  
 
Abdominal pain, back 
pain, headache, phlebitis, 
constipation 
Anaphylaxis, 
angioedema, cardiac 
arrhythmias  
(bradycardia), seizures, 
extravasation reactions 
rare but if occur can lead 
to: (erythema, swelling, 
pain, burning and/or blue 
discoloration of the skin 


37 
 
and rarely tissue 
necrosis), tumor lysis   
Prompt: 
Within 2-3 
weeks, prior to 
the next course 
Myelosuppression (L), 
mucositis /stomatitis, 
immunosuppression, 
alopecia, fatigue  
 
Transient elevation of 
LFTs, pruritis with 
desquamation of the skin 
due to progressive 
dryness  
 
Rash, conjunctivitis, (GI) 
hemorrhage, interstitial 
pneumonitis  
 
Delayed: 
Any time later during 
therapy, excluding the 
above conditions 
Amenorrhea, menstrual 
disorders, temporary 
reduction in sperm count  
 
Cardiotoxicity (decreased 
LVEF) (L)  
 
 
CHF, hepatotoxicity  
 (L)  
 
Late: 
Any time after 
completion of treatment  
 
 
 
Secondary malignancy  
 
Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of mitoxantrone have been noted in animals. 
Toxicities include: low birth weight and prematurity. Mitoxantrone is excreted in 
human milk and significant concentrations (18 ng/mL) have been reported for 28 
days after the last administration.  
 
(L) Toxicity may also occur later. 
 
Formulation and Stability: 
The concentrate is a sterile, non-pyrogenic, non-preserved, dark blue aqueous solution containing 
mitoxantrone hydrochloride equivalent to 2 mg/mL mitoxantrone free base, with sodium chloride 
(0.80% w/v), sodium acetate (0.005% w/v), and acetic acid (0.046% w/v) as inactive ingredients 
with 0.14 mEq of sodium per mL. Mitoxantrone is provided as 20 mg (10 mL), 25 mg (12.5 mL) 
and 30 mg (15 mL) vials. Store intact vials at 15°-25°C (59°-77°F). Undiluted mitoxantrone 
injection should be stored not longer than 7 days between 15°-25°C (59°-77°F) or 14 days under 
refrigeration. Refrigeration of the concentrate may result in a precipitate, which redisolves on 
warming to room temperature. DO NOT FREEZE. 
 
Guidelines for Administration:  
See Treatment and Dose Modifications sections of the protocol (Section 4.0 and Section 5.0). 
 
Mitoxantrone must be diluted prior to injection. DO NOT GIVE IV PUSH.  The dose of 
mitoxantrone should be diluted in at least 50 mL (or other published dilution concentration) with 
either 0.9% Sodium Chloride Injection (USP) or 5% Dextrose Injection (USP). The dilution is 
stable at room temperature for 48 hours with no loss of potency. Admixture with heparin may 
result in precipitation. Mitoxantrone is an irritant: Care should be taken to avoid extravasation; 
the use of a central line is suggested. If it is known or suspected that subcutaneous extravasation 
has occurred, it is recommended that intermittent ice packs be Page 60 placed over the area of 
extravasation and that the affected extremity be elevated. Because of the progressive nature of 
extravasation reactions, the area of injection should be frequently examined and surgery 
consultation obtained early if there is any sign of a local reaction. 
 
6.5 Methotrexate 


38 
 
 
Source and Pharmacology: 
A folate analogue which reversibly inhibits dihydrofolate reductase, the enzyme that reduces 
folic acid to tetrahydrofolic acid. Inhibition of tetrahydrofolate formation limits the availability 
of one carbon fragments necessary for the synthesis of purines and the conversion of 
deoxyuridylate to thymidylate in the synthesis of DNA and cell reproduction. The 
polyglutamated metabolites of MTX also contribute to the cytotoxic effect of MTX on DNA 
repair and/or strand breaks. MTX cytotoxicity is highly dependent on the absolute drug 
concentration and the duration of drug exposure. MTX is actively transported across cell 
membranes. At serum methotrexate concentrations exceeding 0.1 μmol/mL, passive diffusion 
becomes a major means of intracellular transport of MTX. The drug is widely distributed 
throughout the body with the highest concentration in the kidney, liver, spleen, gallbladder and 
skin. Plasma concentrations following high dose IV MTX decline in a biphasic manner with an 
initial half-life of 1.5-3.5 hours, and a terminal half life of 8-15 hours. About 50% is bound to 
protein. After oral administration, approximately 60% of a 30 mg/m2 dose is rapidly absorbed 
from the GI tract, with peak blood levels at 1 hour. At doses > 30 mg/m² absorption decreases 
significantly. Even at low doses absorption may be very erratic, varying between 23% and 95%. 
The elimination of MTX from the CSF after an intrathecal dose is characterized by a biphasic 
curve with half-lives of 4.5 and 14 hours. After intrathecal administration of 12 mg/m², the 
lumbar concentration of MTX is ~100 times higher than in plasma. (Ventricular concentration is 
~ 10% of lumbar concentration). MTX is excreted primarily by the kidneys via glomerular 
filtration and active secretion into the proximal tubules. Renal clearance usually equals or 
exceeds creatinine clearance. Small amounts are excreted in the feces. There is significant 
entero-hepatic circulation of MTX. The distribution of MTX into third-space fluid collections, 
such as pleural effusions and ascitic fluid, can substantially alter MTX pharmacokinetics. The 
slow release of accumulated MTX from these third spaces over time prolongs the terminal half-
life of the drug, leading to potentially increased clinical toxicity. 
 
Toxicity (Intrathecal): 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children 
out of every 100 
Immediate: 
Within 1-2 days 
of receiving drug 
Nausea, headache  
 
Arachnoditis: (headache, 
fever, vomiting, 
meningismus, nuchal 
rigidity, and pleocytosis)  
 
Anaphylaxis, vomiting, 
seizures(L), malaise, 
confusion, back pain, rash, 
bleeding into 
subarachnoid or subdural 
space (risk > with platelet 
counts < 20,000),  
Prompt: 
Within 2-3 
weeks, prior to 
the next course 
 
 
Myelosuppression, ataxia, 
somnolence, cranial nerve 
palsy, subacute 
myelopathy 
(paraparesis/paraplegia), 
speech disorders, pain in 
the legs, bladder 
dysfunction  


39 
 
Delayed: 
Any time later during 
therapy, excluding the 
above conditions 
 
Cognitive disturbances 
(L), learning disability (L) 
Leukoencephalopathy (L)  
 
Late: 
Any time after 
completion of treatment  
 
 
 
Progressive CNS 
deterioration 
(L) Toxicity may also occur later. 
 
Formulation and Stability: 
Methotrexate for Injection is available as a lyophilized powder for injection in 1000 mg vials. 
The powder for injection contains approximately 7 mEq sodium in the 1000 mg vial. 
Methotrexate for Injection is also available as a 25 mg/mL solution in 2, 4, 8, 10, and 40 mL 
preservative free vials and 2 and 10 mL vials with preservative. The 2, 4, 8, 10, and 40 mL 
solutions contain approximately 0.43, 0.86, 1.72, 2.15, and 8.6 mEq sodium per vial, 
respectively. The preserved vials contain 0.9% benzyl alcohol as a preservative.  
Sterile methotrexate powder or solution is stable at 20º-25ºC (68º-77ºF); excursions permitted to 
15º-30ºC (59º- 86 Fº). Protect from light. 
 
Guidelines for Administration:  
See Treatment and Dose Modifications sections of the protocol (Section 4.0 and Section 5.0). 
 
For intrathecal administration, dilute with 5-10 mL preservative free 0.9% Sodium Chloride 
Injection, lactated Ringer’s, or Elliot’s B solution as per institutional standard of practice. The 
volume of CSF removed should be equal to at least half the volume delivered. 
 
Patient Age (years) 
Methotrexate dose 
Recommended 
volume 
10% CSF volume 
CSF Volume* 
1–1.99 
8 mg 
5–10 mL 
5 mL 
50 + 10 mL 
 (babies) 
2–2.99 
10 mg 
5-10 mL 
8 mL 
80 + 20 mL 
(younger children) 
3–8.99# 
12 mg 
5-10 mL 
 
10 mL 
 
100 + 20 mL 
(older 
children) 
9 or greater 
15 mg 
5-10 mL 
13 mL 
130 + 30 mL 
(adults) 
*Rieselbach, R.E. et.al. Subarachnoid distribution of drugs after lumbar injection; N Engl J Med. 1962 Dec 20; 
267:1273-8  
 
Of Note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, 
with the patient remaining prone after the procedure may facilitate drug distribution. These 
procedures have not been validated in clinical trials. They are allowed but not mandated for 
patients on COG studies.  
Diluted methotrexate for intrathecal administration is stable for 24 hours at 25ºC but contains no 
preservative and should be administered as soon as possible after preparation. 
 
Diluted methotrexate for intrathecal administration is stable for 24 hours at 25ºC but contains no 
preservative and should be administered as soon as possible after preparation. 


40 
 
 
6.6 Asparaginase Erwinia Chrysanthemi 
 
Source and Pharmacology: 
L-asparagine is a nonessential amino acid synthesized by the transamination of L-aspartic acid by a 
reaction catalyzed by the enzyme L-asparagine synthetase. Neoplastic cells associated with acute 
lymphoblastic leukemia, acute myeloid leukemia and lymphoblastic lymphosarcoma are asparagine-
dependent but lack asparagine synthetase activity. The administration of L-asparaginase produces an anti-
neoplastic effect by catalyzing asparagine into aspartic acid and ammonia. As a result, these cells lack the 
ability to produce the asparagine necessary for protein metabolism and survival. Deamination of 
glutamine may also play a role in the antineoplastic activity of asparaginase.  
 
Asparaginase Erwinia chrysanthemi (ErwinazeTM) is asparaginase derived from cultures of 
Erwinia chrysanthemi. L-asparaginase is a tetrameric enzyme; each of the four identical subunits 
has a molecular weight of approximately 35 kDa. Asparaginase Erwinia chrysanthemi is 
immunologically distinct from E. coli L- asparaginase and may allow continued asparaginase 
therapy when a hypersensitivity reaction occurs to Escherichia coli-derived asparaginase. The 
package labeling states that there is insufficient information to characterize the incidence of 
antibodies to asparaginase Erwinia chrysanthemi. Several factors are involved in 
immunogenicity assay results and the assessment of antibodies, including assay methodology, 
assay sensitivity and specificity, sample handling, timing of sample collection, concomitant 
medications, and the underlying disease state.  
 
Effective asparaginase levels have been defined as activity of ≥ 0.1 International Units per mL. 
Clinical trials with asparaginase Erwinia chrysanthemi demonstrated that 100% of patients 
achieved effective asparaginase levels at 48 and 72 hours (n=35 and n=13, respectively) 
following the third total dose when given on a Monday, Wednesday, Friday schedule. No formal 
drug interaction studies have been performed with asparaginase Erwinia chrysanthemi. 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children 
out of every 100 
Immediate: 
Within 1-2 days 
of receiving drug 
 
Allergic reactions  
Anaphylaxis, urticaria   
 
Local injection site 
reactions, fever  
Prompt: 
Within 2-3 
weeks, prior to 
the next course 
Hyperammonemia (L), 
coagulation abnormalities 
with prolonged PTT, PT 
and bleeding times 
(secondary to decreased 
synthesis of fibrinogen, 
AT-III & other clotting 
factors) (L)  
 
Hyperglycemia, abnormal 
liver function tests, 
pancreatitis (L), increased 
serum lipase/amylase  
 
Pancreatitis, glucose 
intolerance,  
thrombosis, hemorrhage, 
transient ischemic attack, 
disseminated intravascular 
coagulation,  
hyperbilirubinemia, 
alanine aminotransferase 
increased, aspartate 
aminotransferase 
increased,  


41 
 
hyperglycemia, 
hyperammonemia,  
vomiting, nausea, 
abdominal pain,  
headache, diarrhea, 
seizure  
Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of L-asparaginase have been noted in animals. 
It is unknown whether the drug is excreted in breast milk. Adequate, well-controlled 
studies of asparaginase Erwinia chrysanthemi have NOT been conducted. It is not 
known whether asparaginase Erwinia chrysanthemi will cause fetal harm or affect 
the ability to reproduce. It is not known if asparaginase Erwinia chrysanthemi is 
excreted into breast milk. The use of asparaginase Erwinia chrysanthemi should be 
avoided in pregnant or lactating patients. 
 
 
Formulation and Stability: 
Asparaginase Erwinia chrysanthemi is supplied as a sterile, white lyophilized powder for 
reconstitution in a clear glass vial with a 3 mL capacity. Each vial contains 10,000 International 
Units of asparaginase Erwinia chrysanthemi and the following inactive ingredients: glucose 
monohydrate (5.0 mg), sodium chloride (0.5 mg). Store between 2°C and 8°C (36° to 46ºF). 
Store intact vials between 2°C and 8°C (36°- 46ºF). Protect from light. 
 
Guidelines for Administration:  
See Treatment and Dose Modifications sections of the protocol (Section 4.0 and Section 5.0). 
 
Use appropriate precautions for preparation of a hazardous agent. Visually inspect the powder in vial for 
foreign particles or discoloration prior to reconstitution. The contents of each vial should be reconstituted 
by slowly adding 1 mL or 2 mL of sterile, preservative-free NS to the inner vial wall. The final 
concentration is 10,000 International Units per mL when using 1 mL for reconstitution or 5,000 
International Units per mL when using 2 mL for reconstitution. Gently mix or swirl the contents to 
dissolve the contents of the vial. Do not shake or invert the vial. The resulting solution should be clear 
and colorless. Discard if any particulate matter or protein aggregates are visible. Withdraw the 
appropriate dosing volume into a polypropylene syringe within 15 minutes of reconstitution. 
Discard any unused drug; do not save or use any unused drug remaining the in the vial.  
Administer the dose within a 4 hour time period from reconstitution. If the dose is not used within 
this time period, discard the dose. Do not freeze or refrigerate the reconstituted solution.  
Administer the dose intramuscularly (IM). No more than 2 mL should be given at any one injection site. 
Doses larger than 2 mL should be divided and given in separate administration sites. 
 
6.7 Bortezomib  
 
Source and Pharmacology: 
 
Formulation and Stability: 
Bortezomib for Injection is a sterile lyophilized powder for reconstitution and is supplied in vials 
containing bortezomib and mannitol at a 1:10 ratio. For example, vials containing 3.5mg of 
bortezomib contain 35mg of mannitol. 
 
Preparation, Handling, Storage, and Destruction of Drugs 


42 
 
Bortezomib 
Vials containing lyophilized bortezomib for Injection should be stored according to the label 
requirements. For the United States, store at USP Controlled Room Temperature which is 25ºC 
(77ºF); for Europe, do not store above 30ºC (86ºF); excursions permitted from 15 to 30ºC (59-
86ºF). To date, stability data indicate that the lyophilized drug product is stable for at least 18 
months when stored under the recommended conditions. Stability studies are ongoing, and 
Millennium Pharmaceuticals, Inc. will notify the investigator should this information be revised 
during the conduct of the study. 
 
Bortezomib is cytotoxic. As with all cytotoxic drugs, caution is required when preparing and 
handling bortezomib solutions. Cytotoxic drugs should only be handled by staff specially trained 
in the safe handling of such preparations. The use of gloves and other appropriate protective 
clothing is recommended. In case of skin contact, wash the affected area immediately and 
thoroughly with soap and water for at least 15 minutes. If product contacts eye, immediately 
flush eye thoroughly with water for at least 15 minutes. Always contact a physician after any 
form of body contact. All materials that have been used for preparation should be disposed of 
according to standard practices. A log must be kept of all disposed materials. 
Drug is available in sterile, single-use vials containing 3.5 mg of bortezomib. Each vial of 
bortezomib for Injection should be reconstituted under a laminar flow biological cabinet (hood) 
within 8 hours before dosing with 3.5 mL of normal (0.9%) saline, Sodium Chloride Injection 
USP, so that the reconstituted solution contains bortezomib at a concentration of 1 mg/mL. Prior 
to reconstitution the vials should remain in the cartons to protect them from light. Dissolution is 
completed in approximately 10 seconds. The reconstituted solution is clear and colorless, with a 
final pH of 5 to 6.  
Reconstituted bortezomib should be administered promptly and in no case more than 8 hours 
after reconstitution. 
 
Bortezomib Destruction 
Investigational bortezomib (expired or end of study) should be destroyed on site according to the 
institution’s standard operating procedure. Be sure to document removal and destruction on drug 
accountability logs. 
 
Blinding, Packaging, and Labeling 
Bortezomib will be supplied in vials as open-label stock. Both the box label and vial label will 
fulfill all requirements specified by governing regulations. 
 
Treatment Compliance 
All drug will be administered to eligible patients under the supervision of the investigator or 
identified subinvestigator(s). The pharmacist will maintain records of drug receipt (if applicable), 
drug preparation, and dispensing, including the applicable lot numbers, patients’ height, body 
weight, and body surface area (see Appendix 8.1), total drug administered in milliliters and 
milligrams, and date and time of administration. Any discrepancy between the calculated dose 
and dose administered and the reason for the discrepancy must be recorded in the source 
documents. 


43 
 
 
Precautions and Restrictions 
It is not known what effects bortezomib has on human pregnancy or development of the embryo 
or fetus. Therefore, female patients participating in this study should avoid becoming pregnant, 
and male patients should avoid impregnating a female partner. Nonsterilized female patients of 
reproductive age and male patients should use effective methods of contraception through 
defined periods during and after study treatment as specified below. 
Female patients must meet 1 of the following: 
 
• Postmenopausal for at least 1 year before the screening visit, or 
• Surgically sterile, or 
• If they are of childbearing potential, agree to practice 2 effective methods of 
contraception from the time of signing the informed consent form through 30 days after 
the last dose of bortezomib, or agree to completely abstain from heterosexual intercourse. 
It is strongly recommended that at least 1 of these 2 methods be highly effective (see examples 
below). 
 
Highly effective methods 
Other effective methods (barrier methods) 
Intra-uterine devices (IUD) 
Latex condom 
Hormonal contraceptives (birth control 
pills/oral contraceptives, injectable 
contraceptives, contraceptive patches, or 
contraceptive implants) 
Diaphragm with spermicide 
Cervical cap 
Sponge 
If one of the highly effective methods cannot be used, using 2 effective methods at the 
same time is recommended.  
 
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of 
the following: 
• 
Practice effective barrier contraception during the entire study treatment period 
and through a minimum of 30 days after the last dose of study drug, or completely 
abstain from heterosexual intercourse. 
 
Guidelines for Administration:  
See Treatment and Dose Modifications sections of the protocol (Section 4.0 and Section 5.0). 
 
Bortezomib is to be given without further dilution as an IV push over 3 to 5 seconds. 
Consecutive doses must be separated by at least 72 hours.  
 
Special precautions: FOR INTRAVENOUS USE ONLY. 
The syringe containing bortezomib should be clearly labeled for intravenous use only. Three 
fatalities have been reported following accidental intrathecal administration of bortezomib. 


44 
 
Special precautions should be employed to ensure that intravenous bortezomib and intrathecal 
medications are not inadvertently interchanged. 
 
 
 
7.0  SUPPORTIVE CARE AND OTHER CONCOMMITANT THERAPY 
 
7.1 Concurrent Anticancer Therapy 
Concurrent cancer therapy including chemotherapy, immunotherapy or biologic therapy may 
not be administered to patients within 14 days of the start of this study and during the study 
period.  
 
7.2 Investigation Agents 
No other investigational agents may be given while the patient is on study. 
 
7.3 Supportive Care 
Appropriate antibiotics, blood products, antiemetics, anti-hypertensives, fluids, electrolytes, 
and tumor lysis precautions and general supportive care are to be used as necessary.  See 
Appendix II for drugs that should not be used concomitantly with bortezomib. 
 
7.3.1 
Infection Control 
Patients with relapsed ALL have a significant risk of morbidity and mortality with 
intensive chemotherapy.   
• It is strongly recommended that patients remain hospitalized from the 
initiation of therapy until they are clinically stable and have evidence of ANC 
recovery.   
• It is strongly recommended that patients receive broad spectrum antibiotic 
prophylaxis from the initiation of therapy until there is evidence of ANC 
recovery.  A fluoroquinolone such as ciprofloxacin or levofloxacin is 
recommended. 
• All patients should receive anti-fungal therapy with caspofungin, micafungin 
or amphotericin unless contraindicated.  Azole antifungals are not allowed 
until 2 days after the last dose of vincristine.  
 
7.3.2 
Tumor Lysis Syndrome 
Tumor lysis syndrome should be closely monitored at the onset of therapy. Serum 
chemistries including potassium, phosphorus, calcium and uric acid should be 
monitored at least daily after initiation of therapy.  Allopurinol or urate oxidase 
should be used for elevated or increasing uric acid levels.  IV hydration should be 
maintained for a minimum of 3 days and there is no laboratory evidence of tumor 
lysis. 
 
7.3.3 
Growth Factors 
Growth factors are not recommended for routine use but may be administered at the 
discretion of the treating physician for infection, severe mucositis or poor wound 
healing. 


45 
 
 
7.3.4 
Concomitant Medications 
 
Investigators should consider using antiviral prophylaxis in subjects being treated 
with bortezomib. 
 
The use of enzyme inducing anticonvulsants and antifungals is not permitted until 
two days following the last dose of vincristine. Please refer to Appendix __ for a list 
of inhibitors and inducers of CYP3A4. 
 
  
 
8.0  STUDY EVALUATIONS  
 
CSF and bone marrow evaluations should be no more than 14 days prior to starting therapy. 
All other evaluations should take place within 72 hours of the specified time listed in the 
table below. 
 
Evaluation 
Pre-Study 
During Therapy 
End of Therapy 
History 
X 
Weekly 
 
Physical Exam 
X 
Weekly 
 
Vital Signs including 
Pulse Oximetry 
X 
Weekly 
 
Toxicity 
Assessments 
 
Weekly 
X 
SAE Assessments 
 
Weekly 
X 
Height and Weight 
X 
 
X 
Performance Status 
X 
 
X 
CBC with 
differential 
X 
Twice weekly 
X 
Electrolytes (Na, K, 
glucose, Ca, PO4 ) 
X 
Daily for minimum 
3 days, then weekly 
X 
Uric Acid 
X 
Daily for minimum 
3 days, then weekly 
 
Creatinine, ALT, 
Bilirubin 
X 
Weekly 
X 
PT, PTT, Fibrinogen 
X 
 
 
Bone Marrow 
Aspirate 
X 
 
X1 
Bone Marrow for 
MRD 
X 
 
X1 
CSF with cell count 
and cytospin 
X 
Day 85 
 
Pregnancy Test2 
X 
 
 
Chest X-ray (2 
views) 
X 
 
 


46 
 
ECHO/EKG 
X 
 
X 
CT chest, abdomen 
and pelvis3 
X 
 
X 
PET scan4 
X 
 
X 
1 End of Therapy bone marrow evaluation should take place after recovery of blood counts 
no later than Day 36.  If bone marrow is still not recovered (ANC >500) or evidence of 
leukemia, then follow-up bone marrows should be done every 1-2 weeks. 
2Women of childbearing potential require a negative pregnancy test prior to starting 
treatment; sexually active patients must use an acceptable method of birth control.   
3CT scan only for patients with lymphoma or leukemia patients with extramedullary disease 
seen on prior scans 
4PET scan is optional for lymphoma patients, not required for ALL patients 
5For patients receiving additional IT doses, CSF and cytospin should be performed with each 
dose 
 
 
9.0    STATISTICAL CONSIDERATIONS 
 
This is intended as a pilot study to determine the safety and efficacy of the combination of 
bortezomib with reinduction therapy based on the UK ALL R3 protocol for pediatric 
relapsed or refractory ALL or LL.  There is no control group and no plan to increase or 
decrease doses of any medications.  The goal is to recruit a minimum of 10 patients over a 24 
month period to appropriately describe the effects of therapy on patients and resistant 
leukemia or lymphoma.   
 
10.0 EVALUATION CRITERIA 
 
10.1 Common Terminology Criteria for Adverse Events (CTCAE) 
 
Toxicities occurring during the study period will be reported based on the revised 
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.  
The CTCAE version 4.0 can be found on the CTEP website 
(http://Ctep.cancer.gov). 
 
10.2 Response Criteria for Patients with Acute Lymphoblastic Leukemia 
 
10.2.1 Complete Remission (CR) 
Attainment of an M1 bone marrow (<5% blasts in the bone marrow 
aspirate or biopsy if aspirate not available) with no evidence of circulating 
blasts or extramedullary disease and with recovery of peripheral counts 
(absolute neutrophil count (ANC) ≥ 500/µL and platelet count ≥ 
50.000/µL) 
 
10.2.2 Complete Remission with Partial Recovery of Platelet Count (CRp) 


47 
 
Attainment of an M1 bone marrow (<5% blasts) with no evidence of 
circulating blasts or extramedullary disease, but without recovery of ANC 
or platelet count by day 43 as specified in CR. 
 
10.2.3 Partial Remission (PR) 
Complete disappearance of circulating blasts and achievement of M2 
marrow status (≥ 5% or < 25% blasts in the bone marrow aspirate or 
biopsy if aspirate not available).  Attainment of a bone marrow CR 
(above) with proven persistence of extramedullary disease qualifies as a 
PR.   
 
10.2.4 Progressive Disease (PD) 
An increase in the percentage of blasts in either the peripheral blood or 
bone marrow of >25% 
 
10.2.5 Stable Disease (SD) 
This is present when the patient fails to qualify for a CR, PR or PD. 
 
10.3 Response Criteria for Patients with Lymphoblastic Lymphoma 
 
10.3.1 Measurable Disease 
Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter) as ≥10 mm by CT scan or ≥10 
mm with calipers by clinical exam.   
 
10.3.2 Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT scan.  At baseline and 
in follow-up, only the short axis will be measured and followed. 
 
10.3.3 Non-Measurable Disease 
All other lesions (or sites of disease), including small lesions are 
considered non-measurable disease.  Bone lesions, leptomeningeal 
disease, ascites, and pleural/pericardial effusions are considered as non-
measurable. 
 
10.3.4 Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified 
as target lesions and recorded and measured at baseline. Target lesions 
should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should 
be those that lend themselves to reproducible repeated measurements. It 
may be the case that, on occasion, the largest lesion does not lend itself to 
reproducible measurement in which circumstance the next largest lesion 
that can be measured reproducibly should be selected. A sum of the 


48 
 
diameters (longest for non-nodal lesions, short axis for nodal lesions) for 
all target lesions will be calculated and reported as the baseline sum 
diameters. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
 
10.3.5 Non-Target Lesions 
All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target 
lesions and should also be recorded at baseline. Measurements of these 
lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up. 
 
10.4 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up.  
Imaging-based evaluation is preferred to evaluation by clinical examination 
unless the lesion(s) being followed cannot be imaged but are assessable by 
clinical exam.  
  
10.4.1 Clinical Lesions 
Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm 
diameter as assessed using calipers (e.g., skin nodules). In the case of skin 
lesions, documentation by color photography, including a ruler to estimate 
the size of the lesion, is recommended. 
 
10.4.2 Conventional CT and MRI 
The same imaging modality should be used to monitor all disease sites for 
follow-up. 
 
10.4.3 FDG-PET 
While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT 
scanning in assessment of progression (particularly possible 'new' disease). New 
lesions on the basis of FDG-PET imaging can be identified according to the 
following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up 
is a sign of PD based on a new lesion.  
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the 
positive FDG-PET at follow-up corresponds to a new site of disease 
confirmed by CT, this is PD. If the positive FDG-PET at follow-up is not 


49 
 
confirmed as a new site of disease on CT, additional follow-up CT scans 
are needed to determine if there is truly progression occurring at that site 
(if so, the date of PD will be the date of the initial abnormal FDG-PET 
scan). If the positive FDG-PET at follow-up corresponds to a pre-
existing site of disease on CT that is not progressing on the basis of the 
anatomic images, this is not PD.  
Note: A ‘positive’ FDG-PET scan lesion means one that is FDG avid with an 
uptake greater than twice that of the surrounding tissue on the attenuation 
corrected image. 
 
10.5 Methods for Evaluation of Measurable Disease 
 
10.5.1 Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target and non-target 
lesions.  Any pathological lymph nodes 
(whether target or non-target) must have 
reduction in short axis t <10 mm.  If 
immunocytology is available, no disease 
must be detected by that methodology. 
 
Partial Response (PR): 
At least a 30% decrease in the sum of the 
diameters of the target lesions, taking as 
reference the baseline sum diameters. 
 
Progressive Disease (PD): 
At least 20% increase in the sum of the 
diameters of target lesions, taking as 
reference the smallest sum on study (this 
includes the baseline sum if that is the 
smallest on study). In addition to the relative 
increase of 20%, the sum must also 
demonstrate an absolute increase of at least 
5 mm. (Note: the appearance of one or more 
new lesions is also considered progressions). 
Note: in presence of SD or PR in target 
disease but unequivocal progression in non-
target or non-measurable disease, the patient 
has PD if there is an overall level of 
substantial worsening in non-target disease 
such that the overall tumor burden has 
increased sufficiently to merit 
discontinuation of therapy. 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for a 
PR nor sufficient increase to qualify for PD. 
 
10.5.2 Evaluation of Non-Target Lesions 


50 
 
 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level. All 
lymph nodes must be non-pathological in 
size (<10 mm short axis). 
 
Partial Response (PR): 
Persistence of one or more non-target 
lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD): 
Appearance of one or more new lesions 
and/or unequivocal progression of existing 
non-target lesions. Unequivocal progression 
should not normally trump target lesion 
status. It must be representative of overall 
disease status change, not a single lesion 
increase. 
 
 
 


51 
 
11.0 
ADVERSE EVENTS 
 
11.1 Adverse Event Definition 
 
Adverse event (AE) means any untoward medical occurrence in a patient or subject administered 
a medicinal product; the untoward medical occurrence does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product whether or not it is related to the medicinal product.  
This includes any newly occurring event, or a previous condition that has increased in severity or 
frequency since the administration of study drug. 
 
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline. 
 
11.2  Adverse Drug Reaction 
An adverse drug reaction (ADR) is a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. This includes adverse reactions 
which arise from: use of a medicinal product within the terms of the marketing authorization; use 
outside the terms of the marketing authorization, including overdose, misuse, abuse and 
medication errors; and occupational exposure*. 
* This corresponds to the exposure to a medicinal product for human use as a result of one’s 
occupation, such as nurses who may handle products routinely in their occupational setting. 
 
11.3  Serious Adverse Event Definition 
Serious AE (SAE) means any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life-threatening (refers to an AE in which the patient was at risk of death at the time of 
the event.  It does not refer to an event which hypothetically might have caused death if it 
were more severe). 
• Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph below on planned hospitalizations). 


52 
 
• Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions). 
• Is a congenital anomaly/birth defect. 
• Is a medically important event.  This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious 
when, based on appropriate medical judgment, may jeopardize the patient, require 
medical or surgical intervention to prevent 1 of the outcomes listed above, or involves 
suspected transmission via a medicinal product of an infectious agent.   Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse; any 
organism, virus, or infectious particle (e.g., prion protein transmitting Transmissible 
Spongiform Encephalopathy), pathogenic or nonpathogenic, is considered an infectious 
agent.   
Clarification should be made between a serious AE (SAE) and an AE that is considered severe in 
intensity (Grade 3 or 4), because the terms serious and severe are NOT synonymous.  The 
general term severe is often used to describe the intensity (severity) of a specific event; the event 
itself, however, may be of relatively minor medical significance (such as a Grade 3 headache).  
This is NOT the same as serious, which is based on patient/event outcome or action criteria 
described above, and is usually associated with events that pose a threat to a patient’s life or 
ability to function.  A severe AE (Grade 3 or 4) does not necessarily need to be considered 
serious.  For example, a white blood cell count of 1000/mm3 to less than 2000 is considered 
Grade 3 (severe) but may not be considered serious.  Seriousness (not intensity) serves as a guide 
for defining regulatory reporting obligations 
 
11.4  Procedures for Reporting Serious Adverse Events 
 
Adverse Events may be spontaneously identified by the patient and/or in response to an open 
question from study personnel or revealed by observation, physical examination, or other 
diagnostic procedures.  Any clinically relevant deterioration in laboratory assessments or other 
clinical finding is considered an AE.  When possible, signs and symptoms indicating a common 
underlying pathology should be noted as one comprehensive event.   
Adverse Events which are serious must be reported to Millennium Pharmacovigilance (or 
designee) from the first dose of bortezomib up to and including 30 days after administration of 
the last dose of bortezomib.  Any SAE that occurs at any time after completion of bortezomib 


53 
 
treatment or after the designated follow-up period that the sponsor-investigator and/or sub-
investigator considers to be related to any study drug must be reported to Millennium 
Pharmacovigilance (or designee).  Planned hospital admissions or surgical procedures for an 
illness or disease that existed before the patient was enrolled in the trial are not to be considered 
AEs unless the condition deteriorated in an unexpected manner during the trial (e.g., surgery was 
performed earlier or later than planned).  All SAEs should be monitored until they are resolved 
or are clearly determined to be due to a patient’s stable or chronic condition or intercurrent 
illness (es). 
Since this is an investigator-initiated study, the principal investigator Keith August, MD also 
referred to as the sponsor-investigator, is responsible for reporting serious adverse events (SAEs) 
to any regulatory agency and to the sponsor- investigator’s EC or IRB.    
Regardless of expectedness or causality, all SAEs must also be reported in English to 
Millennium Pharmacovigilance or designee: 
Fatal and Life Threatening SAEs within 24 hours of the sponsor-investigator’s 
observation or awareness of the event. 
All other serious (non-fatal/non life threatening) events within 4 calendar days of the sponsor-
investigator’s observation or awareness of the event. 
 
The SAE report must include at minimum: 
• Event term(s) 
• Serious criteria 
• Intensity of the event(s): Sponsor-investigator’s or sub-investigator’s determination.  
Intensity for each SAE, including any lab abnormalities, will be determined by using the 
NCI CTCAE version specified in the protocol, as a guideline, whenever possible.  The 
criteria are available online at http://ctep.cancer.gov/reporting/ctc.html. 
• Causality of the event(s): Sponsor-investigator’s or sub-investigator’s determination of 
the relationship of the event(s) to study drug administration.  
Follow-up information on the SAE may be requested by Millennium Pharmacovigilance (or 
designee).   
In the event that this is a multisite study, the sponsor-investigator is responsible to ensure that the 
SAE reports are sent to Millennium Pharmacovigilance (or designee) from all sites participating 


54 
 
in the study.  Sub-investigators must report all SAEs to the sponsor-investigator so that the 
sponsor-investigator can meet his/her foregoing reporting obligations to the required regulatory 
agencies and to Millennium Pharmacovigilance, unless otherwise agreed between the sponsor-
investigator and sub-investigator(s).   
Relationship to all study drugs for each SAE will be determined by the investigator or sub-
investigator by responding yes or no to the question: Is there a reasonable possibility that the 
AE is associated with the study drug(s)? 
US and Canada 
Toll-Free Fax #: 1-800-963-6290 
E-mail: takedaoncocases@cognizant.com 
Suggested Reporting Form:   
• 
SAE Report Form (a sample will be provided) 
• 
US FDA MedWatch 3500A:  
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
• 
Any other form deemed appropriate by the sponsor-investigator 
 
 
Procedures for Reporting Drug Exposure during Pregnancy and Birth Events 
If a woman becomes pregnant or suspects that she is pregnant while participating in this 
study, she must inform the investigator immediately and permanently discontinue study drug. 
The sponsor-investigator must fax a completed Pregnancy Form to Millennium 
Pharmacovigilance or designee (see Section 11.4). The pregnancy must be followed for the 
final pregnancy outcome (i.e., delivery, still birth, miscarriage) and Millennium 
Pharmacovigilance or designee will request this information from the sponsor-investigator. 
 If a female partner of a male patient becomes pregnant during the male patient’s 
participation in this study, the sponsor-investigator must also immediately fax a completed 
Pregnancy Form to Millennium Pharmacovigilance or designee (see Section 11.4). Every 
effort should be made to follow the pregnancy for the final pregnancy outcome. 
 
Suggested Pregnancy Reporting Form: 
Pregnancy Report Form (a sample will be provided)   
 
Product Complaints 
A product complaint is a verbal, written, or electronic expression which implies 
dissatisfaction regarding the identity, strength, purity, quality, or stability of a drug product. 


55 
 
Individuals who identify a potential product complaint situation should immediately contact 
Millennium (see below) and report the event. Whenever possible, the associated product 
should be maintained in accordance with the label instructions pending further guidance from 
a Millennium Quality representative.  
A medication error is a preventable event that involves an identifiable patient and that leads 
to inappropriate medication use, which may result in patient harm. While overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not. 
Individuals who identify a potential medication error situation should immediately contact 
Millennium (see below) and report the event 
 
For Product Complaints or Medication Errors 
• 
Phone: 1-866-VELCADE (1-866-835-2233) 
• 
E-mail: medical@mlnm.com 
• 
FAX: 1-800-881-6092 
• 
Hours: Mon-Fri, 9 a.m. – 7 p.m. ET 
 
Product complaints and medication errors in and of themselves are not AEs. If a product 
complaint or medication error results in an SAE, an SAE form should be completed and sent 
to Millennium Pharmacovigilance (refer to Section 11.4). 
 
 
 
 
 
 


56 
 
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 
 
Karnofsky (≥17 years old) 
Lansky (≤16 years old) 
Score 
Description 
Score 
Description 
 
100 
Normal, no complaints, no evidence of 
disease 
100 
Fully active, normal.  
90 
Able to carry on normal activity, minor 
signs or symptoms of disease.  
90 
Minor restrictions in physically strenuous 
activity.  
80 
Normal activity with effort; some signs or 
symptoms of disease.  
80 
Active, but tires more quickly  
70 
Cares for self, unable to carry on normal 
activity or do active work.  
70 
Both greater restriction of and less time 
spent in play activity.  
60 
Required occasional assistance, but is able 
to care for most of his/her needs.  
60 
Up and around, but minimal active play; 
keeps busy with quieter activities.  
50 
Requires considerable assistance and 
frequent medical care.  
50 
Gets dressed, but lies around much of the 
day; no active play, able to participate in 
all quiet play and activities.  
40 
Disabled, requires special care and 
assistance.  
40 
Mostly in bed; participates in quiet 
activities.  
30 
Severely disabled, hospitalization 
indicated. Death not imminent.  
30 
In bed; needs assistance even for quiet 
play.  
20 
Very sick, hospitalization indicated. Death 
not imminent.  
20 
Often sleeping; play entirely limited to 
very passive activities.  
10 
Moribund, fatal processes progressing 
rapidly.  
10 
No play; does not get out of bed. 
 
 
 


57 
 
APPENDIX II: LIST OF STRONG AND CLINICALLY RELEVENT MODERATE CYP3A4 
INDUCERS AND INHIBITORS 
 
Strong CYP3A4 Inducers: 
Generic Name 
Common Trade Name 
Carbamazepine 
Tegretol 
Phenobarbital 
Luminal 
Phenytoin 
Dilantin 
Rifampin 
Rifadin 
St. John’s Wart 
N/A 
Systemic dexamethasone 
Decadron 
 
 
Strong* and Clinically Relevant Moderate CYP3A4 Inhibitors: 
Generic Name 
Common Trade Name 
Aprepitant 
Emend 
Clarithromycin* 
Biaxin 
Erythromycin 
Eryc, EryPed 
Fluconazole 
Diflucan 
Grapefruit and its juice 
N/A 
Itraconazole* 
Sporanox 
Ketoconazole* 
Nizoral 
Voriconazole 
VFend 
 
 
 
 


58 
 
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62 
 
 
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