A TACL Phase 1/2 Study of PO Ixazomib in Combination With Chemotherapy for Childhood Relapsed or Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma IND# 140730
Phase: PHASE1
Conditions: ALL, Childhood, Lymphoblastic Lymphoma, Childhood, Lymphoblastic Leukemia, Acute, Childhood
Sponsor: Therapeutic Advances in Childhood Leukemia Consortium

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IND 140730; T2017-002 “A TACL Phase 1/2 Study of PO Ixazomib in Combination with 
Chemotherapy for Childhood Relapsed or Refractory Acute Lymphoblastic Leukemia and 
Lymphoblastic Lymphoma” 
 
 
NCT03817320 
TACL 
Therapeutic Advances in 
Childhood Leukemia & Lymphoma 
 

 
 
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A TACL Phase 1/2 Study of PO Ixazomib in Combination with Chemotherapy for 
Childhood Relapsed or Refractory Acute Lymphoblastic Leukemia and Lymphoblastic 
Lymphoma 
IND# 140730 
 
PROTOCOL CHAIR:  Terzah Horton, MD, PhD 
 
PROTOCOL VICE-CHAIR:  Eric S. Schafer, MD, MHS 
 
 
TACL MEMBER INSTITUTIONS 
 
Children's Healthcare of Atlanta at Egleston 
Oregon Health & Science University 
Children’s Hospital and Clinics of Minnesota 
Primary Children’s Hospital 
Children’s Hospital Los Angeles 
Rainbow Babies & Children’s Hospital 
Children’s Hospital New York-Presbyterian 
Riley Hospital for Children, Indiana University 
Children’s Hospital Orange County 
Royal Children’s Hospital, Melbourne 
Children’s Hospital of Philadelphia 
Seattle Children’s Hospital 
Children’s National Medical Center 
Sidney Kimmel Cancer Center at Johns Hopkins 
Cincinnati Children’s Hospital 
St. Jude Children’s Research Hospital Memphis 
Cook Children’s Medical Center 
Sydney Children’s Hospital 
CS Mott Children’s Hospital, Ann Arbor 
Texas Children’s Cancer Center, Baylor 
Dana-Farber Cancer Institute 
The Children’s Hospital at Westmead 
Levine Children's Hospital  
The Children’s Hospital, University of Colorado  
Lurie Children’s Hospital of Chicago 
UCSF School of Medicine 
Medical College of Wisconsin 
University of Miami 
Nationwide Children’s Hospital 
University of Texas Southwestern Medical Center 
National Cancer Institute, Pediatric Oncology 
Branch 
 
 
 
TACL OPERATIONS CENTER 
CHLA, 4650 Sunset Blvd, MS-54, Los Angeles, CA 90027 
Phone: (323) 361-5132 or (323) 361-5429 Fax: (323) 361-4505 
https://tacl.chla.usc.edu 
PROTOCOL DISCLAIMER 
TACL protocols and their content are for research purposes only and should not be copied, 
redistributed or used for any other purpose. The procedures in this protocol are intended only for use at 
TACL member institutions under the direction of TACL physicians. The most current version of the 
protocol should be accessed at https://tacl.chla.usc.edu. 
 
 
 
TACL Protocol: 
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Activated:  
 
TACL 
Therapeutic Advances in  
Childhood Leukemia and Lymphoma 

 
 
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TABLE OF CONTENTS 
 
TABLE OF CONTENTS .............................................................................................................................................2 
STUDY COMMITTEE .................................................................................................................................................5 
STUDY SCHEMA……………………………………………………………………………………………………………...6 
1.0 
GOALS AND OBJECTIVES ..........................................................................................................................7 
1.1 
Primary Objectives for Phase 1 ...................................................................................................................7 
1.2 
Primary Objective for Phase 2 .....................................................................................................................7 
1.3 
Secondary Objective ....................................................................................................................................7 
1.4 
Exploratory Objectives.................................................................................................................................7 
2.0 
BACKGROUND .............................................................................................................................................8 
2.1 
Introduction and Rationale for Development.............................................................................................8 
2.2 
Introduction of Ixazomib ..............................................................................................................................8 
2.3  
Chemotherapy Backbone Rationale ........................................................................................................ 10 
2.4 
Ixazomib Dosing and Study Design Rationale ....................................................................................... 11 
2.5  
Correlative Biology Studies ...................................................................................................................... 12 
2.6  
Palatability of Oral Ixazomib Study .......................................................................................................... 12 
3.0 
PATIENT ELIGIBILITY CRITERIA AND ENROLLMENT .......................................................................... 13 
3.1 
Patient Reservation/Registration ............................................................................................................. 13 
3.2 
Enrollment .................................................................................................................................................. 13 
3.3 
Inclusion Eligibility Criteria ...................................................................................................................... 14 
3.4 
Exclusion Eligibility Criteria ..................................................................................................................... 16 
4.0 
TREATMENT PROGRAM ........................................................................................................................... 17 
4.1 
Block 1 (35 days) ....................................................................................................................................... 18 
4.2 
Block 2 (35 days) ....................................................................................................................................... 21 
4.3 
Optional standard maintenance cycle ..................................................................................................... 25 
4.4 
Disease Evaluation .................................................................................................................................... 27 
4.5 
Dose Escalation Schedule ........................................................................................................................ 28 
4.6 
Dose-limiting Toxicity (DLT) ..................................................................................................................... 28 
4.7 
Dose Modifications for Toxicity ............................................................................................................... 29 
5.0 
SUPPORTIVE CARE .................................................................................................................................. 42 
5.1 
Concurrent Therapy .................................................................................................................................. 42 
5.2 
Blood Products .......................................................................................................................................... 42 
5.3 
Infection Control ........................................................................................................................................ 43 

 
 
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6.0 
DRUG INFORMATION ................................................................................................................................ 45 
6.1 
IXAZOMIB ................................................................................................................................................... 45 
6.2 
ASPARAGINASE Erwinia chrysanthemi (recombinant)-rywn............................................................... 54 
6.3 
CYCLOPHOSHAMIDE - INJECTIONCYCLOPHOSPHAMIDE - INJECTION ........................................... 56 
6.4 
DOXORUBICIN (Adriamycin®) NSC #123127 (05/09/11) ........................................................................ 57 
6.5 
ETOPOSIDE – INJECTION......................................................................................................................... 59 
6.6 
INTRATHECAL TRIPLE (Methotrexate/Hydrocortisone/Cytarabine) .................................................... 60 
6.7 
LEUCOVORIN CALCIUM (LCV, Wellcovorin®, citrovorum factor, folinic acid) NSC #003590 (05/09/11)
 .................................................................................................................................................................... 62 
6.8 
METHOTREXATE (MTX, amethopterin) NSC #000740 (02/29/12) .......................................................... 64 
6.9 
PEGASPARGASE (PEG-asparaginase, PEGLA, PEG-L-asparaginase, polyethylene glycol-L-
asparaginase, Oncaspar®) NSC #624239 (05/09/11) ............................................................................. 68 
6.10 
CALASPARGASE………………………………………………………………………………………………….69 
6.11 
VINCRISTINE SULFATE (Oncovin®, VCR, LCR) NSC #67574 (11/18/11) ............................................. 71 
6.12  
Dexamethasone (Decadron®, Hexadrol®, Dexone®, Dexameth®) NSC#34521 .................................. 72 
7.0 
REQUIRED OBSERVATIONS/MATERIAL AND DATA TO BE ASSESSIONED ..................................... 74 
7.1 
Clinical and Laboratory Studies ............................................................................................................... 74 
7.2 
Correlative Biology Studies ...................................................................................................................... 77 
7.3 
Bone Marrow Sample for MRD ................................................................................................................. 77 
7.4 
Palatibility Study ........................................................................................................................................ 78 
7.5 
Required Observations Following Completion of Protocol Therapy ................................................... 78 
8.0 
CORRELATIVE STUDIES .......................................................................................................................... 78 
8.1 
Description of Studies ............................................................................................................................... 78 
8.2 
Sampling Schedule for optional PD studies ........................................................................................... 79 
8.3 
Blood for PK Analysis (mandatory) ......................................................................................................... 79 
8.4 
Additional Information for Correlative Studies ...................................................................................... 80 
9.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY, OFF STUDY CRITERIA AND STUDY 
TERMINATION ........................................................................................................................................... 80 
9.1 
Criteria for Removal from Protocol Therapy .......................................................................................... 81 
9.2 
Off Study Criteria ....................................................................................................................................... 81 
9.3 
Termination of the Study by TACL .......................................................................................................... 81 
10.0 
STATISTICAL CONSIDERATIONS ............................................................................................................ 82 
10.1 
Design Overview ........................................................................................................................................ 82 
10.2 
Endpoints ................................................................................................................................................... 83 
10.3 
Patient Evaluability and DLT Definition ................................................................................................... 84 

 
 
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10.4  
Interim Monitoring of Toxic Death ........................................................................................................... 84 
10.5 
Analysis of primary and secondary endpoints ...................................................................................... 84 
10.6 
Analysis of exploratory endpoints ........................................................................................................... 85 
10.7 
Inclusion of Women and Minorities ......................................................................................................... 85 
11.0 
RESPONSE CRITERIA ............................................................................................................................... 85 
11.1 
Bone Marrow Response Criteria for patients with leukemia................................................................. 85 
11.2 
CNS Response Criteria ............................................................................................................................. 88 
11.3 
Response Criteria for Patients with Lymphoma .................................................................................... 89 
12.0 
ADVERSE EVENT REPORTING REQUIREMENTS .................................................................................. 91 
12.1 
Definitions .................................................................................................................................................. 91 
12.2 
Data Collection ........................................................................................................................................... 92 
12.3 
Reporting Serious Adverse Events or Serious Suspected Adverse Reactions.................................. 92 
12.4 
Institutional Reporting to the IRB ............................................................................................................ 94 
13.0 
DATA AND SAFETY MONITORING .......................................................................................................... 94 
13.1 
Data Submission ........................................................................................................................................ 94 
13.2 
Weekly Safety Review ............................................................................................................................... 95 
13.3 
Data Safety and Monitory Committee ...................................................................................................... 95 
14.0 
REFERENCES ............................................................................................................................................ 99 
15.0 
SAMPLE INFORMED CONSENT ............................................................................................................. 102 
APPENDIX I : PERFORMANCE STATUS SCALES/SCORES ........................................................................... 126 
APPENDIX II: CYP3A4 STRONG INDUCERS ..................................................................................................... 127 
APPENDIX III:  PHARMACOKINETIC WORKSHEET – T2017-002 IXAZOMIB STUDY PHASE 1 ................... 128 
APPENDIX IV: GUIDANCE FOR DETERMINING PREVIOUS CUMULATIVE ANTHRACYCLINE DOSE ....... 132 
APPENDIX V: EVALUATING MECHANISMS OF IXAZOMIB RESPONSE AND RESISTANCE IN LEUKEMIA; 
IDENTIFYING BIOMARKERS AND MECHANISMS OF CHEMOTHERAPY RESISTANCE ................ 133 
APPENDIX VI: PALATABILITY STUDY OF LIQUID ORAL IXAZOMIB (BLOCK 1 ONLY) ............................... 136 
APPENDIX VII: NEUROLOGICAL EXAM ............................................................................................................ 138 
 
 

 
 
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Changes from Previous Version:    ☐ N/A 
Section(s) 
               Revisions Made 
Rationale 
2.4.1 
• 
Removed section 2.4.1 as it has 
been replaced with this Changes 
from Previous Version table 
• 
Update 
6.1.4 
• 
Updated Toxicity/Adverse Events 
to reflect recent updates in the 
Ixazomib Investigator’s Brochure 
edition 15 
• 
Update 
15.0 
• 
Updated Potential Discomforts and 
Risks of Ixazomib to reflect new 
risk of bronchitis as stated in the 
Ixazomib Investigator’s Brochure 
edition 15 
• 
Update 
 
 
STUDY COMMITTEE 
 
STUDY CHAIR 
Terzah Horton, MD, PhD 
Texas Children’s Cancer Center, Baylor College of 
Medicine 
Phone: 832-824-4269 
Email: tmhorton@txch.org 
PHARMACIST STUDY COMMITTEE MEMBER 
Teresa Rushing, PharmD, BCPS, BCOP 
Children’s Hospital Los Angeles 
Phone:  323-361-4791 
Email: TRushing@chla.usc.edu  
STUDY VICE CHAIR 
Eric Schafer, MD, MHS 
Texas Children’s Cancer Center, Baylor College of 
Medicine 
Phone: 832-822-4242 
Email: esschafe@tsch.org 
TACL OPERATIONS 
Clinical Research Coordinator 
Phone: 323-361-5132 
FAX: (323) 361-4505 
Email: tacl@chla.usc.edu 
STUDY STATISTICIAN 
Yueh-Yun Chi, PhD 
Phone: 323-361-8582 
Email: ychi@chla.usc.edu 
 
Jemily Malvar, MS 
Phone : 323-361-8720 
Email : jmalvar@chla.usc.edu  
STUDY SUPPORTIVE  CHAIR  
Reuven Schore, MD 
Children’s National Medical Center 
Phone: 202-476-5875 
Email: RSchore@childrensnational.org  
 
PHYSICIAN STUDY COMMITTEE MEMBER 
Andrew Doan, MD 
Children’s Hospital Los Angeles 
Phone: 323-361-6497 
Email: andoan@chla.usc.edu 
PHYSICIAN STUDY COMMITTEE MEMBER 
Holly Pacenta, MD 
Cook Children’s Medical Center 
Phone: 682-885-4845 
Email: Holly.Pacenta@cookchildrens.org 
 
 

 
 
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STUDY SCHEMA 
 
 
 
 
 
 
Bone Marrow Evaluation: pre-study (all patients); end of block 1 – all leukemia patients and only lymphoma 
patients whose MRD was positive at the study entry; end of block 2 – all patients with bone marrow disease 
(including positive MRD) at end of block 1. 
PK Studies: Phase 1: Two mL blood samples will be collected at different time points on Days 1 and 11 in block 1. 
Phase 2: Sparse PK sampling will be conducted on Days 1, 8, and 11 in block 1 and Days 1, 15, and 18 in block 2. 
The PK sampling schedule is listed in protocol section 8.3. *indicates PK samples collected only in phase 2. 
PD Studies: Block 1, Day 1 – Five mL blood sample at 3 time points: prior to start of chemotherapy, at 4-6 hours 
and 24 hours following the first ixazomib dose for patients over 12 kg. If under 12 kg, three mL blood samples drawn 
at 2 time points: prior to start of chemotherapy and 4-6 hours after the first ixazomib dose.  
*indicates that block 2 therapy is not required for patients who achieve CR/CR MRD-/ CRi after block 1 therapy at 
their assigned dose level. These patients will have the option of continuing with block 2 therapy, moving directly 
on to the maintenance cycle, or going off protocol therapy. Any patients who have PR/SD will continue with block 
2 therapy.  
 
 

 
 
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1.0 
GOALS AND OBJECTIVES 
 
1.1 
Primary Objectives for Phase 1 
 
1.1.1 
Determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of PO 
ixazomib administered in conjunction with block 1 re-induction chemotherapy in children with 
relapsed/refractory ALL or lymphoblastic lymphoma (LLy) 
1.1.2 
Define and describe the toxicities of PO ixazomib in combination with block 1 re-induction 
chemotherapy in children with relapsed/refractory ALL or LLy 
1.1.3 
Characterize the pharmacokinetics (PK) of PO ixazomib in combination with block 1 re-induction 
chemotherapy in children with relapsed/refractory ALL or LLy 
 
1.2 
Primary Objective for Phase 2 
 
1.2.1 
Estimate the rate of overall response (CR + CR MRD- and CR + CR MRD- + CRi) after block 1 re-
induction chemotherapy in patients with multiply relapsed/refractory ALL or LLy 
 
1.3 
Secondary Objective 
 
1.3.1 
Describe toxicities occurring in patients receiving PO ixazomib with block 2 re-induction 
chemotherapy after achieving CR/CR MRD-/CRi with PO ixazomib + VXLD 
1.3.2 
Assess the palatability and acceptability of the liquid oral ixazomib in children with multiply 
relapsed/refractory ALL or LLy 
 
1.4  
Exploratory Objectives 
 
1.4.1 
Evaluate the pharmacodynamic (PD) properties of ixazomib, including determination of 
proteasome activity and effects of proteasome inhibition on cell stress proteins including the 
unfolded protein response 
1.4.2 
Assess the tolerability of ixazomib in combination with maintenance chemotherapy 
1.4.3 
Describe the rate of CR + CR MRD- and CR +CR/MRD- + CRi after block 2 re-induction 
chemotherapy 
1.4.4  
Describe EFS and OS at 4 months and 2 years in both phase I and 2 cohorts of patients 
1.4.5 
Describe the proportion of the subjects with ALL who achieve MRD status < 10-3 and < 10-4 by flow 
cytometry after block 1 and block 2 re-induction chemotherapy 
 
 
 

 
 
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2.0 
BACKGROUND 
 
2.1 
Introduction and Rationale for Development 
 
Despite ongoing progress in improving event-free survival (EFS) for patients with acute lymphoblastic 
leukemia (ALL),1,2 nearly 15–20% children will relapse. Outcomes after relapse have not changed in 20 
years and remain poor despite intensive chemotherapy and hematopoietic stem cell transplant.3   
 
In multiple studies, bortezomib, a proteasome inhibitor, has shown the ability to potentiate the anti-tumor 
effects of standard cytotoxic chemotherapy in childhood leukemia.4 Currently, another proteasome inhibitor, 
carfilzomib, is being tested in combination with chemotherapy by TACL (NCT02303821). Ixazomib is a new 
proteasome inhibitor, with both intravenous (IV) and oral (PO) formulations, that has been approved by the 
FDA to treat patients with multiple myeloma (MM).5 Similar to bortezomib, ixazomib selectively inhibits the 
β5 site of the 20S proteasome and also demonstrates synergistic activity with dexamethasone and 
doxorubicin in multiple myeloma.6 In preclinical studies, ixazomib has shown increased potency and 
superior efficacy over bortezomib because it has a shorter proteasome dissociation half-life that leads to a 
higher tumor-to-blood ratio of proteasome inhibition.7-9  
 
The advantage of ixazomib over either bortezomib or carfilzomib is the PO formulation. Currently, no other 
oral proteasome inhibitor is approved. With the development of new promising immunotherapies (CD19 
CAR T-cells, blinatumomab, inotuzumab, etc.) in pediatric ALL, the best use for ixazomib in childhood 
leukemia would be as a PO formulation to intensify maintenance therapy in a subset of newly diagnosed 
high risk patients in order to improve outcome. This study provides a unique opportunity to utilize an oral 
formulation of ixazomib as part of a multi-agent re-induction regimen and optional maintenance 
chemotherapy for patients who have achieved CR/CR MRD-/CRi.  
 
We propose a phase 1 study to estimate the maximum tolerated dose (MTD) of the PO formulation, followed 
by a screening phase 2 study to investigate the efficacy of ixazomib in combination with chemotherapy in 
children with relapsed ALL and LLy. The single arm, screening phase 2 design will allow us to use a minimal 
number of patients to obtain preliminary information about treatment efficacy. After the block 1 
chemotherapy if CR/CR MRD-/CRi is achieved, patients will have the option to receive block 2 intensive 
chemotherapy or maintenance chemotherapy with ixazomib. In addition, we will include a palatability study 
of oral formulation of ixazomib. Infants and patients with Down syndrome (DS) will be included in this study. 
However, since they have their unique biology and toxicity profile, infants and DS patients will be in a 
different stratum and not be included in the primary DLT or response evaluation.  
 
Discovering a safe and tolerable dose of ixazomib in a PO formulation and the preliminary efficacy data will 
significantly increase the possibility of ixazomib moving forward in frontline pediatric treatment protocols in 
both intense chemotherapy courses and maintenance courses. 
 
 
2.2 
Introduction of Ixazomib 
 
 
2.2.1 
Ubiquitin-proteasome pathway  
 
The ubiquitin-proteasome pathway (UPP) is essential for the degradation of most short-lived and 
many long-lived intracellular proteins in eukaryotic cells.10 Proteasome inhibition stabilizes many 
cell cycle-dependent proteins that are overexpressed in leukemia cells.11 Previous studies have 
shown that proteasome inhibition may sensitize malignant hematologic cells to apoptosis induced 
by both radiation and chemotherapy.12,13 Apoptosis following proteasome inhibition is seen in 
leukemia cell lines4,14,15 as well as in primary ALL lymphoblasts4 and mouse leukemia xenografts16 
but not in normal hematopoietic progenitors.17,18 Important regulatory proteins affected by inhibition 

 
 
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of the UPP system include NF-κB, p53, Bax and other cell regulatory proteins such as the cycle-
independent kinase inhibitors p27 and p21.19 It is believed that proteasome inhibition alters the ratio 
of pro-apoptotic and anti-apoptotic proteins within the cell, resulting in the increase in the sensitivity 
to apoptosis.20 
 
In addition to constitutive proteasomes, which are responsible for the degradation of major cellular 
proteins, immune cells also express immunoproteasomes, which are responsible for processing 
antigens for presentation on major histocompatibility class (MHC) 1 molecules. In general, cells 
with a hematologic origin (i.e., leukemic cells) express higher amounts of immunoproteasomes 
compared to constitutive proteasomes.21 The immunoproteasome catalytic subunits β1i, β2i, and 
β5i replace the β1, β2, and β5 subunits of the constitutive proteasome.21 Proteasome inhibitors 
have demonstrated different selectivity for these catalytic subunits.9 Data indicates that sensitivity 
to proteasome inhibition is related to the ratio of immunoproteasomes to proteasomes in leukemia 
cells.22  
 
2.2.2 
Overview of Ixazomib  
 
Ixazomib is a peptide boronic acid proteasome inhibitor with both intravenous (IV) and oral (PO) 
formulations. In 2015, ixazomib was approved by the FDA for the treatment of patients with MM 
who have received at least 1 prior therapy. It was granted conditional marketing authorization in 
the EU for the same indication in 2016.  
 
Like bortezomib, ixazomib selectively and reversibly inhibits the β5c and β5i subunit of the 20S 
proteasome. It has been tested in a panel of > 70 hematologic cell lines, which included 5 pediatric 
ALL cell lines. The IC50 of ixazomib in pediatric ALL lines ranged from 14-37 nM at 48 hours (Study 
E0246-U1616, manuscript in preparation). These results are similar to those reported for 
bortezomib sensitivity in pediatric ALL lines.4,16 In addition, ixazomib has shown antitumor activity 
in a pediatric T-ALL derived xenograft model.23  
 
In vitro, ixazomib showed a shorter proteasome dissociation half-life and greater reversibility of 
proteasome inhibition compared with bortezomib.7 The difference in reversibility also applies to the 
in vivo setting. In mice, the ixazomib MTD is higher than that for bortezomib and the compounds 
show different ratios of blood-to-tissue distribution. When dosed at their respective MTDs, ixazomib 
demonstrates higher levels of proteasome inhibition in xenograft tumors and lower levels of blood 
proteasome inhibition than does bortezomib.  Furthermore, this difference in blood-to-tumor ratio 
corresponded with improved antitumor activity of ixazomib in several xenograft models.7-9 These 
pharmacologic differences warrant the investigation of ixazomib in pediatric ALL.  
 
2.2.3 
Adult studies 
 
 
Ixazomib has been or is currently being evaluated in a total of 23 clinical studies in adults with 
relapsed/refractory and newly diagnosed MM, lymphoma, and amyloidosis as follows:  
 
• 
Eleven completed phase 1 clinical studies investigating the PK, PD, safety, and tolerability 
of ixazomib; relative bioavailability and food effect; absorption, distribution, metabolism, 
and excretion; the effect of renal and hepatic impairment on ixazomib PK, and drug-drug 
interactions. 
• 
Five phase 2 (including phase 1/2) studies, of which 2 are completed and 3 are ongoing 
• 
Seven phase 3 studies, including 1 completed in patients with MM and 6 ongoing (5 in MM, 
and 1 in amyloidosis) 
 

 
 
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To date, no clinical studies have been conducted with ixazomib in patients with pediatric ALL. 
However, there have been 3 investigator-initiated studies of ixazomib in adult patients with ALL.  
 
Phase 1 study of ixazomib as a single agent in adults. Adult phase 1 studies have demonstrated 
that the MTD of ixazomib is schedule and formulation dependent. When administered twice-weekly 
for two weeks in a 21 day cycle, the MTD of the IV and the PO formulation is slightly different. The 
drug related adverse events (AEs) and half-life between the two formulations are similar. Details 
are presented in Table 1 below.  
 
 
Table 1: MTD and Dose limiting toxicity (DLT) of ixazomib in adult patients 
Reference 
Smith et al., 201524 
Richardson et al., 201425 
Formulation 
IV 
PO  
Disease 
Non-hematologic malignancies24 
Multiple myeloma 
MTD 
1.75 mg/m2 
2.0 mg/m2 
DLT 
5 out of 22 
• 
Gr 3 rash (1.0 mg/m2, 1.76 
mg/m2) in two patients 
• 
Gr 4 thrombocytopenia (2.34 
mg/m2) 
• 
Gr 3 thrombocytopenia with 
Gr 1 rectal hemorrhage (2.34 
mg/m2) 
• 
Gr 3 acute renal failure (2.34 
mg/m2) 
2 out of 26 
• 
Gr 3 rash (2.34 mg/m2) 
• 
Gr 4 thrombocytopenia 
(2.34 mg/m2) 
 
≥ 5% Drug related Gr ≥ 3 
AEs 
 
 
     Thrombocytopenia 
23% 
37% 
     Neutropenia 
N/A 
17% 
     Skin/subcutaneous  
16% 
8% 
     Fatigue 
9% 
7% 
     Dehydration 
6% 
N/A 
     Lymphopenia 
5% 
5% 
 
Adult phase 1/2 studies of Ixazomib in combination with other chemotherapy agents. Kumar et al. 
used PO ixazomib in combination with lenalidomide and dexamethasone in 65 adult patients with 
newly diagnosed MM.26 Ixazomib was given orally on days 1, 8, and 15, lenalidomide was given 
daily for 21 days, and dexamethasone at 40mg was given weekly on a 28 day cycle. The RP2D of 
ixazomib was 2.2 mg/m2. Gr 3 or higher AEs related to any drug were reported in 63% patients, 
including skin and subcutaneous tissue disorders (17%), neutropenia (12%), thrombocytopenia 
(8%), and drug-related peripheral neuropathy (6%).  
 
 
2.2.4 
Pediatric Studies 
 
 
 
 
 
No pediatric studies have been performed.  
 
2.3  
Chemotherapy Backbone Rationale 
 
The encouraging data of bortezomib in pediatric ALL and the improved proteasome inhibition by ixazomib 
lead us to consider a phase 1/2 study using ixazomib in combination chemotherapy in children with 
relapsed/refractory ALL. UK ALL R3 block 1 chemotherapy (vincristine, dexamethasone, asparaginase, 
and mitoxantrone) has been widely used to treat children with relapsed/refractory ALL/LL.27 However, when 

 
 
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it was used in the new agent combination trials in TACL and COG, severe adverse events including life 
threatening infections were identified.28,29 Therefore, in this trial, we will use the VXLD backbone (vincristine, 
dexamethasone, asparaginase, doxorubicin), an effective backbone widely used in ALL therapy with a more 
favorable toxicity profile. This is the similar backbone used in the TACL 2005-003 study as well as the COG 
AALL07P1 study.30,31 
 
Infants are included in this study. In previous COG infant study AALL0631, excessive life-threatening 
infection is associated with induction chemotherapy, which resulted in dose reduction.32 In this protocol, the 
cytotoxic chemotherapies will be reduced to 80% in infants ≥ 6 months and < 1 year of age; there is further 
dose reduction of 12% in infants < 6 months of age (total dose 68% of dose in children). This is consistent 
with the COG AALL0631 study and the new COG infant AALL15P1.  
 
 
If patients achieve CR/CR MRD-/CRi after block 1, they will have the option of continuing with block 2 
therapy, or moving directly on to the maintenance cycle for up to 4 cycles, or going off protocol therapy. If 
patients have PR/SD, they will continue with block 2 therapy. After completion of block 2 therapy, subjects 
with CR/CR MRD-/CRi/PR can participate in the optional maintenance cycle for up to 4 cycles. 
 
The block 2 chemotherapy backbone is based on the UK ALL R3 regimen’s block 2 (consolidation) 
schedule27. This will be done to obtain further information on toxicity and estimate whether additional 
ixazomib can further improve the CR + CR MRD- rate. This block is commonly used in the treatment of 
relapsed ALL and had been safely combined with bortezomib in a similar to block 2 therapy in the COG 
AALL07P1 study.9,10 The toxicities defining the DLT will only be evaluable during the block 1 therapy, but 
severe toxicities will be further assessed in block 2 to determine if ixazomib is tolerable with UK ALL R3 
consolidation.  
 
2.4 
Ixazomib Dosing and Study Design Rationale 
 
PO formulation of ixazomib will be used in this study. Since ALL is a rapidly growing and aggressive 
disease, we will use bi-weekly dosing of ixazomib, administering on days 1, 4, 8, & 11 of block 1, and days 
1, 4, 8, 15 &18 of block 2 therapy in order to better achieve prolonged proteasome inhibition. This dosing 
schedule was used in TACL 2005-00330,31 and COG AALL1231 (NCT02112916) using bortezomib in 
combination with chemotherapy. In the optional maintenance block, ixazomib will be given in a weekly basis 
(three weeks on, one week off) on days 1, 8, and 15.  
 
In the phase 1 portion of the study, we will include any patients with relapsed ALL or LLy. A 3+3 design33 
will be used to determine a MTD and/or RP2D for the PO ixazomib in combination with VXLD. For patients 
without Down Syndrome (DS) and no younger than 1 year of age (the primary stratum), the starting dose 
will be 80% (1.6 mg/m2/day) of the adult twice weekly PO MTD (2mg/m2/day),25 and one dose level increase 
to the adult MTD. PK, PD, and toxicity information will be collected. 
 
If an RP2D is established, a phase 2 expansion will be performed at the RP2D. Patients satisfying the 
phase 2 eligibility criteria (i.e., patients with B-cell ALL/LLy who have failed one or more therapeutic 
attempts and any patients with relapsed T-cell ALL/LLy) will be enrolled and treated at the RP2D until 18 
response evaluable patients have been treated at the RP2D or until a total of 24 evaluable patients overall 
are enrolled (the total of DLT evaluable patients during phase 1 and response evaluable patients during the 
phase 2 expansion), whichever occurs first. Response-evaluable patients treated at the PO RP2D in phase 
1 will be included in the phase 2 analysis.Infants (< 1 year of age) and patients with DS will be included in 
phase 1 and 2 of the study. Due to the unique biology and toxicity profile of those patients, they will be in a 
separate stratum and not be included in the DLT or response evaluation for the primary stratum. To ensure 
the safety of these patients, they will be entered at one dose level below a determined safe dose level in 
older, non-DS children, and will follow a 3+3 dose escalation design for safety, although there is no 

 
 
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expectation that this dose escalation will be completed.  At no time will the dose given to infants or DS 
patients exceed the currently established safe dose in non-infant/non-DS patients. For the Phase 2 portion 
of the study, DS patients will be enrolled at 1.6 mg/m2/day, which is one dose level lower than the RP2D of 
ixazomib in non-DS patients (2 mg/m2/day).  These patients will receive leucovorin rescue after intrathecal 
methotrexate or triple intrathecal chemotherapy. We estimate there will be very few infants and Down 
syndrome patients enrolled in the study. 
 
 
2.5  
Correlative Biology Studies   
 
The goal of these correlative studies is to determine if changes in proteasome function or cell stress protein 
expression patterns can predict ixazomib response and drug resistance. The primary aims of these 
correlative studies are: (1) to delineate the mechanisms of ixazomib action and resistance, and to determine 
if proteasome alterations correlate with clinical response; and (2) to determine if protein cell stress pathways 
or other signal transduction pathways identified using reverse phase protein lysate arrays (RPPA) predict 
response or resistance for the ixazomib + chemotherapy regimen.  
 
2.5.1 
Evaluating Mechanisms of Ixazomib Response and Mechanisms of Ixazomib Resistance.  
 
The central hypothesis is that activation of the unfolded protein response (UPR), or induction of 
other protein cell stress pathways, can predict chemotherapy response, and ultimately clinical 
outcome. Work from the Cloos and Horton labs have shown that response to proteasome inhibitor 
therapy is increased in patients that have a high immunoproteasome to constitutive proteasome 
ratio, both in primary cells and in children treated with the proteasome inhibitor bortezomib.22,34 
Additional details are included in Section 7.2 and Section 8. 
 
2.5.2 
Evaluation of Protein Expression and Unfolded Protein Response 
 
Using reverse-phase protein lysate array (RPPA) technology we can globally assess the effects of 
targeted anti-cancer agents on the proteome by studying protein expression and phosphorylation 
of over 200 proteins using as few as 200,000 leukemia cells. While previous work in adult AML has 
demonstrated that functional proteomic profiling can predict treatment response and survival.35  
This correlation has not yet been made in pediatrics.  Recent data from the Horton and Kornblau 
labs has shown that RPPA data correlates with leukemia subtype and vital status (submitted 
manuscripts).36-38 RPPA signals following bortezomib with chemotherapy treatment and clinical 
response are being assessed in two ongoing phase 3 COG clinical trials. We hypothesize that 
functional proteomic profiling and analysis of the unfolded protein response (UPR) will allow us to 
1) further characterize the protein pathways leukemia cell response to ixazomib + chemotherapy 
treatment, and 2) help to identify biomarkers of either clinical response or therapy resistance. 
Potential targets include the NF-κB pathway and pathways controlled by the ubiquitin-proteasome 
pathway which regulates how rapidly leukemia cells multiply, die or mature.39 Proteasome inhibitors 
are known to block NF-κB activation, and to trigger the UPR, suggesting that this may be a means 
of selectively enhancing ixazomib targeting.  
 
2.6  
Palatability of Oral Ixazomib Study 
 
Patient acceptance of medication (acceptability) can be defined as the overall ability of the patient to use 
the medicine as intended. Acceptability of an oral medication is an important consideration in patients, 
especially children, because it is likely to have a significant impact on the patient’s adherence.40,41 It is even 
more critical for a medication that is intended to be administered chronically (such as in ALL maintenance 
therapy). Palatability is one of the main elements of patient acceptability and included tablet/capsule size, 

 
 
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physical burden of dose (number of pills or dosing volume), and the appearance, smell, taste, after-taste 
and texture of the oral preparations.42 It is determined by the characteristics of the user and the medication. 
For pediatric drug development, it is important to consider palatability at the early stage of clinical trials to 
allow time for pharmaceutical companies to optimize children-friendly formulation. Palatability tests have 
been performed in several pediatric medications using different measurement scales.42 In this study, we 
will incorporate a questionnaire with questions related to the taste and smell using a 5-point facial hedonic 
scale. This scale allows for indication of preference by pointing at a pictorial scale of facial expressions that 
has been commonly used in palatability studies.42,43  
 
3.0 
PATIENT ELIGIBILITY CRITERIA AND ENROLLMENT 
 
3.1 
Patient Reservation/Registration 
 
Investigators should consult the Member’s Section of the TACL web site to determine if the study is currently 
open for accrual before approaching patients for participation.  Before enrolling a patient on the study, the 
patient must first be registered with TACL and a reservation must be made with the TACL Operations 
Center.  In order to register the patient and make a reservation, you may call (323) 361-5132 or send an 
email to tacl@chla.usc.edu with the following information (if sending an email, please put “Reservation 
Request” in the subject line): 
 
• Study for which you want to make a reservation:  
• Name of the institution requesting reservation with contact information 
• Patient Initials (Last, First) 
• Patient month and year of birth 
 
Each patient will be assigned a unique TACL registration number.  If an enrollment slot is available, you will 
receive an email from the TACL Operations Center to confirm your reservation.  All reservations are good 
for 5 full calendar days starting with the next full day after the day the reservation is made. It is allowable to 
enroll a patient that has received IT ARA-C, IT MTX or triple IT therapy within 7 days of enrollment as part 
of their evaluation to diagnose disease relapse.  
 
3.2 
Enrollment  
 
An enrollment guide is available on the web site (https://tacl.chla.usc.edu). Patients must be enrolled prior to 
beginning treatment on this study. Patients will be enrolled by contacting the TACL Operations Center Monday 
through Friday, 8:30 am – 5:00 pm Pacific Time at (323) 361-5132, except holidays.  You will be asked to 
complete the eligibility form prior to making your call.  In addition, the supporting documentation, which 
confirms eligibility, should be faxed or emailed to the TACL Operations Office.   
 
Each patient will be assigned a study subject number. An email confirming eligibility and assigned dose level 
will be sent to the treating facility, Study Chair, and Study Vice-Chair. No patient should be enrolled or started 
on protocol treatment until the enrollment confirmation e-mail has been received from the TACL Operations 
Office.  Enrolled patients should begin treatment within 3 calendar days of study enrollment.   
 
 Contact Person:  
TACL Operations Center 
 
 
 
 
 
Children’s Hospital Los Angeles 
 
 
 
 
 
4650 Sunset Blvd, MS #54 
 
 
 
 
 
Los Angeles, CA 90027 
 
 
 
 
 
Phone: (323) 361-5132 
 
 
 
 
 
FAX: (323) 361-5405 

 
 
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Email: tacl@chla.usc.edu 
 
3.3 
Inclusion Eligibility Criteria  
 
The eligibility criteria listed below are interpreted literally and cannot be waived. 
 
3.3.1 
Age 
Patients must be < 22 years of age at the time of enrollment*.  
a) Phase 1 – Initial enrollment will be restricted to patients < 18 years of age until 9 such patients 
are enrolled  
 
b) Phase 2 – Initial enrollment will be restricted to patients < 18 years of age until 6 such patients 
are enrolled (applies to Stratum A only) 
*Change made for clarification in Phase 2 that patients 21 years of age prior to their 22nd birthday 
are eligible 
 
3.3.2 
Diagnosis 
Patients must have a diagnosis of relapsed/refractory ALL or LLy with or without extramedullary 
disease (including CNS2 and CNS3). Patient with mixed phenotype ALL or mature B (Burkitt-like) 
leukemia are not eligible.  
  
a) Patients with ALL must have ≥ 5% blasts by morphology.  
 
b) Patients with LLy must have measurable disease documented by clinical, radiologic or 
histologic criteria (see Section 11) 
 
3.3.3 
Performance Level 
Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥ 50% for patients ≤ 16 years of age. 
(See Appendix I for Performance Scales) 
 
3.3.4 
Prior Therapy 
A. Prior therapeutic attempts  
• 
Phase 1 – Any patients with relapsed/refractory ALL or LLy   
• 
Phase 2  
1. B-cell ALL/LLy: all patients must have failed one or more therapeutic attempts. 
2. T-cell ALL/LLy: all patients must have failed one or more therapeutic attempts. 
B. Recent prior chemotherapy 
Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, 
immunotherapy, or radiotherapy prior to entering this study. 
o 
Myelosuppressive chemotherapy: At least 14 days must have elapsed since the 
completion of myelosuppressive therapy.  However patients may receive any of the 
following medications within 14 days without a “wash-out” period: Hydroxyurea – 
Hydroxyurea can be initiated and/or continued for up to 24 hours prior to the start of 
protocol therapy.  
o 
“Maintenance-style” therapy – Therapy including vincristine (dosed a maximum of one-
time weekly), oral 6-mercaptopurine, oral methotrexate (dosed a maximum of one-time 
weekly), dexamethasone (dosed at ≤ 3 mg*/m2/dose twice daily), and prednisone (dosed 
at ≤ 20 mg*/m2/dose twice daily) can be initiated and/or continued for up to 24 hours prior 
to the start of protocol therapy. 
*Doses can be rounded to adjust for pill size 

 
 
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C. Hematopoietic stem cell transplant: Patients who have experienced their relapse after a 
HSCT are eligible, provided they have no evidence of acute or chronic Graft-versus-Host 
Disease (GVHD), are not receiving GVHD prophylaxis or treatment, and are at least 90 days 
post-transplant at the time of enrollment. 
 
D. Hematopoietic growth factors: It must have been at least 7 days since the completion of 
therapy with G-CSF or other growth factors at the time of enrollment. It must have been at least 
14 days since the completion of therapy with long-acting filgrastim (pegfilgrastim or biosimilar)  
 
E. Biologic (anti-neoplastic agent):  
 
At least 7 days since the last dose of a biologic agent. 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. The duration of this interval must be 
discussed with the study chair 
 
• 
Monoclonal antibodies: At least 3 half-lives of the antibody or 21 days (whichever is 
shorter) must have elapsed after the last dose of monoclonal antibody. (i.e., 
blinatumomab half-life = 6 hours,44 therefore wash-out is 18 hours; inotuzumab half-
life = 37 days therefore wash-out is 21 days; rituximab half-life = 66 days, therefore 
wash-out is 21 days).  If steroids are being used to modify immune-related adverse 
events of antibody therapy, at least 14 days must have elapsed since the last dose of 
corticosteroid. 
 
• 
Immunotherapy: At least 30 days after the completion of any type of immunotherapy, 
e.g., tumor vaccines, CAR T cells.  If steroids are being used to modify immune-related 
adverse events of immunotherapy, at least 14 days must have elapsed since the last 
dose of corticosteroid. 
 
F. XRT: Craniospinal XRT is prohibited during protocol therapy. No washout period is necessary 
for radiation given to any extramedullary site other than CNS; ≥90 days must have elapsed if 
prior total body irradiation (TBI) or craniospinal XRT. 
 
G. Anthracyclines: Patients must have had a lifetime exposure of <400 mg/m2 of doxorubicin 
equivalents of anthracyclines (anthracycline equivalence to doxorubicin conversion, see 
Appendix IV). 
 
H. Proteasome inhibitors: Patients with a prior exposure to proteasome inhibitors (e.g., 
bortezomib, carfilzomib) are eligible as long as the patient demonstrated at least a partial 
response (see Section 11) to a proteasome inhibitor with chemotherapy combination.  This 
criteria only applies to the Phase 2 portion of the study. 
  
3.3.5 
Renal and hepatic function 
Patients must have adequate renal and hepatic functions as indicated by the following laboratory 
values: 
 
A. Adequate renal function defined as: Patient must have a calculated creatinine clearance or 
radioisotope GFR ≥ 70ml/min/1.73m2 OR a normal serum creatinine based on age/gender in 
the chart below: 

 
 
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Age 
 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 month to < 6 months 
0.4 
0.4 
6 months to < 1 year 
0.5 
0.5 
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. 
 
B. Adequate Liver Function Defined as: Direct bilirubin ≤ 1.5 x upper limit of normal (ULN) for 
age or normal (except in the presence of Gilbert’s syndrome), AND alanine transaminase (ALT) 
≤ 5 x ULN for age. The hepatic requirements are waived for patients with known or suspected 
liver involvement by leukemia or lymphoma. This must be reviewed by and approved by the study 
chair or vice chair. 
 
 
3.3.6 
Adequate Cardiac Function Defined as: Shortening fraction of ≥ 27% by echocardiogram, 
OR ejection fraction of  ≥ 50% by radionuclide angiogram (MUGA). 
 
3.3.7 
Reproductive Function 
A. Female patients of childbearing potential must have a negative urine or serum pregnancy test 
confirmed within 2 weeks prior to enrollment. 
 
B. Female patients with infants must agree not to breastfeed their infants while on this study. 
 
C. Male and female patients of child-bearing potential must agree to use an effective method of 
contraception approved by the investigator during the study and for a minimum of 6 months 
after study treatment. 
 
3.3.8 
Informed Consent 
Patients and/or their parents or legal guardians must be capable of understanding the 
investigational nature, potential risks and benefits of the study. All patients and/or their parents or 
legal guardians must sign a written informed consent. Age appropriate assent will be obtained per 
institutional guidelines. To allow non-English speaking patients to participate in this study, bilingual 
health services will be provided in the appropriate language when feasible. 
 
3.3.9 
Protocol Approval 
All institutional, FDA, and OHRP requirements for human studies must be met. 
 
 
3.4 
Exclusion Eligibility Criteria 
 

 
 
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Patients will be excluded if they meet any of the following criteria 
 
 
3.4.1  
Patients will be excluded if they have isolated CNS or testicular disease. 
 
3.4.2 
Patients will be excluded if they have ≥ grade 2 peripheral sensory or motor neuropathy (defined 
by the Modified “Balis” Pediatric Scale of Pediatric Neuropathies) at the time of enrollment (see 
section 4.7.1.1). 
 
3.4.3 
Patients will be excluded if they have a known allergy or intolerance to any of the drugs used in the 
study – except for Pegaspargase or Calaspargase for which asparaginase Erwinia chrysanthemi 
(recombinant)-rywn (Rylaze®) or (if available) crisantaspase (Erwinase®), may be substituted for 
allergy to Pegaspargase or Calaspargase 
 
3.4.4   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. 
 
3.4.5 
Patients will be excluded if there is a plan to administer non-protocol chemotherapy, radiation 
therapy, or immunotherapy during the study period. 
 
3.4.6  
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. 
 
3.4.7  
Patients with DNA fragility syndromes (such as Fanconi anemia, Bloom syndrome) are excluded. 
 
3.4.8 
Patients will be excluded if they have had a lifetime exposure of ≥400 mg/m2 doxorubicin 
equivalents of anthracyclines (anthracycline equivalence to doxorubicin conversion, see Appendix 
IV). 
 
3.4.9  
Concomitant medications 
3.4.9.1 Investigational drugs: Patients currently receiving another investigational drug are not 
eligible. 
 
3.4.9.2 Anti-GVHD agents post-transplant: patients who are receiving cyclosporine, tacrolimus or 
other agents to prevent graft-versus-host disease post hematopoietic stem cell transplant 
are not eligible. 
 
3.4.9.3 CYP3A4 agents: patients who are currently receiving drugs that are strong inducers of 
CYP3A4 are not eligible. See Appendix II for a list of agents which fall into this category. 
 
 
3.4.10 Patients with Ph+ALL and Ph-like ALL who are currently receiving TKI therapy 
 
 
4.0 
TREATMENT PROGRAM 
 
The following sections detail the treatment plan for each block of therapy. Please refer to the Drug 
Information section for additional administration guidelines. Treatment should begin within 3 calendar days 
following enrollment.   
 

 
 
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Phase 1 – PO For ixazomib dose escalation details see section 4.5. Patient will receive the same dose in 
block 1, block 2, and optional maintenance therapy.   
 
Phase 2 – Both phase 1 and 2 will use the same treatment program. 
 
Timing of protocol therapy administration, toxicity and response assessments, and surgical interventions 
are based on schedules derived from the experimental design or on established standards of care.  With 
the exception of the start date, minor unavoidable departures (up to 72 hours) from protocol directed 
therapy and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable (except when 
explicitly prohibited within the protocol). 
 
4.1 
Block 1 (35 days)  
 
Use treatment dose based on age on day of administration.  For ixazomib, dose should be based on Day 
1 BSA/weight (- 3 days) and remain consistent throughout a cycle unless the patient’s BSA changes by 
more than 10% at which point the dose should be adjusted to meet the new BSA 
 
Please see Section 4.7 for ixazomib dose modifications for ixazomib-related toxicities.   
 
• 
 
DLT will be assessed during block 1 only (Refer to Section 4.6).  
 
Days 
1 
2 
4 
8 
9 
11 
14 
15 
16 
18 
22 
23 
29 
30 
Ixazomib** 
● 
 
● 
● 
 
● 
 
 
 
 
 
 
BM 
 
Vincristine IV (1.5mg/m2) 
● 
 
 
● 
 
 
 
● 
 
 
● 
 
 
Dexamethasone IV/PO (10mg/m2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pegaspargase IV/IM (2500 IU/m2)√ ± 
 
● 
 
 
 
 
 
● 
 
 
 
 
 
OR Calaspargase IV (2500 IU/m2) √ ± 
 
● 
 
 
 
 
 
 
 
 
 
 
 
Doxorubicin (60mg/m2) 
● 
 
 
 
 
 
 
 
 
 
 
 
 
Initial IT chemotherapy* 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
CNS 1/2: IT Methotrexate 
 
 
 
 
 
 
 
● 
 
 
 
 
●‡ 
 
CNS 3: ITT# 
 
 
 
● 
 
 
 
● 
 
 
● 
 
●‡ 
 
Leucovorin IV/PO (5 mg/m2 at hr 24 
and 30 post-ITs^ 
 
● 
 
 
● 
 
 
 
● 
 
 
● 
 
● 
Dose for patient < 1 years of age see below 
IT – intrathecal therapy; ITT – Triple IT 
√ Either Pegaspargase OR Calaspargase will be administered according to current approved labeling based 
on age and regional availability. Patients who start on either Pegaspargase or Calaspargase must continue 
the same treatment throughout the treatment cycle and are not to be used interchangeably.  Patients 
receiving Calaspargase will only receive one dose in this cycle 
± asparaginase Erwinia chrysanthemi (recombinant)-rywn Rylaze ®)OR crisantapase (Erwinase®) may be 
substituted for allergy to Pegaspargase OR Calaspargase. If reaction to Day 2 calaspargase requires 
Erwinia replacement, 2 courses of Erwinia (beginning at or around Day 2 and at or around Day 15) should 
be administered (i.e. 12 total Erwinia doses). See below. 
* Initial IT – age based dosing. May include MTX, ITT, or cytarabine. Patient may receive up to 7 days prior 
to initiation of the systemic chemotherapy.  
# ITT therapy for infants is described in detail below. 
‡ IT therapy assigned to be given on Day 29 may be moved such that it may be given at the time of the end 
of Block 1 bone marrow/disease evaluation. 
^For patients with DS only (based on dates when IT MTX or ITT given) 

 
 
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 Protocol Amendment #7 Version Date: 
 
19December2019 
16September2020 
11May2021 
24January2022 
26October2022 
20July2023 
07September2023 
 
**Timing of ixazomib 
• 
After administration of vincristine, doxorubicin, and IT (if applicable) 
 
Ixazomib  
Days  1, 4, 8, and 11. Note: at least 72 hours must have elapsed between doses 
Dose  Phase 1 – Assigned upon study entry.   
Phase 2 – PO formulation at RP2D (2 mg/m2 for non-DS patients ) Down syndrome patients 
will receive 1.6 mg/m2 
 
Vincristine: IV push over 1 minute or infusion via minibag as per institutional policy 
Days  1, 8, 15 and 22 
Dose:  ≥ 1 year: 1.5mg/m2/dose (maximum dose 2mg) 
 
≥ 6 months and < 1 year: 1.2mg/m2/dose   
 
< 6 months: 1mg/m2/dose   
 
Dexamethasone: PO or IV 
Days  1-14 
Dose:  ≥ 1 year: 10mg/m2/day, divided BID (i.e., 5mg/m2/dose, BID) 
≥ 6 months and < 1 year: 8mg/m2/day, divided BID (i.e., 4 mg/m2/dose, BID)  
 
< 6 months: 7mg/m2/day, divided BID (i.e., 3.5 mg/m2/dose, BID)   
 
Pegaspargase: IV over 1-2 hours or IM 
Days  2, 15 
Dose  ≥ 1 year: 2,500 International units (IU)/m2/dose 
 
≥ 6 months and < 1 year: 2,000 IU/m2/dose   
 
< 6 months: 1,750 IU/m2/dose   
OR 
 
Calaspargase: IV over 1-2 hours  
Day  
2 
Dose  ≥ 1 month and < 22 years of age: 2,500 International units (IU)/m2/dose 
 
Due to the pharmacokinetics and pharmacodynamics of Calaspargase, the half-life of Calaspargase 
asparagine depletion was significantly longer than that of Pegaspargase at conventional dosing (2500 
IU/m2)58,59 therefore patients receiving Calaspargase will only receive one dose in this cycle. 
If reaction to calaspargase requires Erwinia replacement, 2 courses of Erwinia (beginning at or around Day 
2 and at or around Day 15) should be administered (i.e. 12 total Erwinia doses). See below. 
 
NOTE: Obesity (defined as ≥ 95% BMI for age for patients < 20 y.o or BMI ≥30 for patients ≥ 20 y.o) has 
been linked to increased risk of toxicity in patients ≥ 10 years of age.  
• 
Dose capping at 3,750 units/dose (1 vial) per institutional policy is permissible in cases of 
baseline obesity.  
 
For severe allergic reaction, discontinue pegaspargase or calaspargase and substitute asparaginase 
Erwinia therapy. Asparaginase Erwinia therapy should begin within 72 hours of the pegaspargase or 
calaspargase reaction or sooner if possible. Either of the following asparaginase Erwinia formulations are 
permissible if available: asparaginase Erwinia chrysanthemi (recombinant)-rywn (Rylaze) or 
crisantaspase (Erwinase), Refer to prescribing information for dosing of asparaginase Erwinia 
chrysanthemi (recombinant)-rywn (Rylaze®) or crisantapase (Erwinase®) . Please note that the most 
current FDA approved dosing route and schedule of Rylaze® or Erwinase® should be followed at the 
time of administration.  If available and approved Crisantaspase (Erwinase®) should be dosed at the FDA 

 
 
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 Protocol Amendment #7 Version Date: 
 
19December2019 
16September2020 
11May2021 
24January2022 
26October2022 
20July2023 
07September2023 
approved dose of asparaginase 25,000 International Units/m2. .The number of doses of Erwinia should be 
based on pegaspargase replacement. That is: if a reaction to the Day 2 pegaspargase requires Erwinia 
repalacement, 12 total doses of Erwinia will be administered (6 dose for the Day 2 dose of pegaspargase 
and 6 doses for the Day 15 dose). If there is a reaction to the Day 15 pegaspargase which requires 
Erwinia replacement 6 doses will be administered.  If reaction to calaspargase requires Erwinia 
replacement, 2 courses of Erwinia (beginning at or around Day 2 and at or around Day 15) should be 
administered (i.e. 12 total Erwinia doses). 
Route of administration, dose schedule and total doses administered should be documented, as this 
could contribute to variability in PK data for ixazomib. 
 
Dosing guideline for  crisantapase (Erwinase®): 
≥ 1 year: 25,000 IU/m2/dose 
 
≥ 6 months and < 1 year: 20,000 IU/m2/dose   
 
< 6 months: 17,500 IU/m2/dose   
 
Dosing guideline for asparaginase Erwinia chrysanthemi (recombinant)-rywn (Rylaze®): 
Refer to current FDA product information for dosing Erwinia chrysanthemi (recombinant)-rywn 
(Rylaze®) at the time of product administration. 
 
Doxorubicin: IV over 15 minutes 
Day  
1 
Dose  ≥ 1 year: 60 mg/m2/dose 
≥ 6 months and < 1 year: 48 mg/m2/dose   
 
< 6 months: 42 mg/m2/dose   
 
Initial IT chemotherapy: 
Day 1, age-based dosing (see below). May include MTX, Triple IT, or cytarabine.  
 
IT Methotrexate: for CNS 1/2 patients only 
Days IT methotrexate given intrathecally to patients on days 15 and 29‡. 
Omit IT methotrexate on Day 1 of course 1 if patient received IT therapy within 7 days prior to 
study enrollment as part of diagnostic lumbar puncture procedure. 
‡IT therapy assigned to be given on Day 29 may be moved such that it may be given at the time 
of the end of Block 1 bone marrow/disease evaluation. 
 
 
Dose 
Defined by age (yrs.) 
– 
6 mg patients age < 1 
– 
8 mg for patients age 1-1.99 
– 
10 mg for patients age 2-2.99 
– 
12 mg for patients 3-8.99 years of age 
– 
15 mg for patients ≥9 years of age 
 
Triple IT: for CNS 3 patients only 
Days 
 8, 15, 22, and 29‡ 
Dose  Defined by age (yrs.) 
Age (yrs.):  
Dose Methotrexate (MTX)  
Hydrocortisone (HC) 
Cytarabine (ARAC) 
< 1 years 
MTX: 6mg 
 
 
HC: 12 mg 
 
ARAC: 15 mg 
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 

 
 
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TACL Protocol: 
T2017-002 
Protocol Amendment #1 Version Date: 
 Protocol Amendment #2 Version Date:  
 Protocol Amendment #3 Version Date:  
 Protocol Amendment #4 Version Date:  
 Protocol Amendment #5 Version Date: 
 Protocol Amendment #6 Version Date 
 Protocol Amendment #7 Version Date: 
 
19December2019 
16September2020 
11May2021 
24January2022 
26October2022 
20July2023 
07September2023 
 
‡IT therapy assigned to be given on Day 29 may be moved such that it may be given at the time of the 
 
end of Block 1 bone marrow/disease evaluation. 
 
Leucovorin: PO or IV FOR DOWN SYNDROME PATIENTS ONLY  
Days 2, 9, 16, 23, 30 (based on dates when IT MTX or ITT given) 
Dose: 5 mg/m2/dose x 2 doses given 24 and 30 hours after IT methotrexate  or ITT 
 
Leucovorin rescue will be given after intrathecal methotrexate for patients with Down syndrome. The first 
dose to be given 24 hours after the lumbar puncture and the second dose to be given approximately 30 
hours after the lumbar puncture.  
 
Administer with or without food. Administer doses on schedule as determined by timing of methotrexate 
administration. If a dose is missed, administer dose immediately. Give the next scheduled dose according 
to the original dosing schedule. Do not deviate from the original schedule. Notify provider if a dose is 
delayed or missed. 
 
IT Cytarabine (for initial IT chemotherapy) 
Days 
1 (may be administered up to 7 days prior to the initiation of systemic chemotherapy) 
Dose 
Defined by age (yrs.) 
- 
15mg for patients < 1 
- 
30mg for patients age 1-1.99 
- 
50mg for patients age 2-2.99 
- 
70mg for patients age ≥ 3 
 
4.2 
Block 2 (35 days)  
 
4.2.1 
Criteria to begin block 2 therapy 
 
• 
If patients achieve CR/CR MRD-/CRi after block 1, they will have the option of continuing with 
block 2 therapy, moving directly on to the maintenance cycle for up to 4 cycles, or going off 
protocol therapy. If patients have PR/SD, they will continue with block 2 therapy. After 
completion of block 2 therapy, subjects with CR/CR MRD-/CRi/PR can participate in an optional 
maintenance cycle for up to 4 cycles.  
• 
Block 2 therapy should start as soon as all grade 3 and 4 non-hematologic toxicities have 
resolved to grade 2 or less, and patient is clinically acceptable to receive therapy judged by 
treating physician.  
• 
Please start dexamethasone and vincristine if the count has not yet recovered (ANC ≥ 
500/µL and platelet ≥ 20,000/µL, platelet infusion independent) but patient is well and 
the bone marrow evaluation has been performed and CR/CR MRD-/CRi/PR/SD is 
confirmed (see section 4.3) 
• 
Patients with progression of disease (PD) will be removed from study (response criteria see 
11.0).  
 
4.2.2 
Block 2 
 
Therapy delivery map 
Please see Section 4.7 for ixazomib dose modifications for ixazomib-related toxicities.   
 
 
Days 
1 
3 
4 
5 
8 
9 
10 
11 
15 
18 
19 
21 
Ixazomib** 
● 
 
● 
 
● 
 
 
 
● 
● 
 
 

 
 
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 Protocol Amendment #2 Version Date:  
 Protocol Amendment #3 Version Date:  
 Protocol Amendment #4 Version Date:  
 Protocol Amendment #5 Version Date: 
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 Protocol Amendment #7 Version Date: 
 
19December2019 
16September2020 
11May2021 
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07September2023 
Dexamethasone IV/PO (6mg/m2) 
 
 
 
 
 
 
 
 
 
 
 
 
Vincristine IV (1.5mg/m2) 
 
● 
 
 
 
 
 
 
 
 
 
 
Methotrexate IV (1000mg/m2)* 
 
 
 
 
● 
 
 
 
 
 
 
 
Pegaspargase IV/IM (2500 IU/m2) √ ± 
 
 
 
 
 
● 
 
 
 
 
 
 
OR Calaspargase IV (2500 IU/m2) √ ± 
 
 
 
 
 
● 
 
 
 
 
 
 
Cyclophosphamide IV (440mg/m2)# 
 
 
 
 
 
 
 
 
 
 
 
 
Etoposide IV (100mg/m2)# 
 
 
 
 
 
 
 
 
 
 
 
 
CNS 1/2: IT Methotrexate 
 
 
 
 
● 
 
 
 
 
 
 
 
CNS 3: ITT 
 
 
 
 
●$ 
 
 
 
 
 
 
 
Leucovorin IV/PO (15 mg/m2) 
 
 
 
 
 
 
● 
 
 
 
 
 
Dose for patient < 1 years of age see below 
 
*Timing of Day 8 therapy 
• 
For patients beginning block 2 with M1 marrow, proceed to day 8 chemotherapy only when ANC ≥ 
500/µL and platelet ≥ 20,000/µL, platelet infusion independent.  
• 
Patients beginning block 2 with M2/M3 marrow should proceed without count recovery 
 
#Timing of Day 15 therapy 
• 
Await count recovery to ANC ≥ 500/µL and platelet ≥ 20,000/µL, platelet infusion independent, prior 
to beginning day 15 chemotherapy  
 
**Timing of Ixazomib 
• 
Day 8: after IT methotrexate, before IV methotrexate 
• 
Day 15, 18:  after administration of cyclophosphamide and etoposide 
 
√ Either Pegaspargase OR Calaspargase will be administered according to current approved labeling based 
on age and reasonable availability. Patients who start on either Pegaspargase or Calaspargase must 
continue the same treatment throughout the treatment cycle and are not to be used interchangeably. 
 
± crisantapase (Erwinase®) or asparaginase Erwinia chrysanthemi (recombinant)-rywn (Rylaze®) may be 
substituted for allergy to Pegaspargase or Calaspargase. See below. 
 
$Dose of IT therapy for infants: IT methotrexate and hydrocortisone as listed below 
 
Ixazomib 
Days  1, 4, 8, 15, and 18. Note: at least 72 hours must have elapsed between doses 
Dose  Phase 1 – Assigned upon study entry.  Dose will not change during the treatment in the 
same patient 
Phase 2 – PO formulation at RP2D (2 mg/m2 for non-DS patients ) Down syndrome patients 
will receive 1.6 mg/m2  
 
Dexamethasone: PO or IV 
Days  1-5 
Dose  ≥ 1 year: 6mg/m2/day, divided BID (i.e., 3mg/m2/dose, BID) 
 
≥ 6 months and < 1 year: 5 mg/m2/day, divided BID (i.e., 2.5 mg/m2/dose, BID)   
 
< 6 months: 4 mg/m2/day, divided BID (i.e., 2 mg/m2/dose, BID)   
 
Vincristine: IV push over 1 minute or infusion via minibag as per institutional policy 
Day  
3 
Dose  ≥ 1 year: 1.5mg/m2/dose (maximum dose 2mg) 

 
 
T2017-002 Protocol Version: Amendment #7-07Sep2023                    23 
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 Protocol Amendment #3 Version Date:  
 Protocol Amendment #4 Version Date:  
 Protocol Amendment #5 Version Date: 
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 Protocol Amendment #7 Version Date: 
 
19December2019 
16September2020 
11May2021 
24January2022 
26October2022 
20July2023 
07September2023 
 
≥ 6 months and < 1 year: 1.2mg/m2/dose   
 
< 6 months: 1mg/m2/dose   
 
Intermediate-dose Methotrexate: IV over 36 hours. Timing of methotrexate see above.  
Day  
8 
Does  ≥ 1 year: 1,000 mg/m2/dose, given as a 100mg/m2 bolus over 30 min followed by 900mg/m2 over 
35.5 hrs.  
≥ 6 months and < 1 year: 800 mg/m2/dose, given as a 80mg/m2 bolus over 30 min followed by 
720mg/m2 over 35.5 hrs.  
< 6 months: 700 mg/m2/dose, given as a 70mg/m2 bolus over 30 min followed by 630mg/m2 over 
35.5 hrs.  
           Be certain that the MTX infusion is completed in the 36 hour period 
 
Suggested hydration and alkalinization: Start hydration at least 6 hours prior to the start of 
methotrexate. Hydrate with D5¼NS with 30mEq NaHCO3/L at 125 ml/m2/hr to achieve a urine specific 
gravity ≤ 1.010 and pH between 7 and 8. Ringers lactate maybe used as initial fluid if a bicarbonate 
containing solution is unavailable. Adjust fluid volume and sodium bicarbonate to maintain urine specific 
gravity and pH at above parameters. A bicarbonate bolus (25 mEq/m2 over 15 min) may be given to raise 
the urine pH relatively quickly. A normal saline bolus may also be helpful in facilitating hydration. Continue 
hydration and alkalinization throughout MTX infusion after its completion until the last dose of Leucovorin 
has been given.  
 
Leucovorin: PO/IV 
Days  10, 11 
Dose  (for non-DS patients)15mg/m2/dose every 6 hours beginning 48 hours after the START of 
methotrexate infusion.  
- 
If 48 hour methotrexate level is ≤ 0.5µM, do not give more than two doses of leucovorin (48 
and 54 hours) 
- 
If methotrexate level at 48 hours is > 0.5µM, then continue hydration and leucovorin rescue at 
15mg/m2/dose PO/IV every 6 hours until methotrexate level is < 0.1µM 
(for DS patients) Dose: 15mg/m2/dose every 6 hours beginning 42 hours after the START of 
methotrexate infusion and continue  for a minimum of 5 doses  (Hr 42, 48, 54, 60 and 66)  
if 48 hour plasma methotrexate level is ≤ 0.2 μM may stop after hour 66 dose.  
- 
If methotrexate level at 48 hour is > 0.2µM, then continue hydration and leucovorin rescue at 
15mg/m2/dose PO/IV every 6 hours until methotrexate level is < 0.1µM 
 
Administer with or without food. Administer doses on schedule as determined by timing of methotrexate 
administration. If a dose is missed, administer dose immediately. Give the next scheduled dose according 
to the original dosing schedule. Do not deviate from the original schedule. Notify provider if a dose is 
delayed or missed. 
 
Hold trimethoprim/sulfamethoxazole (TMP-SMX), any nonsteroidal anti-inflammatory medications, 
penicillins, proton pump inhibitors or aspirin-containing medications on the day of ID MTX infusion and for 
at least 72 hours after the start of the ID MTX infusion and until the MTX level is less than 0.5 μM for ID 
MTX. 
 
Pegaspargase: IV over 1-2 hours (or IM) Day 9 or 10, administer 4 hours after completion of day 8 IV 
methotrexate 
Dose  ≥ 1 year: 2,500 International units (IU)/m2/dose 
 
≥ 6 months and < 1 year: 2,000 IU/m2/dose   
 
< 6 months: 1,750 IU/m2/dose   
 

 
 
T2017-002 Protocol Version: Amendment #7-07Sep2023                    24 
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TACL Protocol: 
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Protocol Amendment #1 Version Date: 
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 Protocol Amendment #3 Version Date:  
 Protocol Amendment #4 Version Date:  
 Protocol Amendment #5 Version Date: 
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19December2019 
16September2020 
11May2021 
24January2022 
26October2022 
20July2023 
07September2023 
OR 
 
Calaspargase: IV over 1-2 hours  
Day  
9 or 10, administer 4 hours after completion of day 8 IV methotrexate 
 
Dose  ≥ 1 month and < 22 years of age: 2,500 International units (IU)/m2/dose 
 
 
NOTE: Obesity (defined as ≥ 95% BMI for age for patients < 20 y.o or BMI ≥30 for patients ≥ 20 y.o) has 
been linked to increased risk of toxicity in patients ≥ 10 years of age.  
• 
Dose capping at 3,750 units/dose (1 vial) per institutional policy is permissible in cases of 
baseline obesity.  
 
For patients with severe allergic reaction to pegaspargase or calaspargase may substitute asparaginase 
Erwinia chrysanthemi (recombinant)-rywn (Rylaze).or crisantaspase (Erwinase), Refer to prescribing 
information for dosing of asparaginase Erwinia chrysanthemi (recombinant)-rywn (Rylaze®) or 
crisantapase (Erwinase®) . Please note that the most current FDA approved dosing route and schedule 
of Rylaze® or Erwinase®should be followed at the time of administration.  If available and approved 
Crisantaspase (Erwinase®) should be dosed at the FDA approved dose of asparaginase 25,000 
International Units/m2 administered IM or IV over 1-2 hours three times a week 
(Monday/Wednesday/Friday) for six doses for each dose of planned pegaspargase. Six doses of 
replacement Erwinia should be given to replace either pegaspargase or calaspargase during Block 2.   
 
Route of administration, dose schedule and total doses administered should be documented, as this 
could contribute to variability in PK data for ixazomib 
 
Dosing guideline for  crisantapase (Erwinase®): 
≥ 1 year: 25,000 IU/m2/dose 
 
≥ 6 months and < 1 year: 20,000 IU/m2/dose   
 
< 6 months: 17,500 IU/m2/dose   
 
Dosing guideline for asparaginase Erwinia chrysanthemi (recombinant)-rywn (Rylaze®): 
Refer to current FDA product information for dosing Erwinia chrysanthemi (recombinant)-rywn 
(Rylaze®) at the time of product administration. 
 
Cyclophosphamide: IV over 15-30 minutes. Timing of Cyclophosphamide see above 
Days  15-19 
Dose  ≥ 1 year: 440 mg/m2/dose 
 
≥ 6 months and < 1 year: 350 mg/m2/dose 
 
< 6 months: 300 mg/m2/dose 
 
Etoposide: IV over 1-2 hours. Timing of Etoposide see above 
Days  15-19 
Dose  ≥ 1 year: 100 mg/m2/dose 
 
≥ 6 months and < 1 year: 80 mg/m2/dose 
 
< 6 months: 70 mg/m2/dose 
 
IT Methotrexate: for CNS1/2 patients only 
Day  
8 
 
Dose 
Defined by age 
– 
6 mg patients age < 1 
– 
8 mg for patients age 1-1.99 

 
 
T2017-002 Protocol Version: Amendment #7-07Sep2023                    25 
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TACL Protocol: 
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Protocol Amendment #1 Version Date: 
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 Protocol Amendment #3 Version Date:  
 Protocol Amendment #4 Version Date:  
 Protocol Amendment #5 Version Date: 
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 Protocol Amendment #7 Version Date: 
 
19December2019 
16September2020 
11May2021 
24January2022 
26October2022 
20July2023 
07September2023 
– 
10 mg for patients age 2-2.99 
– 
12 mg for patients 3-8.99 years of age 
– 
15 mg for patients >9 years of age 
 
Triple IT: for CNS 3 patients only 
Day  
8 
Dose  Defined by age 
Age (yrs.):  
Dose Methotrexate (MTX)  
Hydrocortisone (HC) 
Cytarabine (ARAC) 
< 1 
 
MTX: 6 mg 
 
 
HC: 12 mg 
 
ARAC: 15 mg 
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 
 
Leucovorin: PO or IV FOR DOWN SYNDROME PATIENTS ONLY  
Day 9 (based on dates when IT MTX or ITT given) 
Dose: 5 mg/m2/dose x 2 doses given 24 and 30 hours after IT methotrexate or ITT 
 
Leucovorin rescue will be given after intrathecal methotrexate for patients with Down syndrome. The first 
dose to be given 24 hours after the lumbar puncture and the second dose to be given approximately 30 
hours after the lumbar puncture.  
 
Administer with or without food. Administer doses on schedule as determined by timing of methotrexate 
administration. If a dose is missed, administer dose immediately. Give the next scheduled dose according 
to the original dosing schedule. Do not deviate from the original schedule. Notify provider if a dose is 
delayed or missed. 
 
 
4.3 
Optional standard maintenance cycle  
 
4.3.1 
Criteria to begin maintenance therapy 
• 
If patients achieve CR/CR MRD-/CRi after block 1, they will have the option of moving directly 
on to the maintenance cycle for up to 4 cycles. After completion of block 2 therapy, subjects 
with CR/CR MRD-/CRi/PR can also participate in the optional maintenance cycle for up to 4 
cycles$.  
• 
Block 2 therapy should start when patient is clinically acceptable to receive therapy judged by 
treating physician 
 
4.3.2 
Therapy Delivery Map 
 
Please see Section 4.7 for ixazomib dose modifications for ixazomib-related toxicities.   
 
Days 
1 
2 
5 
8 
11 
15 
18 
22 
28 
Ixazomib$ 
● 
 
 
● 
 
● 
 
 
 
Vincristine IV (1.5mg/m2) 
● 
 
 
 
 
 
 
 
 
Prednisone (20mg/m2/dose BID) 
 
 
 
 
 
 
 
 
 
Mercaptopurine (75mg/m2/day)# 
 
 
 
 
 
 
 
 
 
Methotrexate 20mg/m2/week* 
● 
 
 
● 
 
● 
 
● 
 
IT Methotrexate# 
● 
 
 
 
 
 
 
 
 

 
 
T2017-002 Protocol Version: Amendment #7-07Sep2023                    26 
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 Protocol Amendment #5 Version Date: 
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19December2019 
16September2020 
11May2021 
24January2022 
26October2022 
20July2023 
07September2023 
Leucovorin IV/PO (5 mg/m2 at hr 
24 and 30 post-IT)** 
 
● 
 
 
 
 
 
 
 
Dose for patient < 1 years of age see below 
 
$ Patients on maintenance cycle can receive compassionate use of ixazomib with maintenance chemotherapy for 
up to 12 months. 
# Standard dose for mercaptopurine is 75mg/m2/day. The dose can be modified by treating physician based on 
TPMT and/or NUDT15 genotype and based on platelet/ANC (see dose modification sections).    
* Oral methotrexate dose will be omitted in the week of IT methotrexate dosing 
# Optional per treating physician 
** For patients with DS only 
 
**Timing of ixazomib administration 
• 
After administration of vincristine and IT (if applicable) 
 
Ixazomib 
Days  1, 8, and 15  
Dose  We will use PO formulation at RP2D  
Phase 1 – Assigned upon study entry.  Dose will not change during the treatment in the same 
patient 
Phase 2 – PO formulation at RP2D (2 mg/m2 for non-DS patients ) Down syndrome patients will 
receive  1.6 mg/m2  
 
Vincristine: IV push over 1 minute or infusion via minibag as per institutional policy 
Day  
1 
Dose  ≥ 1 year: 1.5mg/m2/dose (maximum dose 2mg) 
 
≥ 6 months and < 1 year: 1.2mg/m2/dose   
 
< 6 months: 1mg/m2/dose   
 
Prednisone 
Days  1-5 
Dose  ≥ 1 year: 40mg/m2/day, divided BID (i.e., 20mg/m2/dose, BID) 
 
≥ 6 months and < 1 year: 32 mg/m2/day, divided BID (i.e., 16 mg/m2/dose, BID)    
 
Mercaptopurine: PO  
Days  1-28 
Dose  ≥ 1 year: 75mg/m2/day, QHS 
 
≥ 6 months and < 1 year: 56mg/m2/day, QHS  
 
 
Methotrexate: PO  
Day  
1, 8, 15, 22, hold on the week of receiving LP/IT 
Does  ≥ 1 year: 20mg/m2/dose 
 
≥ 6 months and < 1 year: 15mg/m2/dose 
 
 
IT Methotrexate: optional 
Day  
1 
 
Dose 
Defined by age 
– 
6 mg patients age < 1 
– 
8 mg for patients age 1-1.99 
– 
10 mg for patients age 2-2.99 
– 
12 mg for patients 3-8.99 years of age 

 
 
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– 
15 mg for patients >9 years of age 
 
 
Triple IT: optional for CNS 3 patients only 
Day  
1 
Dose  Defined by age 
Age (yrs.):  
Dose Methotrexate (MTX)  
Hydrocortisone (HC) 
Cytarabine (ARAC) 
< 1 
 
MTX: 6 mg 
 
 
HC: 12 mg 
 
ARAC: 15 mg 
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 
 
Leucovorin: PO or IV FOR DOWN SYNDROME PATIENTS ONLY  
Days 2 (based on dates when IT MTX or ITT given) 
Dose: 5 mg/m2/dose x 2 doses given 24 and 30 hours after IT methotrexate or  ITT 
 
Leucovorin rescue will be given after intrathecal methotrexate for patients with Down syndrome. The first 
dose to be given 24 hours after the lumbar puncture and the second dose to be given approximately 30 
hours after the lumbar puncture.  
 
Administer with or without food. Administer doses on schedule as determined by timing of methotrexate 
administration. If a dose is missed, administer dose immediately. Give the next scheduled dose according 
to the original dosing schedule. Do not deviate from the original schedule. Notify provider if a dose is 
delayed or missed. 
 
 
4.4 
Disease Evaluation 
4.4.1 
Disease evaluation end block 1  
 
• 
A bone marrow aspiration (biopsy is optional) and CT and PET (lymphoma patients only) to 
assess remission status should be performed no earlier than day 29. For lymphoma patients, 
Gallium scan may be substituted for PET scan at sites where PET is not available. PET without 
CT should not be used as a substitute for CT with contrast. Combined PET/CT is acceptable.  
• 
The bone marrow evaluation may be delayed no later than day 36 (± 1 day) if ANC < 500/µL 
and platelet < 20,000/µL, platelet infusion independent, on day 29. 
• 
If the marrow is hypoplastic and/or there is little or no evidence of normal hematopoiesis, a 
repeat marrow should be performed after every 7-21 days (based upon peripheral blood count 
recovery and the clinician’s judgment) and remission status assessed at this later time point.  
• 
For lymphoma patients, if the bone marrow was M1 marrow with negative MRD at the beginning 
of the block 1, repeat bone marrow aspiration/biopsy is not necessary.   
 
4.4.2 
Disease evaluation end block 2 (only applies to leukemia patients not in MRD negative CR, or 
lymphoma patients not in CR)  
 
• 
A bone marrow aspiration (biopsy is optional) and CT and PET (lymphoma patients only) to 
assess remission status should be performed no earlier than day 29 (± 3 days). Gallium scan 
may be substituted for PET scan at sites where PET is not available. PET without CT should 
not be used as a substitute for CT with contrast. Combined PET/CT is acceptable. 
• 
The evaluation may be delayed no later than day 36 (± 1 day) if ANC < 500/µL and platelet < 
20,000/µL, platelet infusion independent, on day 29. 

 
 
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4.5 
Dose Escalation Schedule 
 
 
Phase 1 (PO formulation): The following dose levels for ixazomib are planned starting at dose level 1 
 
Level 
Patients ≥ 1 year of age 
Dose 
Patients < 1 year of age 
Dose 
-1 
1.2 mg/m2/day 
0.04 mg/kg/day 
1 
1.6 mg/m2/day 
0.05 mg/kg/day 
2 
2 mg/m2/day 
0.07 mg/kg/day 
 
 
4.6 
Dose-limiting Toxicity (DLT) 
 
Toxicity will be graded according to the NCI Common Toxicity Criteria (CTC) version 5.0. A copy of the 
CTCAE can be downloaded from the CTEP home page: 
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference
_5x7.pdf#search=%22CTCAE%22). Any DLT should be reported immediately through the TACL 
Operation Center to the Study Chair.  
 
For the purposes of determining DLT/dose escalation: DLT will be assessed in the first block only and only 
in non-DS children ≥ 1 year of age. Since infants and patients with DS have more toxicities with 
chemotherapy, the toxicity data of those patients will be collected but will not be used as DLT assessment.  
 
DLT will be defined as any of the following events that are deemed by the investigator as possibly, 
probably, or definitely attributable to ixazomib: 
 
1) Any Grade 4 non-hematologic toxicity that occurs after the first dose of ixazomib, and is probably or 
definitely attributable to ixazomib, with the following exceptions:  
(a) Fever or infection with or without hospitalization  
(b) Fatigue and gastrointestinal symptoms (anorexia, vomiting, dehydration, mucositis)  
(c) Hypofibrinogenemia 
(d) Metabolic/laboratory abnormalities that resolve to ≤ Grade 2, either 
i. prior to the start of the next block of chemotherapy, or  
ii. within 7 days  
 
2) Any Grade 4 non-hematologic toxicity that occurs after the first dose of Ixazomib that is possibly 
attributable to Ixazomib, and results in omission of the subsequent block of chemotherapy or delay of 
the beginning of the subsequent block of chemotherapy for greater than 7 days, with the exception of 
fever or infection. 
 
3) Any Grade 3 non-hematologic toxicity that occurs after the first dose of ixazomib that is possibly, 
probably or definitely attributable to ixazomib, and results in omission of the subsequent block of 
chemotherapy or delay of the beginning of the subsequent block of chemotherapy for greater than 7 
days, with the exception of fever or infection.  
 

 
 
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4) Hematologic toxicities: Failure to recover a peripheral ANC ≥ 500/µL and PLT > 20,000/µL, platelet 
infusion independent, due to documented bone marrow hypoplasia (cellularity < 10-20%) within 49 days 
of the beginning of systemic chemotherapy without evidence of active disease or active infection by 
bone marrow aspiration.  Subjects with abnormal blood counts (Grade 1 through 4) at baseline due to 
disease will not be evaluable for hematologic DLT and will be considered not having had hematologic 
DLT. 
 
No other hematologic grade 3 or 4 adverse events will be considered dose-limiting.  
 
4.7 
Dose Modifications for Toxicity 
 
 
4.7.1 
Ixazomib related toxicities 
 
 
4.7.1.1 Peripheral neuropathy will be closely monitored during each block of treatment and 
toxicities graded. A complete neurological exam that includes at a minimum assessment of cranial 
nerve function, deep tendon reflexes of the brachioradialis, patellar and achiles tendons, balance, 
gait and general sensation should be documented prior to the start of therapy.  
 
Neuropathy grading should be based on the maximum toxicity occurring during the previous block. 
All dose modifications should be based on the worst preceding toxicity. Since vincristine can also 
cause peripheral neuropathy, dose modification will be performed as follows:  
 
Modifications for Neuropathy and Neuropathic Pain (modifications should be made at any time 
during a cycle that neuropathies are noted:  
 
Grade 1 with pain* or 
Grade 2 
Hold ixazomib and vincristine until neuropathy has resolved to 
Grade 1 or baseline. When symptoms subside, restart ixazomib and 
vincristine at full dose. 
Grade 2 with pain* or 
Grade 3  
Hold ixazomib and vincristine until neuropathy has resolved to < 
Grade 2. When symptoms subside, restart ixazomib at one dose 
level below and vincristine at full dose.  
Grade 4 
Discontinue ixazomib and hold vincristine until neuropathy has 
resolved to < Grade 2. When symptoms subside, restart vincristine 
at 50% previous dose and escalated to full dose as tolerated. 
*pain uncontrolled by NSAID or narcotics. 
 

 
 
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4.7.1.2 Renal impairment 
 
 
Patients with mild to moderate renal impairment (creatinine clearance ([CrCL] ≥ 30 ml/min) were 
included in all clinical studies of ixazomib. In the population PK model, CrCL was not identified as 
a significant covariate. Therefore, no dose adjustment is required for patients with mild or 
moderate renal impairment.  
 
The PK of ixazomib in adult patients with severe renal impairment (CrCL<30 mL/min, including 
patients with end-stage renal disease [ESRD] requiring dialysis) was examined in a dedicated 
clinical study (Study C16015). The geometric least squares mean ratio (90% CI) for unbound AUC 
for the combined analysis of severe renal impairment and ESRD patients requiring hemodialysis 
versus normal renal function was 1.38 (0.93-2.04), indicating that unbound exposures of ixazomib 
were 38% higher in these patients compared with patients with normal renal function. For patients 
with severe renal impairment (creatinine clearance <30mL/min/1.73m2) that is not a DLT (Section 
4.6), reduce ixazomib by 1 dose level.  For those patients already at dose level -1, reduce ixazomib 
dose to 0.8 mg/m2.  
 
 
 
4.7.1.3 Hepatic impairment 
 
Adult patients with mild hepatic impairment (total bilirubin ≤ the upper limit of the normal range 
[ULN] and aspartate aminotransferase [AST] >ULN or total bilirubin >1-1.5×ULN and any AST) 
were included in all clinical studies during ixazomib development. In the population PK model, 
Modified (“Balis”) Pediatric Scale of Peripheral Neuropathies  
 
Peripheral Motor Neuropathy:  
• 
Grade 1: Subjective weakness, but no deficits detected on neurological exam, other than abnormal 
deep tendon reflexes.  
 
• 
Grade 2: Weakness that alters fine motor skills (buttoning shirt, coloring, writing or drawing, using 
eating utensils) or gait without abrogating ability to perform these tasks.  
 
• 
Grade 3: Unable to perform fine motor tasks (buttoning shirt, coloring, writing or drawing, using 
eating utensils) or unable to ambulate without assistance.  
 
• 
Grade 4: Paralysis.  
 
Peripheral Sensory Neuropathy:  
• 
Grade 1: Paresthesias, pain, or numbness that do not require treatment or interfere with extremity 
function.  
 
• 
Grade 2: Paresthesias, pain, or numbness that are controlled by non-narcotic medications (without 
causing loss of function), or alteration of fine motor skills (buttoning shirt, writing or drawing, using 
eating utensils) or gait, without abrogating ability to perform these tasks.  
 
• 
Grade 3: Paresthesias or pain that are controlled by narcotics, or interfere with extremity function 
(gait, fine motor skills as outlined above), or quality of life (loss of sleep, ability to perform normal 
activities severely impaired).  

 
 
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bilirubin was not identified as a significant covariate on CL; therefore, no dose adjustment is 
necessary for patients with mild hepatic impairment.  
 
The PK of ixazomib in adult patients with moderate (total bilirubin >1.5-3×ULN) or severe (total 
bilirubin >3×ULN) hepatic impairment was assessed in a dedicated clinical study (Study C16018). 
For the combined analysis of moderate and severe hepatic impairment versus normal hepatic 
function, the geometric least squares mean ratio (90% CI) for unbound dose-normalized AUC was 
1.27 (0.75-2.16), indicating that unbound systemic exposures of ixazomib are 27% higher in these 
patients compared with patients with normal hepatic function. Reduce ixazomib by 1 dose level for 
patients with severe hepatic impairment (i.e. total bilirubin >3x ULN for age) that is not a DLT 
(Section 4.6). For those patients already at dose level -1, reduce ixazomib dose to 0.8 mg/m2.  
 
4.7.1.4 Dose de-escalation for non-heme, non-neurologic adverse events due to ixazomib 
 
Ixazomib will be stopped and not restarted for any Grade 4 toxicity probably or definitely related to 
ixazomib. Ixazomib will be dose de-escalated one lower Dose Level (Section 4.5) for non-excluded 
Grade 3 and 4 toxicities that are possibly, probably or definitely related to ixazomib.  
 
4.7.1.4.1 Dose de-escalation within a block 
 
If a patient experiences a Grade 3 or 4 ixazomib-related toxicity that does not require 
cessation of ixazomib (see above), and once this Grade 3 or 4 toxicity resolves to ≤ Grade 
1, ixazomib can be restarted at one lower Dose Level (Section 4.5) for subsequent doses. 
Missed doses of ixazomib in a block will not be made up. See Section 7.4.1.4.5 if ixazomib 
is discontinued. 
 
4.7.1.4.2 Dose de-escalation between blocks 
 
The ixazomib dose will be decreased one lower Dose Level (Section 4.5) for qualifying 
Grade 3 or 4 toxicities (see above) that resolve to ≤ Grade 1 prior to the beginning of the 
next block. Doses reduced for an adverse event will not be re-escalated, even if there is 
minimal or no toxicity at the reduced dose.  
 
4.7.1.5 Protocol therapy and dose reductions for ixazomib-related toxicities 
 
Patients with an ixazomib-related severe toxicity will discontinue ixazomib but will remain on 
protocol therapy.  
 
4.7.2 
Asparaginase [pegaspargase (Oncospar), asparaginase Erwinia chrysanthemi (recombinant)-rywn 
(Rylaze), or crisantaspase (Erwinase)] 
 
 
 
4.7.2.1 Allergy 
 
 
 
• 
Local 
Allergic 
Reactions 
(inflammation 
at 
injection 
site, 
swelling): 
Note: 
these 
recommendations only apply when the asparaginase product is administered IM. Continue 
pegaspargase administration in the presence of Grade 1 allergy as defined by CTCAE v5.0 
(transient flushing or rash; drug fever < 38ºC).  
 
• 
Systemic Allergic Reactions: Discontinuation may be considered for severe Grade 2 or higher 
allergic reactions as defined by CTCAE v5.0.  

 
 
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Note: Premedication with antihistamines to decrease the risk of overt allergy symptoms is 
strongly discouraged since anti-histamine use may mask the appearance of systemic allergy. 
Systemic allergy is frequently associated with the presence of asparaginase neutralizing 
antibodies, which render asparaginase therapy ineffective. In the event of severe systemic or 
recurrent local allergic reaction, asparaginase Erwinia chrysanthemi (recombinant)-rywn 
(Rylaze®) or crisantapase (Erwinase®) should be substituted.  
 
• 
Anaphylaxis: Discontinue pegaspargase if the patient develops Grade 3 anaphylaxis as defined 
by CTCAE v5.0 (symptomatic bronchospasm, with or without urticaria, parenteral intervention 
indicated; allergy-related edema/angioedema; hypotension). If this occurs, crisantapase 
(Erwinase®) or asparaginase Erwinia chrysanthemi (recombinant)-rywn (Rylaze®) should be 
substituted.  
 
Please note that the most current FDA approved dosing route and schedule of Rylaze® or 
Erwinase®should be followed at the time of administration.  If available and approved 
Crisantaspase (Erwinase®) should be dosed at the FDA approved dose of asparaginase 
25,000 International Units/m2 administered IM or IV over 1-2 hours three times a week 
(Monday/Wednesday/Friday) for six doses for each dose of planned pegaspargase.  
 
The dose modification guidelines for ALL trials recommend the substitution for replacement of 
Erwinia asparaginase for pegaspargase utilizing the following schedule: 
 
Phases of Treatment 
Drugs 
Replacement Schedule for 
Erwinia asparaginase* 
Block 1/Block 2 
One or more doses of 
pegaspargase (2,500 IU/m2) 
Crisantaspase (Erwinase®) 
25,000 IU/m2/dose IM or IV 
M/W/F x 6 doses for each 
dose of pegaspargase 
asparaginase Erwinia 
chrysanthemi (recombinant)-
rywn (Rylaze®) 
Refer to most current FDA 
approved dosing route and 
schedule.  
 
 
 
*If a patient develops a Grade 3 or higher anaphylaxis to Erwinia, discontinue future 
asparaginase therapy. Consider discontinuation for severe Grade 2 or higher allergic 
reactions 
 
In the event that a pegaspargase infusion is discontinued for an allergic reaction, regardless of 
amount received, substitution with Erwinia asparaginase should begin within 72hours ( or 
sooner if possible) after pegaspargase has been discontinued and continue for up to 6 doses 
if using  Cristantaspase (Erwinase) or per current FDA approved dose and schedule if using 
Rylaze.   
 
Erwinia asparaginase may be administered, as tolerated, to replace the incomplete intravenous 
pegaspargase dose. Of note, Erwinia asparaginase is recommended only for pegaspargase 
hypersensitivity reactions, and not for pancreatitis, hepatitis, coagulation abnormalities, or other 
non-hypersensitivity toxicities associated with pegaspargase. To best suit the needs of each 
individual patient, additional modifications to these recommendations may be made at the 
discretion of the treating physician. 

 
 
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Centers may elect to discontinue pegaspargase and switch to erwinia asparaginase based 
upon laboratory evidence of silent inactivation of asparaginase activity in the absence of clinical 
symptoms of hypersensitivity at their discretion. 
 
For use of Erwinia chrysanthemi (recombinant)-rywn (Rylaze®): refer to current FDA 
product information for dosing at the time of product administration. 
 
4.7.2.2 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.  
 
4.7.2.3 Hyperbilirubinemia 
 
Asparaginase may need to be withheld in patients with an elevated direct bilirubin, since 
asparaginase has been associated with hepatic toxicity..  
 
 
Direct Bilirubin  
Dose Adjustment 
< 3.0  mg/dL 
Full dose  
3.1-5.0mg/dL 
Hold pegaspargase and resume when direct bilirubin is < 2 mg/dL 
> 5.0 mg/dL 
Hold the dose and administer next scheduled dose if toxicity has 
resolved.  
 
 
 
4.7.2.4 Hyperglycemia 
 
Do not modify dose. Treat hyperglycemia as medically indicated.  
 
 
 
4.7.2.5 Hyperlipidemia 
 
Do not modify dose.  
 
 
 
4.7.2.6 Ketoacidosis 
 
Hold asparaginase until blood glucose can be regulated with insulin.  
 
4.7.2.7 Pancreatitis  
 
Discontinue asparaginase in the presence of Grade 3 or 4 pancreatitis. In the case of asymptomatic 
Grade 2 pancreatitis (enzyme elevation or radiologic findings only), asparaginase should be held 
until symptoms and signs subside, and amylase/lipase levels return to normal and then resumed. 
Grade 3-4 pancreatitis is a contraindication to additional asparaginase administration.  
 
 
 
4.7.2.8 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.  
 

 
 
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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. 
 
4.7.3 
Cyclophosphamide  
 
4.7.3.1 Hematuria 
 
Omit in the presence of macroscopic hematuria. If there is a history of previous significant 
hematuria, hydrate before cyclophosphamide until specific gravity is < 1.010 and hydrate at 125 
mL/m2/hr for 24 hours after dose. Monitor for adequate urine output as per institution guidelines. 
Give IV mesna at a total dose that is 60% of the cyclophosphamide dose divided to 3 doses (e.g., 
if the cyclophosphamide dose is 1000 mg/m2, the total mesna dose is 600 mg/m2 or 200 
mg/m2/dose). Give the first mesna dose 15 minutes before or at the same time as the 
cyclophosphamide dose and repeat 4 and 8 hours after the start of cyclophosphamide. This total 
daily dose of mesna can also be administered as IV continuous infusion. The continuous infusion 
should be started 15-30 minutes before or at the same time as cyclophosphamide and finished no 
sooner than 8 hours after the end of cyclophosphamide infusion.  
 
4.7.3.2 Renal Dysfunction 
 
If creatinine clearance or radioisotope GFR is < 10 mL/min/1.73m2, reduce dose of 
cyclophosphamide by 50%. Prior to dose adjustment of cyclophosphamide, the creatinine 
clearance should be repeated with good hydration.  
 
4.7.4 
Doxorubicin (Anthracycline)  
 
 
 
4.7.4.1 Cardiac Toxicity 
 
Discontinue for clinical or echocardiographic evidence of cardiomyopathy (SF < 27% or EF < 50%) 
or Grade 3 - 4 left ventricular systolic dysfunction (LVSD) per CTCAE version 5.0.  
 
4.7.4.2 Hyperbilirubinemia 
 
Direct Bilirubin  
Dose Adjustment 
≤ 3.0  mg/dL 
Full dose  
3.1-5.0 mg/dL 
Administer 50% of calculated dose  
5.1-6.0 mg/dL 
Administer 25% of calculated dose  
> 6.0 mg/dL 
Withhold dose and administer next scheduled dose if toxicity has 
resolved. Do not make up missed doses. 
 
4.7.4.3 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. Also see 
https://members.childrensoncologygroup.org/_files/disc/Nursing/extravasationguidelines.pdf for 
COG guidelines. 

 
 
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Do not make up missed doses. 
 
 
4.7.5 
Etoposide (VP-16)  
 
4.7.5.1 Allergic Reaction 
 
Premedicate with diphenhydramine (1-2 mg/kg slow IV push, maximum dose is 50 mg). If 
symptoms persist, add hydrocortisone 100-300 mg/m2. Continue to use premedication before 
etoposide in future. Also consider substituting an equimolar amount of etoposide phosphate, in the 
face of significant allergy and/or hypotension. Etoposide phosphate is a water soluble prodrug that 
does not contain polysorbate 80 and polyethyleneglycol, the solubilizing agent in etoposide that 
may induce allergic reactions and hypotension. Etoposide phosphate is rapidly converted to 
etoposide in vivo and provides total drug exposure, as represented by AUC (0-infinity) that is 
statistically indistinguishable from that measured for etoposide at equimolar doses.  
 
4.7.5.2 Hypotension 
 
If diastolic or systolic blood pressure (BP) falls 20 mm Hg during infusion, reduce infusion rate by 
50%. Start a simultaneous infusion of NS 10 mL/kg if BP fails to recover or falls further. Stop 
infusion if BP does not recover, continue NS. If the patient has had any episode of hypotension, 
prehydrate with 0.9% NaCl at 10 mL/kg/hr for 2 hours prior to any subsequent infusion.  
 
 
 
4.7.5.3 Renal Insufficiency 
 
If renal function decreases, adjust etoposide as follows: CrCl 10-50 mL/min/1.73 m2, decrease dose 
by 25%; if CrCl < 10 mL/min/1.73 m2, decrease dose by 50%.  
 
4.7.5.4 Hyperbilirubinemia 
 
If direct bilirubin is > 2 mg/dL, decrease dose by 50%. If direct bilirubin is > 5 mg/dL, hold etoposide.  
 
4.7.6 
Intrathecal Methotrexate/Triple Intrathecal Therapy  
 
6-Mercaptopurine (6-MP) Thiopurine Pharmacology Testing and Dosage Mercaptopurine is 
methylated by thiopurine methyltransferase (TPMT) to an inactive metabolite. Patients with 
polymorphisms in TPMT resulting in decreased activity are more susceptible to toxicities when 
given mercaptopurine (i.e., myelosuppression). More recently, germline variants in the gene 
encoding the nucleoside diphosphate–linked moiety X-type motif 15 (NUDT15) have been 
reported in approximately 4% of Hispanic/Native American and nearly 10% of East Asian children 
with ALL; these polymorphisms are strongly associated with mercaptopurine intolerance. There 
are CLIA certified tests for TPMT genotype and phenotype (genotyping can be performed even 
after recent RBC transfusions), thiopurine metabolites (MMP and TGN measurements), and for 
NUDT15 polymorphisms. General comments about TGN metabolite testing: High TGN 
concentrations: high values should not preclude further increases in mercaptopurine doses if 
ANC is high and there are no contraindications to dose increases. Likewise, high concentrations 
of methylated derivatives should not influence dosing in asymptomatic patients without 
hyperbilirubinemia. When ANC is high despite dose increases, consider non-adherence. Although 
there are no specific values to use to indicate non-adherence, low concentrations of TGN and 
methylated derivatives in a sample taken after at least three weeks after continuous dosing may 
indicate non-adherence.” 
 

 
 
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Suggested starting doses of mercaptopurine for patients with known mutations in 
TPMT/NUDT15 
Mercaptopurine 
TPMT or NUDT15 
Normal metabolizer 
TPMT or NUDT15 
Intermediate or 
Possible 
intermediate 
TPMT or 
NUDT15  Poor 
Metabolizer 
75mg/m2/day 
Full dose 
(75mg/m2/day) and 
adjust every 2 
weeks as clinically 
indicated 
Reduced dose (30-
80% of normal 
starting dose) 
22.5-60mg/m2/day) 
and adjust every 2-
4 weeks as clinically 
indicated 
Reduced dose (10% 
of normal starting 
dose) 
10mg/m2/day given 
3 days a week and 
adjust every 4-6 
weeks as clinically 
indicated 
Relling MF et al Clin Pharmacol Ther 2019 May; 105(5): 1095-1105 
 
4.7.6.1 Systemic toxicity 
 
The dosage for IT methotrexate will not be reduced for systemic toxicity (myelosuppression, 
mucositis, etc.). Instead, leucovorin may be used at a dose of 5 mg/m2/dose every 6 hours x 2 
doses, beginning 24 hours after the IT therapy has been delivered. This may reduce the risk of 
worsening already existent myelosuppression (ANC < 0.5 x 109/L) or mucositis. Do not administer 
leucovorin solely to prevent myelosuppression.  
 
 
 
4.7.6.2 An episode of acute neurotoxicity 
 
Neurotoxicity has extremely protean manifestations, ranging from transient events, seizures or 
episodes of acute hemiparesis, to severe necrotizing encephalopathies. These toxicities are poorly 
understood and currently it is impossible to predict who will suffer these complications. In addition, 
there are no data clearly linking the occurrence of an acute neurotoxic event with an increased risk 
of long-term neurocognitive dysfunction, nor do changes present on MRI at the time of an acute 
event clearly correlate with or predict outcome.  
 
The following guidelines are offered for consideration following an acute event, but it must be 
recognized that there are little data to support these approaches or any others. Thus the treating 
physician must evaluate the patient and, with the family, make the best possible decision with 
respect to the relative risk and benefit of continued therapy.  
 
Following an acute neurotoxic event, a history and physical exam should guide the differential 
diagnosis. A neurology consult may be of value and should be considered. Seizures and other 
transient events may be linked to fever, infection, encephalitis, meningitis, hypertension, electrolyte 
disturbance, hypoglycemia, trauma, intracranial hemorrhage or thrombosis, narcotic withdrawal, 
illicit drug use, or other causes in addition to the direct side effects of chemotherapy. Appropriate 
laboratory studies may include, but are not limited to, blood cultures, a CBC, electrolytes, including 
glucose, calcium, magnesium and phosphorus, renal and liver function studies and/or an 
examination of the CSF. Imaging studies may include a CT scan and/or an MRI. The CT is 
commonly normal, in the absence of stroke, but if calcifications are present, this finding may be 
indicative of a more severe mineralizing leukoencephalopathy. MRI abnormalities may be 
pronounced, but transient. Posterior reversible encephalopathy may be present on MRI with 
extensive diffusion abnormalities, but these do not appear to correlate with subsequent 

 
 
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demyelination or gliosis. Additional studies, including MR angiography and/or venogram should be 
considered, if clinically indicated (e.g., focal deficits).  
 
Many acute events, seizures or episodes of transient hemiparesis, are temporally related to the 
administration of intrathecal therapy, commonly 9 to 11 days after the IT administration. For patients 
who return to their “pre-event” status, without residual deficits of physical or neurologic exam, there 
are few data to support or guide therapeutic interventions. It is reasonable to hold the next dose of 
IT therapy, or, substitute IT Ara-C for one dose of IT MTX, or triple IT therapy. It is also reasonable 
to include leucovorin rescue at a dose of 5 mg/m2 q 6 hrs x 2 doses beginning 24 hours after the 
LP. This pattern of rescue was associated with a clear diminution in the incidence of acute 
neurotoxicity in one case series. There have been questions about potential interference of 
leucovorin with the efficacy of the IT MTX, but there are little data to support or refute this position. 
Moreover, the administration 24 hours later would minimize any potential interference. If the event 
does not recur, resumption of standard therapy should be considered, following one modified or 
omitted IT dose. In the face of multiply recurrent events, or evidence of progressive 
encephalopathy, another evaluation is warranted and the treating physician may consider a more 
prolonged or definitive change in therapy. These decisions are extremely difficult and may hinge 
on an individual’s view of the importance of quality of life versus an increase in the risk of relapse. 
Since the greatest impact of CNS prophylaxis occurs early in therapy, the timing of these events 
may also influence clinical decisions. Cranial radiation has been suggested as an alternative to 
continued IT therapy though much of the literature on long-term neurocognitive dysfunction 
supports a more deleterious effect from CRT than IT therapy. Cranial radiation is not allowed during 
protocol therapy.  
 
The use of dextromethorphan (DM) has been suggested as a neuroprotectant, capable of 
preventing NMDA mediated neurotoxicity without prohibitive toxicity. Low dose therapy has been 
recommended, in part, based on data suggesting that DM is concentrated in brain relative to serum. 
However, the literature on the use of DM supports a tight dose response relationship, with the 
likelihood of sparing an initially unaffected area, following ischemic damage, linked to dose, in both 
clinical trials and animal models of CNS ischemia. At doses thought to be therapeutic, side effects 
have included nystagmus, nausea and vomiting, distorted vision, ataxia, and dizziness. In addition, 
Hollander et al have raised concerns about the potential deleterious effects of long-term NMDA 
receptor blockade on memory because hippocampal long-term potentiation is dependent on the 
activation of the NMDA receptor. Thus in the absence of a clinical trial there are few data to support 
the addition of DM. 
 
4.7.6.3 Hydrocephalus, microcephaly or known abnormality of CSF flow precluding intrathecal 
chemotherapy via lumbar puncture 
 
Intraventricular chemotherapy via Ommaya catheter may be used in place of intrathecal therapy 
delivered by LP. Intraventricular chemotherapy should be given according to the same schedule, 
but at 50% of the corresponding age-based doses that would be given by LP.  
 
NOTE: Obstruction to CSF flow may be a contraindication to intrathecal and/or intraventricular 
therapy.  
 
 
 
4.7.6.4 Viral, bacterial, or fungal meningitis 
 
Omit until resolved. 
 
4.7.7 
Intermediate-Dose Methotrexate (ID MTX, refers to IV MTX 1000 mg/m2 given over 36 hrs) and 
Leucovorin Rescue  

 
 
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4.7.7.1 ID MTX Infusion Guidelines and dose modifications for toxicity  
 
When IT therapy and ID MTX are scheduled for the same day, it is strongly recommended to deliver 
the IT therapy within 6 hours of the beginning of the IV MTX infusion (hour -6 to +6, with 0 being 
the start of the MTX bolus).  
 
Hold trimethoprim/sulfamethoxazole (TMP-SMX), any nonsteroidal anti-inflammatory medications, 
penicillins, proton pump inhibitors or aspirin-containing medications on the day of ID MTX infusion 
and for at least 72 hours after the start of the ID MTX infusion and until the MTX level is less than 
0.5 μM for ID MTX. In the presence of delayed clearance continue to hold these medications until 
MTX level is less than 0.1 μM.  
 
Recommended Prehydration: to start at least 6 hours prior to commencement of intravenous 
methotrexate. Fluid: D5 ¼ NS with 30 - 50 mEq NaHCO3/L at 125 mL/m2/hour. Ringers Lactate 
may be used as the initial fluid if a bicarbonate containing solution is unavailable. Adjust fluid 
volume and sodium bicarbonate to maintain urine specific gravity ≤ 1.010 and pH between 7 and 
8. A bicarbonate bolus (25 mEq/m2 over 15 min) may be given to raise the urine pH relatively 
quickly; a normal saline bolus may also be helpful in facilitating hydration.  
 
Hour 0: MTX 100 mg/m2 IV infused over 30 minutes. This is followed, immediately, by MTX 900 
mg/m2 given by continuous IV infusion over 35.5 hours. Be certain that the ID MTX infusion is 
completed in the 36 hour period. Note, even if the infusion is not complete at this time point, 
it must be stopped.  
 
Recommended Post hydration: Continue hydration using D 5 ¼ NS with 30 – 50 mEq NaHCO3/L 
at 125 mL/m2/hour (3 L/m2/day) throughout IDMTX infusion until the last dose of leucovorin has 
been given. In patients with delayed MTX clearance, continue hydration until the plasma MTX 
concentration is below 0.1 μM.  
 
Leucovorin rescue: 15 mg/m2 PO/IV at 48 and 54 hrs after the start of the MTX infusion. If 48 hr 
methotrexate level is ≤ 0.5 μM, then only two doses of leucovorin are administered (at 48 and 54 
hours). If MTX level at 48 hours is > 0.5 μM, then continue hydration and leucovorin rescue at 15 
mg/m2/dose 
po/IV 
every 
6 
hours 
until 
MTX 
levels 
are 
< 
0.1 
μM.   
        For DS patients begin leucovorin rescue at hour 42 and continue every 6 hours for a minimum 
of 5 doses [Hour 42, 48, 54, 60 and 66] 
 
Hour 48: Check plasma methotrexate level at 48 hours after start of the methotrexate infusion. If 
the level is ≤ 0.5 μM, then do not give more than two doses of leucovorin (48 and 54 hours). If MTX 
level at 48 hours is > 0.5 μM, then continue hydration and leucovorin rescue at 15 mg/m2/dose 
po/IV 
every 
6 
hours 
until 
MTX 
levels 
are 
< 
0.1 
μM.     
            DS patients:  If hour 48 MTX level ≤ 0.2 μM may stop after hour 66 dose.  If hour 48 MTX 
level > 0.2 μM continue until MTX levels are < 0.1. 
 
 
 
For MTX levels that exceed these expected values modify the rescue regimen as noted 
below and increase hydration to 200 mL/m2/hr. Monitor urine pH to assure a value ≥ 7.0 and 
monitor urine output to determine if volume is ≥ 80% of the fluid intake, measured every 4 hours. If 
serum creatinine rises significantly, at any time point (> 100% in 24 hours), assure appropriate 
urine pH and urine volume as above and consider glucarpidase If urine output fails to continue at 

 
 
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80% of the fluid intake, consider furosemide or acetazolamide. Regardless of urine output, also 
consider glucarpidase (carboxypeptidase G2) (see below). 
 
48 hr MTX level  Leucovorin Rescue  
≤ 0.5 μM  
Continue 15 mg/m2 IV/PO q 6hrs for 2 doses.  
0.5 – 1 μM  
Increase to 15 mg/m2 q 6 hrs until MTX level < 0.1 μM (draw q 6-24 hrs).  
1 – 5 μM  
Increase to 15 mg/m2 q 3 hrs until MTX level < 0.1 μM (draw q 6-24 hrs).  
5 – 10 μM  
Increase to 100 mg/m2 q 6hrs until MTX level < 0.1 μM (draw q 6-24 
hrs).  
> 10 μM  
Increase to 1000 mg/m2 q 6hrs until MTX level < 0.1 μM (draw q 6-24 
hrs).  
Consider glucarpidase.  
 
4.7.7.2 Nephrotoxicity  
 
Postpone course if pre-treatment (MTX) serum creatinine is > 1.5 x baseline or GFR creatinine 
clearance < 65 mL/minute/1.73m2. If there is a rising creatinine (> 100% in 24 hours) or the 48 hour 
methotrexate level is > 10 μ/L consider using glucarpidase. If renal function does not recover, omit 
MTX. Do not give ID MTX to a patient with this degree or renal impairment, assuming that prolonged 
excretion can be managed with glucarpidase.  
 
NOTE: For patients who have markedly delayed MTX clearance secondary to renal dysfunction, 
consider using glucarpidase (carboxypeptidase G2, VoraxazeTM). To obtain supplies of 
glucarpidase in the US contact the Voraxaze 24-hour Customer Service line at 855-786-7292. 
Additional 
information 
can 
be 
found 
at 
http://www.btgplc.com/products/specialty-
pharmaceuticals/voraxaze regarding product availability through ASD Healthcare, Cardinal, and 
McKesson. Canadian sites should contact McKesson at (877) 384-7425 for further information. 
Sites in Australia and New Zealand should contact Hospira at 1300 – 046 – 774 (local) or 
medicalinformationAUS@hospira.com. Patients requiring glucarpidase rescue will remain on 
study.  
 
Stop leucovorin 2 hours before administering glucarpidase as it is a competitive substrate and may 
compete with MTX for glucarpidase binding sites.  
 
Dose of glucarpidase: 50 units/kg administered by intravenous bolus over 5 minutes. Reconstitute 
each vial with 1 mL sodium chloride 0.9% (do not further dilute). Each vial contains 1,000 units/mL 
(after reconstitution) and round dose up to vial size. No further dose is required.  
Maintaining alkalinization of urine with sodium bicarbonate is essential to maintain urinary pH > 7.  
It is essential that patients are NOT co-prescribed the following medicines which reduce MTX 
excretion: NSAIDS, aspirin, ciprofloxacin, co-trimoxazole, penicillin, probenecid, omeprazole. 
 
Two hours after administration of glucarpidase, leucovorin should be administered at a dose of 250 
mg/m2 every 6 hours by IV bolus (maximum rate: 160 mg/min) for up to 48 hours and then 
decreased based on plasma MTX concentrations to 15 mg/m2 intravenously or orally every 6 hours 
until the plasma MTX concentration is < 0.2 μM.  
 
4.7.7.3 Liver dysfunction 
 
Samples for the determination of ALT value must be drawn within 72 hours, PRIOR to a course of 
intravenous MTX. Blood samples for ALT should not be drawn following the start of MTX infusions 
as MTX causes significant short term elevation in ALT levels. 
 

 
 
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ALT 
IV Methotrexate 
< 10 X ULN  
Continue with therapy as scheduled  
10 – 20 X ULN  
Continue with therapy as scheduled  
10 – 20 X ULN for 2 
consecutive cycles  
Discontinue TMP/SMX*  
Hold therapy until ALT < 10 X ULN, then resume at full doses  
> 20 X ULN  
Hold therapy until ALT < 10 X ULN, then resume at full doses at 
point of interruption. Do not skip doses.  
> 20 X ULN for > 2 weeks  Evaluate with AST, Bili, Alkaline phosphatase, PT, albumin, total 
protein, and hepatitis A, B, C, CMV, and EBV serologies.  
Consider liver biopsy before additional therapy given. Notify 
Study Chair.  
* Please see COG Supportive care Guidelines at: https://members.childrensoncologygroup.org/prot/reference_materials.asp for TMP/SMX 
substitutions.  
 
Hold IV MTX for direct hyperbilirubinemia of > 2.0 mg/dL.  
 
 
 
4.7.7.4 Mucositis 
 
For Grade 3 - 4 mucositis, withhold IV MTX until resolved.  
 
4.7.7.5 Excess extravasation of fluids into tissues (third spacing) 
 
For Grade 3-4 fluid third-spacing, withhold IV MTX until toxicity has resolved to Grade 2 or less.  
 
4.7.8 
Dexamethasone 
  
4.7.8.1 Hypertension 
 
Dose should not be reduced. Sodium restriction and anti-hypertensives should be employed in an 
effort to control hypertension. Avoid calcium channel blockers due to their potential prohemorrhagic 
effect.  
 
 
 
4.7.8.2 Hyperglycemia 
 
Dose should not be reduced for hyperglycemia. Rather, insulin therapy should be employed to 
control the blood glucose level.  
 
 
 
4.7.8.3 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.  
 
4.7.8.4 Osteonecrosis 
 
Do not modify corticosteroid therapy for osteonecrosis (CTCAE v5.0 term: avascular necrosis) 
during Block 1.  
 
 
 
4.7.8.5 Varicella  
 
Steroids should be held during active infection unless being taken as per protocol therapy 
guidelines. Do not hold during incubation period following exposure.  
 

 
 
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4.7.8.6 Severe infection 
 
Do not hold or discontinue steroids during Block 1 without serious consideration, as this is a critical 
period in the treatment of ALL. Later in therapy, one may consider holding steroid until patient 
achieves cardiovascular stability, except for “stress doses.”  
 
 
 
4.7.8.7 Severe psychosis 
 
Dexamethasone dose may be reduced by 50% for severe psychosis. If symptoms persist, switch 
to prednisone 
 
4.7.9 
Vincristine (VCR) 
 
In this protocol, it may be difficult to determine if peripheral neuropathy in Block 1 is due to VCR or 
ixazomib. Both agents can cause peripheral neuropathy and there is some overlap in their 
presentation. Ixazomib is commonly associated with painful sensory peripheral neuropathy. VCR 
neuropathy, in contrast, is commonly associated with motor or mixed neuropathy, including distal 
extremity weakness.  
 
 
 
4.7.9.1 Severe neuropathic pain (Grade 3 or greater) 
 
 
 
Please use “Balis” Scale for grading neuropathy (see text box in 4.7.1.1) 
 
Hold dose(s). When symptoms subside, resume at 50% previous calculated VCR dose (maximum 
dose: 1 mg), then escalate to full dose as tolerated. NOTE: neuropathic pain can be not only severe 
but difficult to treat. However, because vincristine is an important component of curative therapy 
and the majority of neuropathies are ultimately reversible, vincristine therapy may be given at full 
dose at investigator discretion. Severe peripheral neuropathies, with or without a positive family 
history might suggest the need for a molecular diagnostic evaluation to rule out Charcot Marie 
Tooth Disease (CMT), Type 1A or Hereditary neuropathy with liability to pressure palsies. Drugs 
such as gabapentin may be of value.  
 
 
 
4.7.9.2 Vocal Cord paralysis 
 
Hold dose(s). When symptoms subside, resume at 50% previous calculated dose (maximum dose: 
1 mg), then escalate to full dose as tolerated. See above for comment on CMT.  
 
 
 
4.7.9.3 Foot Drop, paresis 
 
Should be Grade 3 to consider holding or decreasing dose. These toxicities are largely reversible 
but over months to years. Accordingly, holding doses of vincristine and/or lowering the dose may 
not result in rapid resolution of symptoms and may compromise cure. See above for comment on 
CMT. Physical therapy may be beneficial to maintain range of motion and provide AFO’s and other 
forms of support. Drugs such as gabapentin may be of value.  
 
 
 
4.7.9.4 Jaw pain 
 
Treat with analgesics; do not modify vincristine dose. 
 
 
 
4.7.9.5 Hyperbilirubinemia  
 
 
 
Direct Bilirubin 
Dose Adjustment  

 
 
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≤ 3.0 mg/dL  
Full dose (maximum dose: 2 mg),  
3.1- 5.0 mg/dL  
50% of calculated dose (maximum dose: 1 mg) 
5.1-6.0 mg/dL  
75% of calculated dose (maximum dose: 0.5 mg) 
> 6.0 mg/dL  
Withhold dose and administer next scheduled dose if toxicity has resolved. 
Do not make up missed doses.  
 
4.7.9.6 Constipation or ileus (≥ Grade 3) or typhlitis 
 
Hold dose(s); institute aggressive regimen to treat constipation if present. When symptoms abate, 
resume at 50% of calculated dose (maximum dose: 1 mg) and escalate to full dose as tolerated.  
 
4.7.9.7 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. Also see 
https://members.childrensoncologygroup.org/_files/disc/Nursing/extravasationguidelines.pdf for 
COG guidelines 
 
 
5.0 
SUPPORTIVE CARE 
 
Best supportive care and treatment will be given as appropriate to each patient (antiemetics, antibiotics, 
transfusions, oxygen therapy, nutritional support, palliative treatment for pain or cough, etc.). Patients may 
experience profound myelosuppression and immune suppression during this time. Caregivers must also 
be made aware that patients may experience very rapid clinical deterioration. This suggests the need for a 
supportive care network that can recognize and respond to sudden changes in a patient’s condition. 
 
Hospitalization during each course of chemotherapy is strongly recommended until the absolute phagocyte 
count (sum of the neutrophils, bands and monocytes) is rising for two successive days, and the patient is 
afebrile and clinically stable. An additional discharge criterion of an absolute neutrophil count (ANC) of at 
least 200/μL is also suggested. 
 
Aggressive supportive care improves outcome. The following guidelines are intended to give general health 
direction for optimal patient care and to encourage uniformity in the treatment of this patient population. 
Notify the Study Chair of any unexpected or unusually severe complications. 
 
5.1 
Concurrent Therapy 
 
5.1.1 
Chemotherapy or Investigational Therapy 
Patients must not receive any non-protocol chemotherapy, investigational therapy, or immune 
modulating agents.  
 
5.1.2 
Cranial Irradiation for CNS disease is NOT allowed during protocol therapy. 
 
5.1.3 
Radiotherapy for Chloroma is NOT allowed  
 
5.1.4 
Appropriate Antibiotics, Blood Products, Antiemetics, Fluids, Electrolytes and general supportive 
care are to be used as necessary.  See section 5.3 for additional information regarding infection 
control 
 

 
 
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5.1.5 
Patients May Have Received Hydroxyurea to keep WBC below 50,000/μL prior to beginning 
protocol therapy, but hydroxyurea must be discontinued 24 hours prior to starting systemic protocol 
therapy. 
 
5.1.6 
Cardiac Protectants: Patients can receive cardiac protectants such as Dexrazoxane (Zinecard®) 
while treated on this protocol per treating physician’s decision. 
 
5.1.7 
Alternative Medications: Use of alternative medications (eg, herbal or botanical for anticancer 
purposes) is not permitted during the entire study period. 
 
5.2 
Blood Products 
 
Investigators should follow institutional guidelines regarding the administration of blood products. 
 
5.3 
Infection Control 
 
5.3.1 
Pneumocystis Prophylaxis 
 
All patients are to receive prophylaxis with Trimethoprim/Sulfamethoxazole (TMP-Sulfa) for 
Pneumocystis for two sequential days each week at a dose of 2.5 mg/kg/dose TMP-Sulfa 
(maximum dose of 160 mg) twice daily (BID) or according to institutional policy, unless they have 
a documented sulfa allergy. Sulfa-allergic patients should receive dapsone 2 mg/kg orally (PO) q 
day with a maximum dose of 100 mg/day, or monthly pentamidine (IV or aerosolized). 
Pneumocystis prophylaxis should be continued throughout the entire study period. 
 
5.3.2 
Bacterial, Fungal and Viral Prophylaxis 
 
Secondary to the high risk of serious invasive bacterial and fungal infection in patients with relapsed 
ALL and LLy, prophylaxis for bacterial and fungal infections is MANDATED on this protocol. 
Subjects should receive levofloxacin at a dose based on each institution’s formulary (but as a 
recommendation, levofloxacin could be dosed at 10 mg/kg/dose (MAX 750 mg/dose) IV or PO twice 
daily if <5 years old and at 10 mg/kg/dose (MAX 750 mg/dose) IV or PO once daily if ≥5 years old).   
 
All patients MUST receive antifungal prophylaxis during each course of therapy. Anti-fungal 
prophylaxis may be given per each institution’s standards. It is strongly encouraged to use a 
drug with anti-mold activity such as caspofungin or micafungin. The doses used should be in the 
treatment range more so than prophylactic as that is when colonization and infection may occur 
with patients at high risk for fungal infection.  
 
For subjects with a history of documented or suspected HSV or varicella zoster virus infection, it is 
recommended for them to receive prophylactic acyclovir per institutional standard (as a 
recommendation acyclovir could be dosed at 750 mg/m2/day divided BID.) 
 
It is strongly recommended that patients have quantitative immunoglobulins checked per 
institutional policy, but at least once per cycle.  Those with quantitative Ig <500 should receive IVIG 
monthly.  
 
Bacterial, fungal and viral prophylaxis should be initiated on DAY 8 of each cycle and continued at 
least until the post-nadir ANC is > 500/µL. 
 

 
 
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5.3.3 
Fever and Neutropenia 
 
All patients with a fever >38.5°C on a single occasion, or >38°C on 2 occasions within 12 hours, 
and an ANC <0.50 x 109/L are to be hospitalized and treated immediately with intravenous broad-
spectrum antibiotics after obtaining appropriate cultures. The specific choice of antibiotics to be 
used in empiric treatment of febrile neutropenia is dependent on each institution’s experience 
regarding the type of infecting organisms, and their antibiotic sensitivity patterns. Duration of 
therapy should be determined by site of infection, culture results, and response to treatment. 
Antifungal treatment is to be considered for the persistence of fever, or emergence of a new fever 
in neutropenic patients after 3 days of broad-spectrum antibiotic coverage. Surveillance 
radiographic imaging surveillance for sites of infection should also be performed as clinically 
indicated. When severe mucositis or a sepsis syndrome is present in patients with febrile 
neutropenia, or a patient has a history of prior alpha hemolytic sepsis, consider inclusion of 
Vancomycin in the empiric antibiotic regimen. 
 
5.3.4 
Empiric Management of Pulmonary Infiltrates 
 
Pulmonary infiltrates should be evaluated in the context of the patient's clinical and laboratory 
profile as well as institutional infection patterns. If the patient is not neutropenic, and the pulmonary 
lesions on CT scan are not particularly suggestive of a fungal infection (Aspergillus, mucor), 
consider using broad spectrum antibiotics. If the patient develops progressively worsening clinical 
or laboratory features, or if, the pulmonary lesions on CT scan are suggestive of a fungal infection 
(Aspergillus, mucor), then more aggressive diagnostic measures should be undertaken. Pulmonary 
infiltrates may be evaluated with bronchoscopy and biopsy, lavage or open lung biopsy. If a 
procedure cannot be tolerated, and/or if there is high clinical suspicion consider beginning empiric 
treatment with amphotericin B given the high likelihood of fungal disease. It is advisable to seek an 
infectious disease consult under these circumstances. Empiric coverage may include treatment of 
gram-negative and positive bacteria, Legionella (erythromycin), Pneumocystis (TMP/SMX), and 
fungi (amphotericin) pending culture results. 
 
If fungal pulmonary disease is documented, surveillance radiographic imaging studies of the 
sinuses, abdomen/pelvis are indicated. Surgical excision of pulmonary lesions should be 
considered at the discretion of the treating physician. Treatment of fungal infections with 
amphotericin B and/or other antifungal agents will be at the discretion of the treating physician.  
 
5.3.5 
Management of Mucositis/Perirectal Cellulitis 
 
Mucositis should be managed with IV hydration and hyperalimentation (if indicated), effective 
analgesia, broad-spectrum gram-positive and gram-negative antibiotic therapy and empiric antiviral 
and antifungal therapy as indicated. Management of perirectal cellulitis should include broad-
spectrum antibiotic therapy with dual gram-negative coverage as well as anaerobic coverage (i.e. 
ceftazidime + aminoglycoside + metronidazole; or piperacillin-tazobactam + aminoglycoside), Sitz 
baths, a strong barrier technique and effective analgesia. 
 
5.3.6 
Use of growth factors (G-CSF) 
The routine use of G-CSF outside of protocol therapy is not generally recommended, but may be 
used at the discretion of the investigator in situations such as serious infection with neutropenia. 
 
 

 
 
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6.0 
DRUG INFORMATION 
 
6.1 
IXAZOMIB  
 
6.1.1 
Nomenclature and Molecular Structure 
 
Ixazomib citrate (Ixazomib citrate (MLN9708), the active pharmaceutical ingredient, is a new active 
substance and a pro-drug of the active moiety, ixazomib (MLN2238).  
 
The chemical structure of ixazomib citrate (chemical name: CAS: 2,2'-{2-[(1R)-1-({[(2,5-
Dichlorobenzoyl)amino]acetyl}amino)-3-methylbutyl]-5-oxo-1,3,2-dioxaborolane-4,4-diyl}diacetic 
acid; molecular formula: C20H23BCl2N2O9) is presented below. 
  
             Figure 1   Chemical structure of ixazomib citrate (MLN 9708) 
 
 
                                     
 
                                  
6.1.2 
Mode of Action and Pharmacology 
 
6.1.2.1 Pharmacodynamics related to mechanism of action 
 
In adults, after IV administration, maximum inhibition of 20S proteasome activity occurred 
within 30 minutes in most patients, indicating rapid target engagement in blood. Prolonged 
inhibition of 20S proteasome activity (>24 hours) was not apparent. The observed 
pharmacodynamic profile is consistent with ixazomib being a reversible proteasome 
inhibitor. 
 
6.1.2.2 Pre-clinical pharmacology data   
 
Pre-clinical safety pharmacology studies and assessments both in vitro and in vivo 
indicated that effects on the cardiovascular (CV), respiratory, and nervous system were 
limited to microscopic neuronal injury, primarily in dogs, that was occasionally associated 
with neurological clinical signs. The microscopic neuronal injury associated with ixazomib 
in animals has also been reported with the PI bortezomib and is associated with peripheral 
neuropathy that has been observed in adult patients treated with bortezomib. Peripheral 
neuropathy has also been infrequently observed in pediatric patients treated with 
bortezomib. In adult patients with MM, the reported incidence of peripheral neuropathy 
after ixazomib treatment was much less than that reported after bortezomib treatment. 
Ixazomib did not cause the CV electrocardiography effects that have been reported with 
another PI, carfilzomib.  
 

 
 
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The overall safety pharmacology data with ixazomib indicate a low potential for CV-, 
respiratory-, renal, or CNS-related safety pharmacology effects in patients; however, there 
is a potential for peripheral nervous system effects in both adult and pediatric patients. 
 
Additional details, including results of in vitro binding and enzymatic assays, are available 
in Section 4.2 of the Investigator Brochure  
 
6.1.2.3 Clinical pharmacology data 
 
The clinical pharmacology of ixazomib has been characterized in adults using data from 
14 clinical studies. In each study, blood samples (rich or sparse sampling) were collected 
for assessment of relevant PK endpoints. A population PK analysis has also been 
performed using data from 755 patients (108 patients receiving IV ixazomib; 647 patients 
receiving oral ixazomib) enrolled across 10 clinical studies, including the phase 3 study 
C16010.45 Two single-agent studies (C16001 and C16002) in 146 patients were conducted 
with the IV formulation. All other studies have investigated oral ixazomib either alone or in 
combination with other agents.  
 
The potential for drug-drug interactions with strong CYP3A inhibitors and strong CYP3A 
inducers and the effect of a high-fat meal on ixazomib PK have been investigated in Study 
C16009. The ADME properties of ixazomib have been investigated in Study C16016. 
Studies in special populations have been conducted to investigate the effects of renal 
impairment (Study C16015)46 and hepatic impairment (Study C16018)47 on the PK of 
ixazomib. Studies have also been conducted in Asian patient populations (Studies C16013 
[East Asian patients]48 and TB-MC010034 [Japanese patients]).49 
  
The key clinical pharmacology information for ixazomib is summarized below. Please refer 
to Section 5.3 of the Investigator’s Brochure for additional details. 
 
Absorption  
 
After PO administration, ixazomib absorption is fast with an overall median time to 
maximum observed concentration of approximately 1 hour postdose. The plasma exposure 
of ixazomib following multiple-dose administration (IV or oral) increased approximately 
dose proportionally over the 0.48 to 3.95 mg/m2 dose range (1.4-8.9 mg actual 
administered dose range) based on noncompartmental analysis. On the basis of the 
population PK analysis, no readily apparent relationship was observed between the oral 
dose (0.2-10.6 mg) and apparent oral clearance, supporting the conclusion from the 
noncompartmental analysis of dose-linear PK. An absolute oral bioavailability of 58% was 
determined for ixazomib on the basis of the population PK analysis of IV and oral PK data.  
 
The effect of a high-fat meal on the PK of orally administered ixazomib was investigated in 
adults.50 A high-fat meal decreased both the rate and extent of ixazomib absorption with a 
69% and 28% reduction in the maximum observed concentration (Cmax) and area under 
the plasma concentration-time curve (AUC), respectively, observed in the fed versus fasted 
state. The results from this food effect study are consistent with the Biopharmaceutics 
Classification System Class 3 category of ixazomib.51 Therefore, PO ixazomib should be 
taken on an empty stomach, at least 1 hour before or 2 hours after food.  
  
Distribution  
 

 
 
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The steady-state volume of distribution of ixazomib is large and is estimated to be 543 L 
on the basis of the population PK model. Ixazomib is 99% bound to plasma proteins and 
the extent of binding is not altered by severe renal or hepatic impairment. Ixazomib 
distributes into red blood cells with a blood-to-plasma ratio of 10. 
 
Metabolism  
 
Metabolism is expected to be the major mechanism of clearance (CL) of ixazomib as renal 
CL contributes approximately 6.4% to total CL. At clinically relevant concentrations of 
ixazomib, in vitro studies using recombinant CYPs indicated that no specific CYP isozyme 
predominantly contributes to ixazomib metabolism and that non-CYP proteins contribute 
to overall metabolism. Therefore, at clinically relevant concentrations of ixazomib, minimal 
CYP-mediated DDIs with a selective CYP inhibitor are expected.  
 
Elimination  
 
The geometric mean terminal half-life for ixazomib is 9.5 days and the mean plasma CL is 
1.86 L/hr on the basis of the population PK analysis. The geometric mean renal CL of 
ixazomib is 0.119 L/hr, which is 6.4% of total CL; thereby indicating that renal CL does not 
meaningfully contribute to ixazomib CL in humans. Taken together with the blood-to-
plasma AUC ratio of approximately 10, it can be inferred that ixazomib is a low CL drug.  
 
In the human absorption, distribution, metabolism, and excretion (ADME) study, 
approximately 62% of the administered radioactive PO dose was recovered in the urine 
and 22% was recovered in the feces. Only 3.2% of the administered ixazomib dose was 
recovered in the urine as unchanged drug up to 168 hours after oral dosing, suggesting 
that most of the total radioactivity in urine was attributable to metabolites. Metabolite 
profiling of excreta indicated that ixazomib is metabolized to multiple deboronated 
metabolites that are pharmacologically inactive and predominantly excreted in the urine. 
 
6.1.2.4 Effect of Intrinsic Factors on the PK of Ixazomib  
 
Age, Sex, and Race  
 
There was no clinically meaningful effect of age (23-91 years), sex, or race on the CL of 
ixazomib on the basis of the results of a population PK analysis. The mean AUC was 35% 
higher in Asian patients; however, there was overlap in the distribution of AUC across white 
and Asian patients. 
  
Renal Impairment  
 
Adult patients with mild or moderate renal impairment (creatinine clearance [CrCL] ≥30 
mL/min) were included in all clinical studies during ixazomib development. In the population 
PK model, CrCL was not identified as a significant covariate; therefore, no dose adjustment 
is required for patients with mild or moderate renal impairment. 
 
The PK of ixazomib in adult patients with severe renal impairment (CrCL<30 mL/min, 
including patients with end-stage renal disease [ESRD] requiring dialysis) was examined 
in a dedicated clinical study (Study C16015). The geometric least squares mean ratio (90% 
CI) for unbound AUC for the combined analysis of severe renal impairment and ESRD 
patients requiring hemodialysis versus normal renal function was 1.38 (0.93-2.04), 
indicating that unbound exposures of ixazomib were 38% higher in these patients 

 
 
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compared with patients with normal renal function. A reduced starting dose of ixazomib is 
recommended for patients with severe renal impairment or ESRD requiring hemodialysis. 
Ixazomib is not readily dialyzable and thus, can be administered without regard to the 
timing of dialysis.  
 
Hepatic Impairment  
 
Adult patients with mild hepatic impairment (total bilirubin less than or equal to the upper 
limit of the normal range [ULN] and aspartate aminotransferase [AST] >ULN or total 
bilirubin >1-1.5×ULN and any AST) were included in all clinical studies during ixazomib 
development. In the population PK model, bilirubin was not identified as a significant 
covariate on CL; therefore, no dose adjustment is necessary for patients with mild hepatic 
impairment. 
 
The PK of ixazomib in adult patients with moderate (total bilirubin >1.5-3×ULN) or severe 
(total bilirubin >3×ULN) hepatic impairment was assessed in a dedicated clinical study 
(Study C16018). For the combined analysis of moderate and severe hepatic impairment 
versus normal hepatic function, the geometric least squares mean ratio (90% CI) for 
unbound dose-normalized AUC was 1.27 (0.75-2.16), indicating that unbound systemic 
exposures of ixazomib are 27% higher in these patients compared with patients with 
normal hepatic function. A reduced starting dose of ixazomib is recommended for patients 
with moderate or severe hepatic impairment. 
 
Additional details are available in Section 5.3 of the Investigator Brochure.  
 
6.1.3 
Drug Interactions 
 
6.1.3.1 CYP Inhibitors  
 
The effect of a strong CYP3A inhibitor on the PK of ixazomib was examined in a dedicated 
clinical study (C16009 Arm 5). The effect of strong CYP1A2 inhibitors on the PK of ixazomib 
was examined using population PK analysis. These CYPs were chosen for investigation 
on the basis of the rank order of relative biotransformation activity for 10 μM ixazomib of 
the major human CYP isozymes, where they contributed >25% to the metabolism of 
ixazomib in recombinant CYPs.  
 
Ixazomib Cmax and AUC were similar when ixazomib was co-administered with or without 
a strong CYP3A inhibitor (clarithromycin). The geometric least squares mean ratios (90% 
CIs) for Cmax and AUC were 0.96 (0.67-1.36) and 1.11 (0.86-1.43), respectively, indicating 
that clarithromycin did not have a clinically meaningful effect on the PK of ixazomib. No 
dose adjustment is necessary when ixazomib is co-administered with strong CYP3A 
inhibitors.  
 
The effect of strong CYP1A2 inhibitors (eg, ciprofloxacin) on the PK of ixazomib was 
examined in the population PK analysis as a time-dependent categorical covariate. On the 
basis of covariate analysis, CYP-modulatory drugs, including strong CYP1A2 inhibitors, 
had no statistically significant effect on the PK of ixazomib. No dose adjustment is 
necessary when ixazomib is co-administered with strong CYP1A2 inhibitors.  
 
6.1.3.2 CYP Inducers 
 

 
 
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The effect of rifampicin, a pleiotropic inducer of multiple pregnane X receptor (PXR)-
inducible drug-metabolizing enzymes and transporters and an established strong CYP3A 
inducer, on the PK of ixazomib was examined in a dedicated clinical study (C16009 Arm 
4). Ixazomib Cmax was reduced in the presence of rifampicin by approximately 54%; 
corresponding geometric least squares mean ratio (90% CI) of 0.46 (0.29-0.73). Ixazomib 
AUC was reduced by approximately 74%; corresponding least squares geometric mean 
ratio (90% CI) of 0.26 (0.18-0.37). On the basis of these data, the co-administration of 
strong CYP3A inducers (such as carbamazepine, phenytoin, rifampicin, and St. 
John’s wort) with ixazomib should be avoided.  
 
6.1.3.3 Effect of Ixazomib on Other Drugs and Transporter-Based Interactions  
 
Ixazomib is neither a time-dependent nor reversible inhibitor of CYPs 1A2, 2B6, 2C8, 2C9, 
2C19, 2D6, or 3A4 (IC50 >30 μM, inhibitory concentration [Ki] >15 μM); therefore, the 
potential for ixazomib to produce drug-drug interactions via CYP isozyme inhibition is low.  
 
Ixazomib did not induce CYP1A2, CYP2B6, and CYP3A4 activity or corresponding 
immunoreactive protein levels under conditions where prototypical inducers caused 
anticipated increases in CYP activity (with ixazomib concentrations up to 9.67 μM). 
Therefore, ixazomib is unlikely to produce drug-drug interactions via induction of 
metabolism- or transporter-mediated CL of co-administered drugs, as it did not induce 
expression of any of the representative sensitive downstream CYP enzymes that are 
induced via the arylhydrocarbon receptor (eg, CYP1A2), constitutive androstane receptor 
(eg, CYP2B6), or PXR (eg, CYP3A4/5).  
 
Ixazomib is not a substrate of BCRP, MRP2, and OATPs. Ixazomib is not an inhibitor of P-
gp, BCRP, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, multidrug and toxin 
extrusions protein (MATE) 1, and MATE2-K. Ixazomib is unlikely to cause or be susceptible 
to clinical drug-drug interactions with substrates or inhibitors of clinically relevant drug 
transporters. 
 
6.1.4 
Toxicity/Adverse Events 
 
As of 27March2022, the overall safety population in oncology studies comprises 3360 patients in 
phase 1 to 3 studies who have received at least 1 dose of ixazomib or placebo in ongoing and 
completed open-label or unblinded studies.  Safety data is available from 1974 patients who have 
received at least 1 dose of ixazomib in open-label or unblinded studies, regardless of route of 
administration. 
 
Study C16010, a global, pivotal, phase 3, double-blind multicenter trial in patients with 
relapsed/refractory MM, was conducted to evaluate the safety of ixazomib when added to LenDex 
as the background chemotherapeutic regimen. At the primary analysis, the median age of enrolled 
patients was 66 years (range 30–91 years). Given the advanced age (median of 70 years) of 
patients with MM at diagnosis,52 distinguishing between disease-related and treatment-related AEs 
in nonrandomized clinical trials is difficult because of the multiple co-morbidities in patients or 
overlapping toxicities of the background regimen; therefore, the results of this double-blind, 
placebo-controlled study are informative to characterize the safety of the addition of ixazomib to 
the background regimen.  
 
At the final analysis as of the data cut off date of 28September2020, the percentage of patients 
reporting at least 1 treatment-emergent AE (TEAE) was similar between the ixazomib regimen and 
placebo regimen, with incidence rates of 99% for both, consistent with an oncology setting where 

 
 
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patients’ life-threatening disease is being treated with cytotoxic therapy. Grade ≥3 TEAEs were 
reported in 80% of patients in the ixazomib regimen and 74% of patients in the placebo regimen. 
The frequency of serious AEs was 57% and 56%, respectively, with 21 (6%) and 30 (8%) on-study 
deaths, respectively. The frequency of TEAEs resulting in treatment discontinuation 
(discontinuation of all 3 agents) was similar between the regimens (25% ixazomib regimen; 22% 
placebo regimen), suggesting that ixazomib does not add substantial toxicity to the background 
regimen. The most frequently reported AEs are noted in Table 2. The most frequently reported 
treatment-related serious adverse event (SAE) in both the ixazomib and placebo regimen was 
pneumonia (6% and 8%, respectively). 
 
Table 2 The most frequently reported AE (≥20%) in patients with relapsed/refractory MM 
 
Adverse Events 
Ixazomib 
Placebo 
Diarrhea 
52% 
43% 
Constipation 
35% 
28% 
Anemia 
35% 
31% 
Fatigue 
32% 
29% 
Nausea 
32% 
23% 
Neutropenia 
31% 
28% 
Thrombocytopenia 
28% 
13% 
Back pain 
27% 
24% 
Upper respiratory tract infection 
27% 
23% 
Peripheral edema 
27% 
21% 
Vomiting 
26% 
13% 
Nasopharyngitis 
25% 
24% 
Peripheral sensory neuropathy 
24% 
17% 
Insomnia 
23% 
30% 
Pneumonia 
22% 
20% 
Bronchitis 
22% 
17% 
Cough 
20% 
18% 
Muscle spasms 
19% 
28% 
Pyrexia 
18% 
22% 
 
Data from the pivotal phase 3 Study C16010 demonstrated that some AEs (eg, thrombocytopenia, 
nausea, vomiting, diarrhea, and rash) are overlapping toxicities with ixazomib and lenalidomide. 
While some TEAE categories (eg, thrombocytopenia, nausea, vomiting, diarrhea, and 
rash,peripheral neuropathy, and bronchitis) occurred more frequently (difference of at least 5 
percentage points) in the ixazomib regimen than in the placebo regimen, they were predominantly 
low grade, manageable with supportive care and dose modification, and generally did not lead to 
more treatment discontinuations with ixazomib.  
 
Overall, ixazomib in combination with LenDex did not substantially increase toxicity of the 
background regimen and there was no evidence of cumulative or long-term toxicity after a 
median follow-up of approximately 7 years as of the data cutoff date of 28September2020. 
The TEAEs were consistent with the reported safety profile of the individual agents in the 
combination regimen and were tolerable and manageable.  
 
 
Per the currently approved Ixazomib Investigator’s Brochure edition 15 dated 25May2022, 
important identified risks associated with ixazomib treatment include rash, nausea, vomiting, 
diarrhea, thrombocytopenia, and peripheral neuropathy. Important potential risks include the 
uncommon risk of Stevens-Johnson Syndrome, and the rare risk of toxic epidermal necrolysis 
(TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, and 

 
 
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pemphigus vulgaris. All of these important identified and potential risks associated with ixazomib 
use have been managed by routine risk minimization measures (product labeling) and routine 
pharmacovigilance measures.  
 
Clinical investigations into the potential benefit of ixazomib are ongoing through a comprehensive 
and global development plan that involves several company-sponsored clinical studies. 
 
6.1.5 
Pregnancy and Nursing Mothers 
 
In an embryo-fetal development study in pregnant rabbits there were increases in fetal skeletal 
variations/abnormalities at doses that were also maternally toxic. In a rat dose range-finding 
embryo-fetal development study, at doses that were maternally toxic, there were decreases in fetal 
weights, a trend toward decreased fetal viability, and increased postimplantation losses.  
 
Embryo-fetal lethality has been observed in rats and rabbits with other proteasome inhibitors (such 
as bortezomib and carfilzomib)53,54 at doses that are minimally toxic to dams. On the basis of the 
data with ixazomib and other drugs in this class, there is the potential for embryo-fetal effects in 
humans with ixazomib.  
 
Fertility and prenatal and postnatal development studies have not been performed.  
Additional details are available in Sections 4.3.4 of the Investigator Brochure. 
 
6.1.6 
Formulation, Preparation and Stability 
 
Ixazomib drug product has been developed for use in clinical studies as both a parenteral 
lyophilized powder for injection formulation and as an oral solid (immediate release capsule) 
dosage formulation. The parenteral lyophilized formulation of ixazomib, MLN9708 Powder for 
Solution for Injection, has been previously investigated in adult clinical trials (Studies C16001 and 
C16002) and is considered suitable for the pediatric population as it can be administered in varying 
doses based on body surface area (BSA) to all age groups.  
 
The parenteral dosage form, MLN9708 Powder for Solution for Injection, is a lyophilized powder 
consisting of 5.72 mg of ixazomib citrate (equivalent to 4.0 mg of ixazomib), citric acid monohydrate, 
sodium citrate dihydrate and glycine as excipients in a single use glass vial.  
 
The solution structure of ixazomib citrate was also evaluated in aqueous solution in the presence 
of excess citric acid. A high percentage of the ester structure is maintained due to the presence of 
excess of citric acid. Under physiological conditions, ixazomib citrate rapidly hydrolyzes to ixazomib 
(Figure 2). Ixazomib is the biologically active, boronic acid form of ixazomib citrate.  
 
 
 
Figure 2 
Hydrolysis of ixazomib citrate (MLN 9708) to ixazomib (MLN 2238) 
 

 
 
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The use of the lyophilized formulation for clinical studies is supported by available long term stability 
data. Satisfactory stability was demonstrated up to 60 months when stored at 5°C ±3°C.  
 
The ixazomib capsule formulation consists of ixazomib citrate and common pharmaceutical 
excipients, including microcrystalline cellulose, talc, and magnesium stearate encapsulated in a 
hard gelatin capsule for oral administration. A total of 7 different capsule strengths consisting of 0.2, 
0.5, 2.0, 2.3, 3.0, 4.0, and 5.5 mg of biologically active ixazomib have been developed for the 
clinical studies. Capsule strengths are differentiated by unique capsule shell color. Ixazomib 
capsules corresponding to 0.2, 0.5, and 2.0 mg strengths are currently being investigated in 
multiple clinical studies whereas 2.3, 3.0, and 4.0 mg ixazomib capsule strengths are registered for 
commercialization.  
 
6.1.7 
Supplier 
 
Ixazomib will be supplied by Takeda Pharmaceuticals.  
 
 
Ingredient 
mg per Capsule 
 0.2-mg 
0.5-mg 
2.0-mg 
 2.3-mg 
3.0-mg 
4.0-mg 
Capsule 
Appearance 
Size 4,  
White 
opaque 
Size 3,  
Dark 
green 
Size 2,  
Swedish 
orange 
Size 4,  
Flesh/light 
pink 
Size 4,  
Light 
grey 
Size 3,  
Ivory 
opaque 
Package Size 
1x4 blister 
strips, 24 
count 
1x4 
blister 
strips, 24 
count 
1x4 blister 
strips, 24 
count 
1x3 blister 
strips, 3 
count 
1x3 
blister 
strips, 3 
count 
1x3 blister 
strips, 3 
count 
 
6.1.8 
Guidelines for Administration  
 
Ixazomib capsules and oral solution should be administered on an empty stomach, at least 1 hour 
before or at least 2 hours after food. If ixazomib cannot be administered on an empty stomach, the 
timing of food intake relative to ixazomib administration should be recorded.  
 
Capsule administration:   
 
Ixazomib capsules will be supplied by the sponsor as single capsules at 6 different dose strengths, 
containing 4.0, 3.0, 2.3, 2.0, 0.5 and 0.2 mg of ixazomib. Ixazomib capsule is dispensed in blisters 
in a child-resistant carton. For the 2.3, 3.0, and 4.0 mg capsule strengths, there are 3 capsules in 
each wallet/carton.  For patients receiving capsules, the BSA-based dose should be rounded to the 
nearest 0.2mg.  
 
Patients should be instructed to swallow ixazomib capsules whole with water and not to break, 
chew, or open the capsules. The capsule should be swallowed with a sip of water. A total of up to 
approximately 20-50 mL of water should be taken with the capsules. Under circumstances where 
home dosing is allowed, a missed dose can be taken as soon as the patient/parent remembers, as 
long as the next scheduled dose is 72 hours or more away. A double dose should not be taken to 
make up for a missed dose. If the patient vomits after taking a dose, the patient should not repeat 
the dose but should resume dosing at the time of the next scheduled dose. Please refer to the 
Pharmacy Manual for detailed instructions. 
 
Oral solution administration:  

 
 
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26October2022 
20July2023 
07September2023 
 
MLN9708 Powder for Solution for Injection will be supplied as a lyophilized drug product vial 
consisting of 5.72 mg of ixazomib citrate (equivalent to 4.0 mg of ixazomib). 
 
The investigational pharmacist will prepare the study treatment for ixazomib oral solution in drug 
product. For preparation of the active ixazomib treatment, each vial of MLN9708 Powder for 
Solution for Injection should be equilibrated at ambient temperature and reconstituted with 4.4 mL 
of water to 1.0 mg/ml. The drug product upon reconstitution should be administered within 4 hours, 
the reconstituted drug product would be further diluted with flavoring agent. The required dose 
should be administered to the patient by mouth [(or via nasogastric tube when clinically indicated)] 
via oral syringe, and should be followed by  approximately 20 – 50 ml of water. Please refer to the 
Pharmacy Manual for detailed instructions. 
  
Handling precautions:   
 
Ixazomib is an anticancer drug and, as with other potentially toxic compounds, caution should be 
exercised during handling. Patients should be instructed not to chew, break, or open capsules. In 
case of contact with broken capsules, raising dust should be avoided during the clean-up operation. 
The product may be harmful by inhalation, ingestion, or skin absorption. Gloves and protective 
clothing should be worn during clean-up and during return of broken capsules and powder to 
minimize skin contact. The area should be ventilated and the site washed with soap and water after 
material pick up is complete. The material should be disposed of as hazardous medical waste in 
compliance with federal, state, and local regulations. 
 
In case of contact with the powder (eg, from a broken capsule) or reconstituted oral solution, skin 
should be washed immediately with soap and copious amounts of water for at least 15 minutes. In 
case of contact with the eyes, copious amounts of water should be used to flush the eyes for at 
least 15 minutes.  Medical personnel should be notified. Please refer to the Pharmacy Manual for 
detailed instructions. 
   
6.1.9 
Storage, Handling, and Accountability 
 
On receipt at the investigative site, ixazomib capsules should remain in the blister and carton 
provided until use or dispensation. The ixazomib drug product is to be stored in a secure facility 
with controlled access. The MLN9708 Powder for Solution for Injection vial must be stored 
refrigerated at 2˚C to 8˚C (36˚F to 46˚F). A drug dispensing log, including records of drug received 
from the sponsor and drug dispensed to the patients, will be provided and kept at the study site. All 
excursions from the temperature storage guidelines should be brought to the sponsor’s attention 
for assessment and authorization for continued use. Ensure that the drug is used before the retest 
expiry date provided by Millennium. Expiry extensions will be communicated accordingly with 
updated documentation to support the extended shelf life. 
 
In the event that take-home dosing of ixazomib capsules is allowed, the capsule dispensed to the 
patient should remain in the blister packaging and carton and stored as directed until the point of 
use. Patients who are receiving take-home medication should be given only 1 cycle of medication 
at a time. Comprehensive instructions should be provided to the patient to ensure compliance with 
dosing procedures. Patients should be instructed to return their empty or partially used cartons to 
the investigative site at their next visit, rather than discarding them, as permitted by site policy. 
Reconciliation will occur accordingly when the patient returns at their next visit for take-home 
medication. Any excursions in temperature should be reported and dealt with on a case-by-case 
basis. Please refer to the Pharmacy Manual for detailed instructions. 
 

 
 
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Protocol Amendment #1 Version Date: 
 Protocol Amendment #2 Version Date:  
 Protocol Amendment #3 Version Date:  
 Protocol Amendment #4 Version Date:  
 Protocol Amendment #5 Version Date: 
 Protocol Amendment #6 Version Date 
 Protocol Amendment #7 Version Date: 
 
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16September2020 
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07September2023 
6.2 
ASPARAGINASE or crisantaspase (Erwinase®) or Erwinia  
chrysanthemi (recombinant)-rywn (Rylaze®) 
 
6.2.1 
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. The following data have been reported on each of the three preparations 
of asparaginase: 
 
Clinical Pharmacology 
of Asparaginase  
Formulation  
Elimination half-life (IM)  
% Anti-Asparaginase Antibody 
positive patients  
Native Escherichia Coli  
26-30 hours 
45-75 
Pegylated-asparaginase  
5.5-7 days 
5-18 
Erwinia Asparaginase  
16 hours (7-13 hrs package 
insert) 
30-50 
From: Avramis, V; Panosyan, E; Pharmacokinetic/Pharmacodynamic Relationships of Asparaginase 
Formulations: The Past, the Present and Recommendations for the Future. Clin Pharmacokinet 2005; 44 
(4): 367-393. 
 
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. 
 
Asparaginase erwinia chrysanthemi (recombinant)-rywn contains an asparagine specific bacterial 
enzyme (L-asparaginase). L-asparaginase is a tetrameric enzyme that consists of four identical 
35 kDa subunits with a combined molecular weight of 140 kDa. The amino acid sequence is 
identical to native asparaginase Erwinia chrystanthemi (also known as crisantaspase). The 
activity of asparaginase erwinia chrysanthemi (recombinant)-rywn is expressed in units, defined 
as the amount of enzyme that catalyzes the conversion of 1μmol of L-asparagine per reaction 
minute, per mg of protein. Asparaginase erwinia chrysanthemi (recombinant)-rywn is produced by 
fermentation of a genetically engineered Pseudomonas fluorescens bacterium containing the 
DNA which encodes for asparaginase Erwinia chrysanthemi. 
 

 
 
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Protocol Amendment #1 Version Date: 
 Protocol Amendment #2 Version Date:  
 Protocol Amendment #3 Version Date:  
 Protocol Amendment #4 Version Date:  
 Protocol Amendment #5 Version Date: 
 Protocol Amendment #6 Version Date 
 Protocol Amendment #7 Version Date: 
 
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16September2020 
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24January2022 
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6.2.2 
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 
 
 
Pancreatitis, glucose intolerance, thrombosis, 
hemorrhage, transient ischemic attack, 
disseminated intravascular coagulation, 
hyperbilirubinemia, alanine aminotransferase 
increased, aspartate aminotransferase 
increased, 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.  
 
6.2.3 
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 intact vials between 2°C and 8°C (36° to 
46ºF). Protect from light.  
 
Asparaginase erwinia chrysanthemi (recombinant)-rywn) Rylaze®) injection is supplied as a 
sterile, clear to opalescent, colorless to slightly yellow, preservative-free solution for intramuscular 
injection. Each 0.5 mL contains 10 mg asparaginase erwinia chrysanthemi (recombinant)-rywn 
and the inactive ingredients: polysorbate 80 (0.1 mg), sodium chloride (1.5 mg), sodium 
phosphate dibasic anhydrous (0.8 mg), sodium phosphate monobasic monohydrate (0.6 mg), and 
trehalose (32.1 mg). Sodium hydroxide may be added to adjust the pH. The pH is approximately 
7. 
 
6.2.4 
Guidelines for Administration 
 
See Treatment and Dose Modification sections of the protocol.  
 
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 

 
 
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 Protocol Amendment #2 Version Date:  
 Protocol Amendment #3 Version Date:  
 Protocol Amendment #4 Version Date:  
 Protocol Amendment #5 Version Date: 
 Protocol Amendment #6 Version Date 
 Protocol Amendment #7 Version Date: 
 
19December2019 
16September2020 
11May2021 
24January2022 
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07September2023 
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. Polycarbonate luer-lok syringes from B-D (1 mL) are also acceptable (personal 
communication, EUSA Pharma). 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. 
 
6.2.5 
Supplier 
 
Commercially available. See package insert for further information. 
 
 
6.3 
CYCLOPHOSHAMIDE - INJECTIONCYCLOPHOSPHAMIDE - INJECTION  
 
6.3.1 
Source and Pharmacology 
 
Cyclophosphamide is an alkylating agent related to nitrogen mustard. Cyclophosphamide is 
inactive until it is metabolized by P450 isoenzymes (CYP2B6, CYP2C9, and CYP3A4) in the liver 
to active compounds. The initial product is 4-hydroxycyclophosphamide (4-HC) which is in 
equilibrium with aldophosphamide which spontaneously releases acrolein to produce 
phosphoramide mustard. Phosphoramide mustard, which is an active bifunctional alkylating 
species, is 10 times more potent in vitro than is 4-HC and has been shown to produce interstrand 
DNA cross-link analogous to those produced by mechlorethamine. Approximately 70% of a dose 
of cyclophosphamide is excreted in the urine as the inactive carboxyphosphamide and 5-25% as 
unchanged drug. The plasma half-life ranges from 4.1 to 16 hours after IV administration.  
 
6.3.2 
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  
Anorexia, nausea & 
vomiting  
(acute and delayed)  
Abdominal discomfort, 
diarrhea  
Transient blurred vision, nasal 
stuffiness with rapid administration, 
arrhythmias (rapid infusion), skin 
rash, anaphylaxis, SIADH  
Prompt:  
Within 2-3 
weeks, prior 
to the next 
course  
Leukopenia, 
alopecia, immune 
suppression  
Thrombocytopenia, 
anemia, hemorrhagic 
cystitis (L)  
Cardiac toxicity with high dose (acute 
– CHF hemorrhagic myocarditis, 
myocardial necrosis) (L), 
hyperpigmentation, nail changes, 
impaired wound healing, infection 
secondary to immune suppression  
Delayed:  
Any time later 
during 
therapy  
Gonadal dysfunction: 
azoospermia or 
oligospermia 
Amenorrhea1  
Gonadal dysfunction: ovarian failure1 
(L), interstitial pneumonitis, 
pulmonary fibrosis2 (L)  

 
 
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Protocol Amendment #1 Version Date: 
 Protocol Amendment #2 Version Date:  
 Protocol Amendment #3 Version Date:  
 Protocol Amendment #4 Version Date:  
 Protocol Amendment #5 Version Date: 
 Protocol Amendment #6 Version Date 
 Protocol Amendment #7 Version Date: 
 
19December2019 
16September2020 
11May2021 
24January2022 
26October2022 
20July2023 
07September2023 
 
1 Dependent on dose, age, gender, and degree of pubertal development at time of treatment.  
2 Risk increased with pulmonary chest irradiation and higher doses.  
(L) Toxicity may also occur later.  
 
 
6.3.3 
Formulation and Stability 
 
Cyclophosphamide for injection is available as powder for injection or lyophilized powder for 
injection in 500 mg, 1 g, and 2 g vials. The powder for injection contains 82 mg sodium 
bicarbonate/100 mg cyclophosphamide and the lyophilized powder for injection contains 75 mg 
mannitol/100 mg cyclophosphamide. Storage at or below 25ºC (77ºF) is recommended. The 
product will withstand brief exposures to temperatures up to 30ºC (86ºF).  
 
6.3.4 
Guidelines for Administration 
 
See Treatment and Dose Modifications sections of the protocol.  
 
Cyclophosphamide for Injection: Reconstitute with NS, SWFI, or Bacteriostatic Water for Injection 
(paraben preserved only) to a concentration of 20 mg/mL. If administered as undiluted drug at the 
20 mg/mL concentration, reconstitute with NS only to avoid a hypotonic solution. Solutions 
reconstituted with preservative should be used within 24 hours if stored at room temperature or 
within 6 days if stored under refrigeration.  
 
Cyclophosphamide may be further diluted in dextrose or saline containing solutions for IV use.  
 
6.3.5 
Supplier 
Commercially available from various manufacturers. See package insert for further information.  
 
6.4 
DOXORUBICIN (Adriamycin®) NSC #123127 (05/09/11)  
 
6.4.1 
Source and Pharmacology 
 
An anthracycline antibiotic isolated from cultures of Streptomyces peucetius. The cytotoxic effect 
of doxorubicin on malignant cells and its toxic effects on various organs are thought to be related 
to nucleotide base intercalation and cell membrane lipid binding activities of doxorubicin. 
Intercalation inhibits nucleotide replication and action of DNA and RNA polymerases. The 
interaction of doxorubicin with topoisomerase II to form DNA-cleavable complexes appears to be 
an important mechanism of doxorubicin cytocidal activity. Doxorubicin cellular membrane binding 
may affect a variety of cellular functions. Enzymatic electron reduction of doxorubicin by a variety 
of oxidases, reductases, and dehydrogenases generate highly reactive species including the 
(prolonged or 
permanent)1 (L)  
Late:  
Any time after 
completion of 
treatment 
 
 
Secondary malignancy (ALL, ANLL, 
AML), bladder carcinoma (long term 
use > 2 years), bladder fibrosis 
Unknown 
Frequency 
and Timing:  
Fetal toxicities and teratogenic effects of cyclophosphamide (alone or in combination 
with other antineoplastic agents) have been noted in humans. Toxicities include: 
chromosomal abnormalities, multiple anomalies, pancytopenia, and low birth weight. 
Cyclophosphamide is excreted into breast milk. Cyclophosphamide is contraindicated 
during breast feeding because of reported cases of neutropenia in breast fed infants 
and the potential for serious adverse effects.  

 
 
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Protocol Amendment #1 Version Date: 
 Protocol Amendment #2 Version Date:  
 Protocol Amendment #3 Version Date:  
 Protocol Amendment #4 Version Date:  
 Protocol Amendment #5 Version Date: 
 Protocol Amendment #6 Version Date 
 Protocol Amendment #7 Version Date: 
 
19December2019 
16September2020 
11May2021 
24January2022 
26October2022 
20July2023 
07September2023 
hydroxyl free radical (OH•). Free radical formation has been implicated in doxorubicin cardiotoxicity 
by means of Cu (II) and Fe (III) reduction at the cellular level. Cells treated with doxorubicin have 
been shown to manifest the characteristic morphologic changes associated with apoptosis or 
programmed cell death. Doxorubicin-induced apoptosis may be an integral component of the 
cellular mechanism of action relating to therapeutic effects, toxicities, or both. 
  
Doxorubicin serum decay pattern is multiphasic. The initial distributive t½ is approximately 5 
minutes suggesting rapid tissue uptake of doxorubicin. The terminal t½ of 20 to 48 hours reflects a 
slow elimination from tissues. Steady-state distribution volumes exceed 20 to 30 L/kg and are 
indicative of extensive drug uptake into tissues. Plasma clearance is in the range of 8 to 20 
mL/min/kg and is predominately by metabolism and biliary excretion. The P450 cytochromes which 
appear to be involved with doxorubicin metabolism are CYP2D6 and CYP3A4. Approximately 40% 
of the dose appears in the bile in 5 days, while only 5 to 12% of the drug and its metabolites appear 
in the urine during the same time period. Binding of doxorubicin and its major metabolite, 
doxorubicinol, to plasma proteins is about 74 to 76% and is independent of plasma concentration 
of doxorubicin. 
 
6.4.2 
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, pink or 
red color to urine, sweat, 
tears, and saliva  
Hyperuricemia, facial 
flushing, sclerosis of the 
vein  
Diarrhea, anorexia, 
erythematous streaking of the 
vein (flare reaction), 
extravasation (rare) but if 
occurs = local ulceration, 
anaphylaxis, fever, chills, 
urticaria, acute arrhythmias  
Prompt:  
Within 2-3 weeks, 
prior to the next 
course  
Myelosuppression 
(leukopenia, 
thrombocytopenia, 
anemia), alopecia  
Mucositis (stomatitis and 
esophagitis), 
hepatotoxicity  
Radiation recall reactions, 
conjunctivitis and lacrimation  
Delayed:  
Any time later 
during therapy 
 
Cardiomyopathy1 (CHF 
occurs in 5-20% at 
cumulative doses ≥ 450 
mg/m²) (L)  
Cardiomyopathy1 (CHF 
occurs in < 5% at cumulative 
doses ≤ 400 mg/m²) (L), 
ulceration and necrosis of 
colon,  
hyper-pigmentation of nail 
bed and dermal crease, 
onycholysis  
Late:  
Any time after 
completion of 
treatment  
Subclinical cardiac 
dysfunction  
CHF (on long term follow 
up in pediatric patients)  
Secondary malignancy (in 
combination regimens)  
Unknown 
Frequency and 
Timing:  
Fetal and teratogenic toxicities. Carcinogenic and mutagenic effects of doxorubicin 
have been noted in animal models. Doxorubicin is excreted into breast milk in humans  
 1 Risk increases with cardiac irradiation, exposure at a young or advanced age.  
(L) Toxicity may also occur later.  
 
6.4.3 
Formulation and Stability 

 
 
T 2 0 1 7 -0 0 2  Pr ot o c ol V er si o n : A m e n d m e nt # 7- 0 7 S e p 2 0 2 3                     5 9  
C O N FI D E N TI A L          
 
T A C L I nt er n al Di stri b uti o n O nl y  
T A C L Pr ot oc ol:  
T 2 0 1 7 -0 0 2  
Pr ot o c ol A m e n d m e nt # 1 V er si o n D at e:  
  Pr ot o c ol A m e n d m e nt # 2 V er si o n D at e :  
  Pr ot o c ol A m e n d m e nt # 3 V er si o n D at e:  
  Pr ot o c ol A m e n d m e nt # 4 V er si o n D at e:   
  Pr ot o c ol A m e n d m e nt # 5 V er si o n D at e : 
  Pr ot o c ol A m e n d m e nt # 6 V er si o n D at e  
  Pr ot o c ol A m e n d m e nt # 7 V er si o n D at e:  
 
1 9 D e c e m b er 2 0 1 9  
1 6 S e pt e m b er 2 0 2 0  
1 1 M a y 2 0 2 1  
2 4 J a n u ar y 2 0 2 2  
2 6 O ct o b er 2 0 2 2  
2 0 J ul y 2 0 2 3  
0 7 S e pt e m b er 2 0 2 3  
 
D o x or u bi ci n i s a v ail a bl e a s r e d -or a n g e l y o p hili z e d p o w d er f or i nj e cti o n i n 1 0 m g¹, 2 0 m g¹, 5 0 m g¹ 
vi al s a n d a pr e s er v ati v e -fr e e 2 m g/ m L s ol uti o n i n 1 0 m g¹, 2 0 m g¹, 5 0 m g¹, 2 0 0 m g² vi al s.  
¹ C o nt ai n s l a ct o s e m o n o h y dr at e, 0. 9 N S, H Cl t o a dj u st p H t o 3. T h e A dri a m y ci n R D F (r a pi d di s s ol uti o n 
f or m ul a) al s o c o nt ai n s m et h yl p ar a b e n, 1 m g p er e a c h 1 0 m g of d o x or u bi ci n, t o e n h a n c e di s s ol uti o n.  
² M ulti pl e d o s e vi al c o nt ai n s l a ct o s e, 0. 9 % N S, H Cl t o a dj u st p H t o 3.  
 
A q u e o u s S ol uti o n: St or e r efri g er at e d 2° -8° C, ( 3 6° -4 6° F). Pr ot e ct fr o m li g ht. R et ai n i n c art o n u ntil 
c o nt e nt s ar e u s e d.  
 
P o w d er f or I nj e cti o n: St or e u nr e c o n stit ut e d vi al at r o o m t e m p er at ur e, 1 5° -3 0° C ( 5 9° -8 6° F). R et ai n 
i n c art o n u ntil c o nt e nt s ar e u s e d. R e c o n stit ut e wit h pr e s er v ati v e-fr e e N S t o a fi n al c on c e ntr ati o n of 
2 m g/ m L. Aft er a d di n g t h e dil u e nt, t h e vi al s h o ul d b e s h a k e n a n d t h e c o nt e nt s all o w e d t o di s s ol v e. 
T h e r e c o n stit ut e d s ol uti o n i s st a bl e f or 7 d a y s at r o o m t e m p er at ur e a n d 1 5 d a y s u n d er r efri g er ati o n, 
2° -8° C ( 3 6° -4 6° F) w h e n pr ot e ct e d fr o m li g ht. D o x or u bi ci n f urt h er dil ut e d i n 5 0 – 1 0 0 0 m L of N S or 
D 5 W i s st a bl e f or u p t o 4 8 h o ur s at r o o m t e m p er at ur e ( 2 5° C) w h e n pr ot e ct e d fr o m li g ht.  
 
6. 4. 4  
G ui d eli n e s f or A d mi ni str ati o n  
 
S e e Tr e at m e nt a n d D o s e M o difi c ati o n s e cti o n s of t h e pr ot o c ol.  
 
A d mi ni st er I V t hr o u g h t h e t u bi n g of r a pi dl y i nf u si n g s ol uti o n of D 5 W or 0. 9 % N a Cl pr ef er a bl y i nt o a 
l ar g e v ei n. Pr ot e ct t h e dil ut e d s ol uti o n fr o m s u nli g ht. T o a v oi d e xtr a v a s ati o n, t h e u s e of a c e ntr al 
li n e i s s u g g e st e d.  
 
6. 4. 5  
S u p pli er  
 
C o m m er ci all y a v ail a bl e fr o m v ari o u s m a n uf a ct ur er s. S e e p a c k a g e i n s ert f or f urt h er i nf or m ati o n.   
 
6. 5  
E T O P O SI D E – I N J E C TI O N  
( V e P e si d ®, Et o p o p h o s ®, V P-1 6) N S C # 1 4 1 5 4 0 ( 0 5/ 0 9/ 1 1)  
 
6. 5. 1  
S o ur c e a n d P h ar m a c ol o g y  
 
A s e mi s y nt h eti c d eri v ati v e of p o d o p h yll ot o xi n t h at f or m s a c o m pl e x wit h t o p oi s o m er a s e II a n d D N A 
w hi c h r e s ult s i n si n gl e a n d d o u bl e str a n d D N A br e a k s. It s m ai n eff e ct a p p e ar s t o b e i n t h e S a n d 
G 2 p h a s e of t h e c ell c y cl e. T h e i niti al t ½ i s 1. 5 h o ur s a n d t h e m e a n t er mi n al h alf -lif e i s 4 t o 1 1 h o ur s. 
It i s pri m aril y e x cr et e d i n t h e uri n e. I n c hil dr e n, a p pr o xi m at el y 5 5 % of t h e d o s e i s e x cr et e d i n t h e 
uri n e a s et o p o si d e i n 2 4 h o ur s. T h e m e a n r e n al cl e ar a n c e of et o p o si d e i s 7 t o 1 0 m L/ mi n/ m² or 
a b o ut 3 5 % of t h e t ot al b o d y cl e ar a n c e o v er a d o s e r a n g e of 8 0 t o 6 0 0 m g/ m². Et o p o si d e, t h er ef or e, 
i s cl e ar e d b y b ot h r e n al a n d n o n r e n al pr o c e s s e s, i. e., m et a b oli s m a n d bili ar y e x cr eti o n. T h e eff e ct 
of r e n al di s e a s e o n pl a s m a et o p o si d e cl e ar a n c e i s n ot k n o w n. Bili ar y e x cr eti o n a p p e ar s t o b e a 
mi n or r o ut e of et o p o si d e eli mi n ati o n. O nl y 6 % or l e s s of a n i ntr a v e n o u s d o s e i s r e c o v er e d i n t h e 
bil e a s et o p o si d e. M et a b oli s m a c c o u nt s f or m o st of t h e n o n -r e n al cl e ar a n c e of et o p o si d e.  
 
T h e m a xi m u m pl a s m a c o n c e ntr ati o n a n d ar e a u n d er  t h e c o n c e ntr ati o n ti m e c ur v e ( A U C) e x hi bit a 
hi g h d e gr e e of p ati e nt v ari a bilit y. Et o p o si d e i s hi g hl y b o u n d t o pl a s m a pr ot ei n s ( ~ 9 4 %), pri m aril y 
s er u m al b u mi n. P h ar m a c o d y n a mi c st u di e s h a v e s h o w n t h at et o p o si d e s y st e mi c e x p o s ur e i s r el at e d 
t o t o xi cit y. Pr eli mi n ar y d at a s u g g e st s t h at s y st e mi c e x p o s ur e f or u n b o u n d et o p o si d e c orr el at e s 
b ett er t h a n t ot al ( b o u n d a n d u n b o u n d) et o p o si d e. T h er e i s p o or diff u si o n i nt o t h e C S F < 5 %.  
 
Et o p o si d e  p h o s p h at e  i s  a  w at er  s ol u bl e  e st er  of  et o p o si d e  w hi c h  i s  r a pi dl y  a n d  c o m pl et el y 
c o n v ert e d  t o  et o p o si d e  i n  pl a s m a.  P h ar m a c o ki n eti c  a n d  p h ar m a c o d y n a mi c  d at a  i n di c at e  t h at  

 
 
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etoposide phosphate is bioequivalent to etoposide when it is administered in molar equivalent 
doses.  
 
6.5.2 
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  
Anorexia  
Transient hypotension during 
infusion; anaphylaxis (chills, fever, 
tachycardia, dyspnea, 
bronchospasm, hypotension)  
Prompt:  
Within 2-3 
weeks, prior to 
next course  
Myelosuppression 
(anemia, leukopenia), 
alopecia  
Thrombocytopenia, 
diarrhea, abdominal pain, 
asthenia, malaise, rashes 
and urticarial  
Peripheral neuropathy, mucositis, 
hepatotoxicity, chest pain, 
thrombophlebitis, congestive heart 
failure, Stevens-Johnson Syndrome, 
exfoliative dermatitis  
Delayed:  
Any time later during 
therapy  
 
Dystonia, ovarian failure, 
amenorrhea, anovulatory cycles, 
hypomenorrhea, onycholysis of nails  
Late:  
Any time after 
completion of 
treatment  
 
Secondary malignancy (preleukemic 
or leukemic syndromes) 
Unknown 
Frequency 
and Timing:  
Fetal toxicities and teratogenic effects of etoposide have been noted in animals at 1/20th of 
the human dose. It is unknown whether the drug is excreted in breast milk.  
 
6.5.3 
Formulation and Stability 
 
Etoposide for Injection is available as a 20 mg/mL solution in sterile multiple dose vials (5 mL, 25 
mL, or 50 mL each). The pH of the clear, nearly colorless to yellow liquid is 3 to 4. Each mL contains 
20 mg etoposide, 2 mg citric acid, 30 mg benzyl alcohol, 80 mg modified polysorbate 80/tween 80, 
650 mg polyethylene glycol 300, and 30.5 percent (v/v) alcohol. Vial headspace contains nitrogen. 
Unopened vials of etoposide are stable until expiration date on package at controlled room 
temperature (20˚-25˚C or 68˚-77˚F).  
 
Etoposide phosphate for injection is available for intravenous infusion as a sterile lyophilized 
powder in single-dose vials containing etoposide phosphate equivalent to 100 mg etoposide, 32.7 
mg sodium citrate USP, and 300 mg dextran 40. Etoposide phosphate must be stored under 
refrigeration (2°-8°C or 36°-46°F). Unopened vials of etoposide phosphate are stable until the 
expiration date on the package.  
 
6.5.4 
Guidelines for Administration 
 
See Treatment and Dose Modification sections of the protocol.  
Etoposide:  
 
Dilute etoposide to a final concentration ≤ 0.4 mg/mL in D5W or NS. Etoposide infusions are stable 
at room temperature for 96 hours when diluted to concentrations of 0.2 mg/mL; stability is 24 hours 
at room temperature with concentrations of 0.4 mg/mL. The time to precipitation is highly 
unpredictable at concentrations > 0.4 mg/mL. Use in-line filter during infusion secondary to the risk 

 
 
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of precipitate formation. However, the use of an in-line filter is not mandatory since etoposide 
precipitation is unlikely at concentrations of 0.1-0.4 mg/mL. Do not administer etoposide by rapid 
intravenous injection. Slow rate of administration if hypotension occurs.  
 
Leaching of diethylhexyl phthalate (DEHP) from polyvinyl chloride (PVC) bags occurred with 
etoposide 0.4 mg/mL in NS. To avoid leaching, prepare the etoposide solution as close as possible, 
preferably within 4 hours, to the time of administration or alternatively as per institutional policy; 
glass or polyethylene-lined (non-PVC) containers and polyethylene-lined tubing may be used to 
minimize exposure to DEHP.  
 
 
Etoposide Phosphate: 
 
Reconstitute the 100 mg vial with 5 or 10 mL of Sterile Water for Injection, D5W, NS, Bacteriostatic 
Water for Injection with Benzyl Alcohol, or Bacteriostatic Sodium Chloride for Injection with Benzyl 
Alcohol for a concentration equivalent to 20 mg/mL or 10 mg/mL etoposide equivalent (22.7 mg/mL 
or 11.4 mg/mL etoposide phosphate), respectively. Use diluents without benzyl alcohol for 
neonates and infants < 2 years of age or patients with hypersensitivity to benzyl alcohol.  
 
When reconstituted as directed, etoposide phosphate solutions can be stored in glass or plastic 
containers under refrigeration for 7 days. When reconstituted with a diluent containing a 
bacteriostat, store at controlled room temperature for up to 48 hours. Following reconstitution with 
SWFI, D5W, or NS, store at controlled room temperature for up to 24 hours.  
 
Following reconstitution, etoposide phosphate may be further diluted to a concentration as low as 
0.1 mg/mL of etoposide with D5W or NS.. The diluted solution can be stored under refrigeration or 
at controlled room temperature for 24 hours.  
 
6.5.5 
Supplier  
 
Commercially available from various manufacturers. See package insert for more detailed 
information.  
 
6.6 
INTRATHECAL TRIPLE (Methotrexate/Hydrocortisone/Cytarabine) 
 
6.6.1 
Source and Pharmacology 
 
The intrathecal route of administration of a drug produces more consistent CSF drug concentrations 
at relatively smaller doses because of the volume difference between the CSF and blood 
compartments (140 mL vs. 3500 mL in an adult). (The CSF volume of children after the first 3 years 
is equivalent to that of an adult). Drug half-lives are longer as well because clearance is related to 
flow rather than metabolism or protein binding. Intrathecal methotrexate has a biphasic elimination 
curve from the CSF with a t½ of 4.5 and 14 hours respectively. Following IT injection of cytarabine 
the elimination of the drug from the CSF is biphasic with a t½ of 1 and 3.4 hours respectively which 
is 8-fold longer than the clearance from plasma. The elimination of hydrocortisone is similarly 
prolonged.  
 
6.6.2 
Toxicity 
 
 
Common 
Happens to 21-
100 children 
Occasional  
Rare  
Happens to < 5 children out of every 100  

 
 
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out of every 
100  
Happens to 5-20 
children out of every 
100  
Immediate:  
Within 1-2 days of  
receiving drug  
Nausea, 
vomiting, fever, 
headache  
Arachnoditis: 
(headache, fever, 
vomiting, meningismus 
and pleocytosis)  
Rash, anaphylaxis (L), paresis, bleeding into 
subarachnoid or subdural space (risk > with 
platelet counts <20,000), confusion, fatigue, 
disorientation, seizures  
Prompt:  
Within 2-3 weeks, 
prior to the next 
course 
 
 
Myelosuppression, somnolence, ataxia, 
cranial nerve palsy, transient and rarely 
permanent paraplegia (L), speech disorders 
Delayed:  
Any time later 
during therapy, 
excluding the 
above condition 
 
Cognitive disturbances 
(L), learning disabilities 
(L)  
Demyelating leukoencephalopathy1 (L), 
blindness1  
Late:  
Any time after the 
completion of 
treatment 
 
 
Progressive CNS deterioration1 
1 May be enhanced by systemic therapy such as high dose methotrexate or cytarabine and/or cranial irradiation.  
(L) Toxicity may also occur later.  
 
6.6.3 
Formulation and Stability 
 
Methotrexate 25 mg/mL preservative free 2 mL vial or methotrexate 20 mg preservative free sterile 
powder for injection vial. Cytarabine 100 mg preservative free sterile powder for injection. 
Hydrocortisone sodium succinate100 mg vial sterile powder for injection.  
 
6.6.4 
Guidelines for Administration 
 
See Treatment and Dose Modification sections of the protocol.  
For intrathecal administration, dilute each agent with 5-10 mL preservative free NS, lactated ringers 
or Elliot’s B solution or as per institutional standard of practice. The volume of CSF removed should 
be equal to at least half the volume delivered.  
 
Patient Age 
(years)  
Doses 
(MTX/hydrocortisone/
Ara-C)  
Recommended 
volume  
10% CSF 
volume  
CSF Volume  
1 – 1.99  
8 mg / 8 mg / 16 mg  
5-10 mL  
5 mL  
50 ± 10 mL  
(babies)  
2 – 2.99  
10 mg / 10 mg / 20 mg  5-10 mL  
8 mL  
80 ± 20 mL  
(younger children)  
3 – 8.99  
12 mg / 12 mg / 24 mg  5-10 mL  
10 mL  
100 ± 20 mL  
(older children)  
9 or greater  15 mg / 15 mg / 30 mg  5-10 mL  
13 mL  
130 ± 30 mL  
(adults)  
 
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.  

 
 
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Intrathecal triples are stable in NS for 24 hours at 25ºC but contain no preservative and should be 
administered as soon as possible after preparation.  
 
6.6.5 
Supplier 
 
Commercially available from various manufacturers. See package insert for further information.  
 
6.7 
LEUCOVORIN CALCIUM (LCV, Wellcovorin®, citrovorum factor, folinic acid) NSC #003590 
(05/09/11)  
 
6.7.1 
Source and Pharmacology 
 
Leucovorin is a mixture of the diastereoisomers of the 5-formyl derivative of tetrahydrofolic acid 
(THF). The biologically active compound of the mixture is the (-)- l-isomer, known as Citrovorum 
factor or (-)-folinic acid. Leucovorin does not require reduction by the enzyme dihydrofolate 
reductase in order to participate in reactions utilizing folates as a source of “one-carbon” moieties. 
Administration of leucovorin can counteract the therapeutic and toxic effects of folic acid 
antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase. In contrast, 
leucovorin can enhance the therapeutic and toxic effects of fluoropyrimidines used in cancer 
therapy, such as 5-fluorouracil. Leucovorin is readily converted to another reduced folate, 5,10-
methylenetetrahydrofolate, which acts to stabilize the binding of fluorodeoxyuridylic acid (an active 
metabolite of 5-FU) to thymidylate synthase and thereby enhances the inhibition of this enzyme. 
Peak serum levels of 5-methyl THF (an active metabolite) were reached at approximately 1.3-1.5 
hours (IV/IM) and 2.3 hours for the oral form. The terminal half-life of total reduced folates was 
approximately 6.2 hours. Following oral administration, leucovorin is rapidly absorbed and expands 
the serum pool of reduced folates. At a dose of 25 mg, almost 100% of the l-isomer (the biologically 
active form) but only 20% of the d-isomer is absorbed. Oral absorption of leucovorin is saturable at 
doses above 25 mg. The apparent bioavailability of leucovorin was 97% for 25 mg, 75% for 50 mg, 
and 37% for 100 mg doses. Both oral and parenteral leucovorin raise the CSF folate levels.  
 
6.7.2 
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 
 
 
Anaphylaxis, 
63rticarial, seizure 
Unknown Frequency 
and timing:  
Fetal toxicities and teratogenic effects of leucovorin in humans are 
unknown. It is unknown whether the drug is excreted in breast milk.  
  
6.7.3 
Formulation and Stability 
 
Leucovorin calcium for injection is supplied as a sterile ready to use liquid and a sterile powder for 
injection. The 10 mg/mL preservative free liquid is available in 50 mL vials containing sodium 
chloride 400 mg/vial. Store preservative free liquid in the refrigerator at 2°-8°C (36°-46°F) protected 
from light. The powder for injection is available in 50 mg, 100 mg, 200 mg, and 350 mg vials. Store 
at room temperature 15°-25°C (59°-77°F) protected from light. Reconstitute the sterile powder with 
sterile water for injection or bacteriostatic water for injection to a concentration of 10 mg/mL 
leucovorin calcium. Do not use diluents containing benzyl alcohol for doses > 10 mg/m² or in 

 
 
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infants < 2 years of age or patients with allergy to benzyl alcohol. When Bacteriostatic Water 
is used, the reconstituted solution is good for 7 days. If reconstituted with SWFI, use solution 
immediately as it contains no preservative. One milligram of leucovorin calcium contains 0.004 mEq 
of leucovorin and 0.004 mEq of calcium.  
 
The oral form of leucovorin is available as 5 mg, 10 mg, 15 mg, and 25 mg tablets. Inactive 
ingredients vary depending on manufacturer but tablet formulations may include: corn starch, 
dibasic calcium phosphate, magnesium stearate, pregelatinized starch, lactose, microcrystalline 
cellulose, and sodium starch glycolate.  
 
6.7.4 
Guidelines for Administration 
 
See Treatment and Dose Modifications sections of the protocol.  
 
Injection:  
Because of the calcium content of the leucovorin solution, no more than 160 mg of leucovorin 
should be injected intravenously per minute (16 mL of a 10 mg/mL solution per minute). IV 
leucovorin and sodium bicarbonate are incompatible.  
 
Oral:  
Oral leucovorin should be spaced evenly (e.g., every six hours) throughout the day and may be 
taken without regard to meals. Doses > 25 mg should be given IV due to the saturation of 
absorption.  
 
Leucovorin should not be administered < 24 hours after intrathecal injections which contain 
methotrexate unless there are special circumstances.  
 
6.7.5 
Supplier 
 
Commercially available from various manufacturers. See package insert for further information.  
 
6.8 
METHOTREXATE (MTX, amethopterin) NSC #000740 (02/29/12)  
 
6.8.1 
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. 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 

 
 
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circulation of MTX. The distribution of MTX into third-space fluid collections, such as pleural 
effusions and 65scetic 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.  
 
 
 

 
 
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6.8.2 
Toxicity 
 1 May be enhanced by HDMTX and/or cranial irradiation.  
(L) Toxicity may also occur later.  
 
Intrathecal Therapy (Methotrexate Single Agent) 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, 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)  
 
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  
Transaminase 
elevations  
Nausea, vomiting, 
anorexia  
Anaphylaxis, chills, fever, dizziness, 
malaise, drowsiness, blurred vision, 
acral erythema, urticaria, pruritis, toxic 
epidermal necrolysis, Stevens-Johnson 
Syndrome, tumor lysis syndrome, 
seizures1, photosensitivity  
Prompt:  
Within 2-3 weeks, 
prior to the next 
course 
 
Myelosuppression, 
stomatitis, 
gingivitis, 
photosensitivity, 
fatigue  
Alopecia, folliculitis, acne, renal toxicity 
(ATN, increased creatinine/BUN, 
hematuria), enteritis, GI ulceration and 
bleeding, acute neurotoxicity1 
(headache, drowsiness, aphasia, 
paresis, blurred vision, transient 
blindness, dysarthria, hemiparesis, 
decreased reflexes) diarrhea, 
conjunctivitis  
Delayed:  
Any time later 
during therapy, 
excluding the 
above conditions 
 
Learning disability1 
(L)  
Pneumonitis, pulmonary fibrosis (L), 
hepatic fibrosis (L), osteonecrosis (L), 
leukoencephalopathy1 (L), pericarditis, 
pericardial effusions, 
hyperpigmentation of the nails  
Late:  
Any time after the 
completion of 
therapy 
 
 
Progressive CNS deterioration1  
Unknown 
Frequency and 
Timing:  
Methotrexate crosses the placenta. Fetal toxicities and teratogenic effects of 
methotrexate have been noted in humans. The toxicities include: congenital 
defects, chromosomal abnormalities, severe newborn myelosuppression, low birth 
weight, abortion, and fetal death. Methotrexate is excreted into breast milk in low 
concentrations  

 
 
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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  
Delayed:  
Any time later during 
therapy, excluding the 
above condition  
Cognitive disturbances 
(L)1,  
learning disability (L)1  
Leukoencephalopathy1 
(L)  
Late:  
Any time after the 
completion of treatment 
 
 
Progressive CNS 
deterioration1 
  
1 May be enhanced by HDMTX and/or cranial irradiation.  
(L) Toxicity may also occur later.  
 
6.8.3 
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- 86ºF). Protect from light.  
 
6.8.4 
Guidelines for Administration 
 
See Treatment and Dose Modifications sections of protocol. Leucovorin rescue may be necessary 
with certain doses of methotrexate.  
 
For IM/IV use: Powder for injection: Dilute 1000 mg vial with 19.4 mL of preservative free SWFI, 
D5W or NS to a 50 mg/mL concentration. The powder for injection may be further diluted in NS or 
dextrose containing solutions to a concentration of ≤ 25 mg/mL for IV use.  
 
The 25 mg/mL solution may be given directly for IM administration or further diluted in Saline or 
Dextrose containing solutions for IV use. Do not use the preserved solution for high dose or 
intermediate dose methotrexate administration due to risk of benzyl alcohol toxicity. 
Methotrexate dilutions are chemically stable for at least 7 days at room temperature but contain no 
preservative and should be used within 24 hours. Diluted solutions especially those containing 
bicarbonate exposed to direct sunlight for periods exceeding 4 hours should be protected from light.  
 
High dose and intermediate dose methotrexate requires alkalinization of the urine, adequate 
hydration and leucovorin rescue. Avoid probenecid, penicillins, cephalosporins, aspirin, proton 
pump inhibitors, and NSAIDS as renal excretion of MTX is inhibited by these agents.  
 
For Intrathecal use: Use preservative free 25 mg/mL solution. 
  

 
 
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For intrathecal administration, dilute with 5-10 mL preservative free NS, 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 109  
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)  
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.  
 
6.8.5 
Supplier 
 
Commercially available from various manufacturers. See package insert for further information.  
 
6.9 
PEGASPARGASE (PEG-asparaginase, PEGLA, PEG-L-asparaginase, polyethylene glycol-L-
asparaginase, Oncaspar®) NSC #624239 (05/09/11)  
 
6.9.1 
Source and Pharmacology 
 
Pegaspargase 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 Pegaspargase 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 naïve adult patients with leukemia and 
lymphoma, initial plasma levels of L-asparaginase following intravenous administration of 
pegaspargase 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 
Pegaspargase. 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 pegaspargase (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 pegaspargase 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.  

 
 
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6.9.2 
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 
especially if previous 
hypersensitivity 
reaction to native 
asparaginase), pain 
at injection site, 
weakness, fatigue, 
diarrhea  
Allergic reactions 
(total likelihood of 
local, and or 
systemic reaction if 
no previous 
hypersensitivity 
reaction to native 
asparaginase), rash  
Anaphylaxis, hyper/hypotension, 
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  
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  
Hemorrhage (L), DIC, thrombosis, 
anorexia, weight loss, CNS ischemic 
attacks, edema, azotemia and 
decreased renal function, mild 
leukopenia, granulocytopenia, 
thrombocytopenia, pancytopenia, 
hemolytic anemia, infections (sepsis 
with/without septic shock, subacute 
bacterial endocarditis [SBE], URI), 
CNS changes including irritability, 
depression, confusion, EEG changes, 
hallucinations, coma and stupor, 
paresthesias, hypertriglyceridemia, 
hyperlipidemia, Parkinson-like 
syndrome with tremor and increase in 
muscular tone, hyperbilirubinemia, 
chest pain  
Delayed:  
Any time later 
during therapy 
 
 
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 pegaspargase. It is not 
known whether pegaspargase 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.  
 
6.9.3 
Formulation and Stability 
 
Each milliliter of pegaspargase 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 pegaspargase 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 

 
 
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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.  
 
For IM administration: the volume at a single injection site should be limited to 2 mL. If the volume 
to be administered is greater than 2 mL, multiple injection sites should be used.  
 
For IV administration: dilute pegaspargase in 100 mL of NS or D5W and infuse over 1 to 2 hours 
through a NS or D5W running infusion line. Pegaspargase admixed in 100 mL of NS or D5W is 
stable for 48 hours at room temperature. Pegaspargase diluted in 100 mL of NS is stable for up to 
72 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.  
 
6.9.4 
Supplier 
 
Commercially available from various manufacturers. See package insert for further information.  
 
6.10 
CALASPARGASE 
 
6.10.1  Source and Pharmacology 
 
L-asparaginase is an enzyme that catalyzes the conversion of the amino acid L-asparagine into aspartic 
acid and ammonia. The pharmacological effect ofCalaspargase-pegol-mknl is thought to be based on the 
killing of leukemic cells due to depletion of plasma asparagine. Leukemic cells with low expression of 
asparagine synthetase have a reduced ability to synthesize asparagine, and therefore depend on an 
exogenous source of asparagine for survival 
 
Calaspargase pegol-mknl contains an asparagine specific enzyme derived from Escherichia coli, as a 
conjugate of L-asparaginase (L-asparagine amidohydrolase) and monomethoxypolyethylene glycol 
(mPEG) with a succinimidyl carbonate (SC) linker. The SC linker is a chemically stable carbamate bond 
between the mPEG moiety and the lysine groups of L-asparaginase. L-asparaginase is a tetrameric 
enzyme that is produced endogenously by E. coli and consists of identical 34.5 kDa subunits. 
Approximately 31 to 39 molecules of SC-PEG are linked to L-asparaginase; the molecular weight of each 
SC-PEG molecule is about 5 kDa. The activity of ASPARLAS is expressed in units (U). ASPARLAS 
injection is supplied as a clear, colorless, preservative-free, isotonic sterile solution in phosphate-buffered 
saline, pH 7.3 that requires dilution prior to intravenous infusion. Each vial of ASPARLAS contains 3,750 
units in 5 mL of solution. Each milliliter contains 750 units of calaspargase pegol-mknl; dibasic sodium 
phosphate, USP (5.58 mg); monobasic sodium phosphate, USP (1.20 mg); and sodium chloride, USP 
(8.50 mg) in water for injection, USP 
 
Calaspargase-pegol-mknl  is an asparagine specific enzyme indicated as a component of a multi-agent 
chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia in pediatric and young adult 
patients age 1 month to 21 years. 
 
Pharmacology / Pharmacokinetics  
 

 
 
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Asparagine concentrations in plasma were maintained below the assay limit of quantification for more 
than 18 days following a single dose of calaspargase pegol 2,500 U/m2 during the induction phase. Mean 
CSF asparagine concentrations decreased from a pretreatment concentration of 0.8 μg/mL to 0.2 μg/mL 
on Day 4 and remained decreased at 0.2 μg/mL 25 days after the administration of a single dose of 
calaspargase pegol 2,500 U/m2 in the induction phase. Plasma asparaginase activity pharmacokinetics 
are nonlinear following calaspargase pegol administration. The time to peak concentration (Tmax) = 1.17 
hours and Cmax = 1.62 U/mL. Area under the curve (AUC0-∞) is 25.5 day x U/mL. Calaspargase pegol 
has a long elimination half-life (T1/2) of 16.1 days, volume of distribution (Vss) of 2.96 L, and clearance of 
0.147 L/day 
 
6.10.2 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 
Hypersensitivity  
 
 
Arrhythmia , Cardiac 
failure 
anaphylaxis 
Prompt:  
Within 2-3 weeks, prior 
to the next course  
Transaminitis  
Bilirubin increased  
Pancreatitis , Abnormal 
coagulation studies , 
Albumin decreased , 
Fibrinogen decreased , 
Diarrhea , 
Thromboembolic 
events,  Infection , 
Sepsis,  Dyspnea , 
Hemorrhage , Antibody 
development 
 
Delayed:  
Any time later during 
therapy  
Advise females of reproductive potential to use effective non-hormonal 
contraceptive methods during treatment with calaspargase pegol and for at 
least 3 months after the last dose. Counsel patients to use non- hormonal 
method(s) of contraception since calaspargase pegol can render hormonal 
contraceptives ineffective.  
There are no data on the presence of calaspargase pegol in human milk, the 
effects on the breastfed child, or the effects on milk production. Because of 
the potential for adverse reactions in the breastfed child, advise women not 
to breastfeed during treatment with calaspargase pegol and for 3 months 
after the last dose 
 
6.10.3 Formulation and stability 
 
Calaspargase pegol - mknl is a clear and colorless solution. Visually inspect parenteral drug products for 
particulate matter, cloudiness, or discoloration prior to administration. If any of these are present, discard 
the vial. Do not administer if calaspargase pegol - mknl has been shaken or vigorously agitated, frozen, or 
stored at room temperature for more than 48 hours.  
 
Dilute calaspargase pegol - mknl in 100 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose 
Injection, USP using sterile/aseptic technique. Discard any unused portion left in a vial.  
After dilution, administer immediately into a running infusion of either 0.9% sodium chloride or 5% 
dextrose, respectively. 
 

 
 
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Administer the dose over a period of 1-2 hours  
Do not infuse other drugs through the same intravenous line during administration of calaspargase pegol 
- mknl. 
The diluted solution may be stored for up to 4 hours at room temperature (15°C to 25°C [59°F to 77°F]) or 
refrigerated at 2°C to 8°C (36°F to 46°F). 
 
Calaspargase pegol – mknl  injection is supplied as a clear, colorless, preservative-free sterile solution in 
a single-dose vial containing 3,750 units of calaspargase pegol-mknl per 5 mL solution (NDC 72694-515-
01). Store calaspargase pegol - mknl. ASPARLAS refrigerated at 2°C to 8°C (36°F to 46°F) in the original 
carton to protect from light. Do not shake or freeze product. Unopened vials may be stored at room 
temperature (15°C to 25°C [59°F to 77°F]) for no more than 48 hours. 
 
6.10.4 Supplier 
 
Servier Pharmaceuticals LLC 
 
 
 
6.11 
VINCRISTINE SULFATE (Oncovin®, VCR, LCR) NSC #67574 (11/18/11)  
 
6.11.1 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 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.  
 
6.11.2 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  
Loss of deep 
tendon reflexes  
Peripheral paresthesias 
including numbness, 
tingling and pain; 
clumsiness; wrist drop, 
Difficulty walking or inability to walk; 
sinusoidal obstruction syndrome 
(SOS, formerly VOD) (in 
combination); blindness, optic 
atrophy; urinary tract disorders 

 
 
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foot drop, abnormal 
gait  
(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.  
 
6.11.3 Formulation and Stability 
 
Vincristine is supplied in 1 mL and 2 mL vials in which each contains vincristine sulfate, 1 mg (1.08 
μmol), mannitol 100 mg, SWFI; 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.  
 
Do not mix with any IV solutions other than those containing dextrose or saline.  
 
6.11.4 Guidelines for Administration 
 
See Treatment and Dose Modifications sections of protocol.  
 
The World Health Organization, the Institute of Safe Medicine Practices (United States) and the 
Safety and Quality Council (Australia) all support the use of minibag rather than syringe for the 
infusion of vincristine. The delivery of vincristine via either IV slow push or minibag is acceptable 
for COG protocols. 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 
intrathecally.  
 
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.”  
 
PLEASE NOTE: The warning statement in the vincristine USP monograph has been revised as 
stated above to the following: "Do not remove covering until moment of injection. For intravenous 
use only. Fatal if given by other routes." The prescribing information for the product by Teva USA 
has been revised to reflect this information. At the writing of this monograph, the Hospira 
prescribing information had not yet been revised.  
 

 
 
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This revision can be found in Pharmacopeial Forum 36(6) which is available free of charge on the 
USP website at http://www.usp.org/USPNF/pf/. The notice of intent to revise can be found at the 
following website: http://www.usp.org/USPNF/compendialNotices/vincristineSulfate.html. The 
official 
FDA-approved 
labeling 
can 
be 
found 
at 
the 
NIH’s 
DailyMed 
website: 
http://dailymed.nlm.nih.gov/dailymed/search.cfm?startswith=vincristine.  
 
6.11.5 Supplier 
 
Commercially available from various manufacturers. See package insert for more detailed 
information. 
 
6.12  
Dexamethasone (Decadron®, Hexadrol®, Dexone®, Dexameth®) NSC#34521 
 
6.12.1  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. 
 
6.12.2  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), 
pituitaryadrenalaxis 
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 
Cushing’s syndrome (moon 
facies, truncal obesity) 
Striae and thinning of the 
skin, easy bruising,  
Spontaneous fractures 
(L), 

 
 
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during therapy, 
excluding the 
above conditions 
 
Muscle weakness, 
osteopenia 
growth suppression, peptic 
ulcer and GI bleeding, 
pseudotumor cerebri 
(increased 
intracranial pressure 
with papilledema, 
headache), aseptic 
necrosis of the femoral 
and humeral heads 
(L) 
Late: 
Any time after 
completion of 
treatment 
 
Cataracts (which may be 
reversible on 
discontinuation of 
dexamethasone in 
children) 
 
Unknown Frequency and Timing: 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. 
 
 
6.12.3  Formulation and Stability: 
 
Available in 0.25, 0.5, 0.75, 1, 1.5, 2, 4, and 6 mg tablets; liquid formulations are available in 
0.5mg/5ml and 0.5mg/0.5ml concentration. 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. 
 
Dexamethasone sodium phosphate solution for injection is available as 4 mg/ml, 10 mg/ml, 20 
mg/ml and 24 mg/ml. 4 mg of dexamethasone sodium phosphate is equivalent to 3.33 mg of 
dexamethasone. Vial sizes include 1 ml, 5 ml, 10 ml, 25 ml, 30 ml and are available in 
multidose 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. 
 
6.12.4  Guidelines for Administration: 
 
See Treatment and Dose Modifications section of the protocol for dose and schedule. 
 
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 benzyl alcohol 
containing dexamethasone solutions for use in neonates. Diluted solutions that contain no 

 
 
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preservatives should be used within 24 hours, but maintain stability for at least 14 days in 
PVC bags at room temperature protected from light. 
 
6.12.5  Supplier: Commercially available. See package insert for further information. 
 
7.0 
REQUIRED OBSERVATIONS/MATERIAL AND DATA TO BE ASSESSIONED 
 
All protocol-specified hematology, blood chemistries, and bone marrow aspirations and/or biopsies are to 
be performed in the local laboratory at each investigational site. 
 
7.1 
Clinical and Laboratory Studies 
 
All entry/eligibility studies must be performed within 1 week prior to study enrollment. Disease evaluation is 
required within 2 weeks prior to study enrollment. Additional assessments may be obtained as needed for 
good patient care. 
 
Any Grade 3 or 4 lab tests or other adverse experiences found should be reviewed and repeated within 
48 hours to determine if the grade and duration meet the definition for DLT (section 4.4) 
 
         
This table represents SOC. Further tests or procedures may be needed for good clinical care. 
STUDIES TO BE 
OBTAINED 
Pre-
Study 
During Block 1 
During Block 2 
During Maintenance 
Block 
History 
X1 
Weekly 
Weekly 
Monthly 
Physical exam with vital 
signs 
X1 
Weekly 
Weekly 
Monthly 
Height, weight, BSA 
X1 
Start of the block 
Start of the block 
Start of the block 
Performance status 
X1 
N/A 
N/A 
N/A 
CBC, differential, platelets 
Chemistry panel2 
X1 
Twice weekly13  
Weekly 
Start of the block 
Neurological Exam14 
X1 
Prior to each 
Ixazomib dosing 
Prior to each Ixazomib 
dosing 
Perform every 28 
days prior to First 
dose of  Ixazomib  
Urine pregnancy or serum β-
HCG3 
X1 
 
Start of the block 
Start of the block 
Echocardiogram/MUGA/ECG 
X1 
End of block 
End of block 
Every 3 months   
CSF cell count and cytospin 
cytology 
X1 
With each dose of IT 
chemotherapy 
With each dose of IT 
chemotherapy 
With each dose of IT 
chemotherapy 
Bone marrow aspirate and/or 
biopsy for morphology, 
immunophenotyping   
X1 
Day 29-364 (section 
4.4) 
Day 29-364,6 (section 
4.4) 
X (optional)12 
Cytogenetic analysis 
X1,11 
X (optional)12 
X (optional)12 
X (optional)12 
Bone marrow for MRD7  
X1 
Day 29-364 (section 
7.3) 
Day 29-364,6 (section 
7.3) 
X (optional)12 
CT and PET or gallium – 
lymphoma patients or 
leukemia patients with 
cholorma5 
X1,8 
Day 29-368 (section 
4.4) 
Day 29-366 (section 4.4) 
X (optional)12 
Pharmacokinetics Studies9 
N/A 
X (required) 
X (required for Phase 2) 
N/A 

 
 
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Correlative biology studies10 
X 
(optional) 
X (optional) 
X (optional) 
N/A 
Palatibility studies 
N/A 
With each dose of 
ixazomib 
N/A 
N/A 
1Required for verification of eligibility. FAX or email all results to the TACL Operations Center with study registration eligibility.  
If a patient has labs done prior to study entry that establish eligibility, then abnormal Day 1 labs do not deem them ineligible. 
2Chemistry panel should include: chloride, sodium, potassium, magnesium, phosphorus, bicarbonate, BUN, creatinine, calcium, 
glucose, uric acid, total protein, albumin, total bilirubin, direct bilirubin, AST and ALT  
3Females of childbearing potential require a negative pregnancy test prior to start treatment and must use an acceptable 
method of birth control. Abstinence is an acceptable methods of birth control 
4This does not apply to lymphoma patients without marrow disease 
5Gallium scan may be substituted for PET scan at sites where PET is not available. PET without CT should not be used as a 
substitute for CT with contrast at any required evaluation point. The same scanning modality (gallium or PET) should be used 
for all required evaluation points. Combined PET/CT is acceptable.  
6Perform only if previous test was positive 
7See section 7.3 
8For lymphoma patients or leukemia patients with chloroma only 
9Detail see section 8.3 
10Detal see section 8.2 
11If cytogenetics is not done at the time of pre-study evaluation, diagnostic cytogenetics is accepted. 
12 If it is performed according to standard of care, please submit data  
13CBC twice a week are required until day 49 in the absence of hematological recovery  
14Neurological exam should be completed using Appendix VII: Neurological Exam form 
 
 
7.2 
Correlative Biology Studies  
 
Correlative biology studies include required pharmacokinetic (PK) studies and optional pharmacodynamic 
(PD) studies. Note: PD studies are limited to those with peripheral blasts with an absolute blast count of 
at least 1000 cell/uL. Unless otherwise noted, all PD studies are optional and require patient consent. For 
detailed information of sample collection, processing, and shipping see Section 8.0.  
 
 
Studies to be obtained 
 
Baseline (before start 
of chemotherapy) 
Day 1 Hour 0 
Day 1 Hour 6 
Day 1 Hour 24 
Proteasome activity 
X 
 
 
 
Cell Stress protein 
assessment (RPPA)* 
 
X 
X 
X 
Banking** 
X 
 
 
 
*RPPA for cell stress proteins: collect three time points if over 12kg.  If under 12 kg collect 2 time points at Day 1 
Hour 0 and Day 1 Hour 6 only. 
**Banking: for those over 12 kg only.  Please see Section 8 for volumes and tube types for sample collection.  
 
7.3 
Bone Marrow Sample for MRD 
 
Samples requested: 
Bone Marrow Sample for MRD  
• 
End of block 1 - all leukemia patients and lymphoma patients whose MRD 
was positive at the study entry 
• 
End of block 2 – all patients with positive MRD at end of block 1 

 
 
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Bone marrow Collection 
procedure: 
a. Collect minimum of 2 mL of marrow into a syringe and place marrow into a 
large purple EDTA tube that are commonly used in all hospitals. Mix well. 
b. Use multiple syringes and tubes as needed. Reposition marrow aspirates 
needle at least once during procedure to ensure the maximum quality of 
marrow 
Specimen Labeling: 
Please refer to the TACL MRD Lab Manual, Section V.2 for instructions regarding 
specimen labeling. 
Specimen Packaging and 
Shipping: 
 
Please refer to the TACL MRD Lab Manual, Section V.4 for instructions regarding 
specimen packaging and shipping. 
 
 
7.4 
Palatibility Study 
 
After each dose of ixazomib during block 1, a questionnaire will be provided to patient and parent/care 
giver. If the patient is too young to fill the survey, only parent/care giver will be surveyed. In each case, a 
nurse or research staff will record the verbal responses to the questions. When facial hedonic scales is 
utilized, the child or parent/care giver will be asked to indicate their preference by circling on the pictorial 
scale of facial expression. The palatability study questionnaire is provided in Appendix VI.  
 
7.5 
Required Observations Following Completion of Protocol Therapy 
 
Upon completing protocol therapy or exiting the study, all patients will be followed for 2 years or until 
otherwise notified by the study committee that the study is closed. Sites should submit follow-up a minimum 
of every 6 months. Events such as patient death, relapse or development of toxicity related to this therapy 
should be reported right away. The purpose is to assess safety, remission status, administration of 
alternative therapies, and survival. The following data will be collected: 
 
1) Disease status information 
2) Anti-cancer therapy received after exiting the protocol 
3) All adverse events thought to be related to this study’s treatment 
4) Date and cause of death 
 
8.0 
CORRELATIVE STUDIES 
 
An important component of this study is the correlative biology studies to preliminarily assess the 
mechanisms of ixazomib action in vivo. Prior to proteasome and protein analysis, peripheral lymphoblasts 
will be separated from non-malignant white blood cells using magnetic bead sorting. The Horton 
laboratory has experience with the isolation and purification of leukemia cells, which was done as part of 
two Phase 3 COG studies. 
  
8.1 
Description of Studies 
 
8.1.1  
Studies from peripheral blood mononuclear cells (PBMCs): PK studies will be performed on 
plasma samples collected for this purpose (see Section 8.3). PBMCs from blood will be used for 
analysis of proteasome activation and protein expression profiling by reverse-phase protein 
microarray (RPPA). If sample is available, we will also assess protein expression for proteins 
regulated by the ubiquitin-proteasome pathway (UPP).  Extra sample will be banked for future 
use. See Section 8.2 and 8.3 for test details.   
  
 

 
 
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8.1.2  
Study Prioritization: Due to limited sample availability, sample studies will be prioritized as follows 
(1=highest priority, 5=lowest priority): 1. MRD assessment (bone marrow) 2. Ixazomib PK 
analysis (blood) 3.  Characterization of proteasome activation before and after ixazomib treatment 
(blood) 4. Characterization of cell stress proteins by RPPA (blood) 5. Banking excess 
lymphoblasts and plasma for future studies (bone marrow and blood).  
  
8.2 
Sampling Schedule for optional PD studies 
 
Peripheral blood samples should be sent to the Horton lab only if the patient samples meet the following 
criteria: Eligible patients must have an initial absolute blast count of at least 1000 lymphoblasts/µL. To 
calculate the absolute blast percentage, multiply the total WBC by the % peripheral blasts:  
(WBC)(% blast)(1000) = absolute blast count/µL 
 
Sample collection volumes and time points during block 1:  
 
 
Baseline 
Day 1 Hour 0 
(baseline) 
Day 1 Hour 6 
Day 1 Hour 24 
Bone marrow 
(induction only)1 
3mL green top2  
 
 
 
Peripheral blood 
(induction only)3 
5mL in heparin for 
proteasome assessment4 
3mL in Cellsave5 
2mL in heparin4 
3mL in Cellsave5 
2mL in heparin4 
(4-6h after start of 
systemic chemo) 
3mL in Cellsave5 
2mL in heparin4 
(24h after the start 
of systemic 
chemotherapy) 
1Only applies to patients ≥ 12 Kg  
2Peripheral blood (20mL) with >80% blasts can be substituted if bone marrow not obtained.  
3Modified blood volumes for those under 12 kg (see 8.2.1 and 8.2.2 below) 
4Before the start of systemic chemotherapy.  Can be collected after IT chemotherapy 
5Cell Save preservation tubes will be provided by the Horton lab on study activation.  Replacement tubes will be 
provided once the first set us utilized. Call the Horton lab for replacement tubes. If Cell Save tubes are not 
available, collect 5cc in heparin tubes.  
 
 
8.2.1  
Patients ≥12 kg: On study: Five mL blood sample obtained prior to beginning Block 1 treatment 
on the same day as the pretreatment bone marrow aspirate (3ml). Block 1, Day 1: Five mL total 
blood sample at 3 time points: prior to start of chemotherapy, at 4-6 hours and 24 hours following 
the first ixazomib dose  
  
8.2.2  
Patients under 12 kg: On study: Three mL blood sample obtained prior to beginning Block 1 
treatment. No pretreatment bone marrow aspirate is needed. Block 1, Day 1: Three mL blood 
sample drawn at 2 time points: prior to start of chemotherapy and 4-6 hours after the first 
ixazomib dose.   
  
8.2.3  
If possible, do not perform end of block bone marrow aspirate on a Friday to avoid sample 
shipment on the weekend. This means the “Day 36” sample may actually be collected on Day 34-
37.  
  
 
8.3 
Blood for PK Analysis (mandatory) 
 
Blood samples will be collected from all subjects enrolled in phase 1 for determination of plasma 
concentrations of ixazomib. Sparse PK sampling will be used in patients enrolled in the phase 2 

 
 
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study. The PK sampling schedule is provided in the tables below. The exact date and time of each 
ixazomib dose, and each PK sample collection will be recorded.   
 
PK parameters for ixazomib will be calculated as appropriate from the ixazomib plasma concentration-time 
data.  PK parameters will be summarized using descriptive statistics. The PK data collected in these studies 
will contribute to population PK analyses of ixazomib and may also be used to examine the exposure-
efficacy and exposure-safety relationships for ixazomib.   
 
Phase 1, PO dosing 
 
 
Phase 2, PO dosing 
 
 
 
Samples requested: 
Blood samples for PK studies 
Blood Collection 
procedure: 
2 mL PK samples should be collected into tubes provided in the ixazomib PK 
collection kit. This will be provided by Takeda Pharmaceuticals. 
 
Materials 
 
Blood samples for PK assessment must be collected in 2-mL vacutainer tubes 
containing K2EDTA as the anticoagulant.  Resulting blood and plasma PK 
samples must be stored in plastic storage tubes with caps.  No blood collection 
tubes with separation gel should be used. 
 
Plasma (0.5 mL) is stored in tubes containing 250 mg lyophilized citric acid.  
 
Weight 
Block 1 Day 1 
Block 1 Day 11 
Volume/30 days 
<20 kg 
72 h post-dose (to be collected prior 
to the Block 1 Day 4 dose of 
ixazomib) 
Pre-dose, 30 min, 4 h, 72 h post-dose 
10 mL 
≥20 kg 
30 min, 1 h, 2 h, 4 h, 8 h, 24 h, 72 h 
post-dose (the 72 h sample is to be 
collected prior to the Block 1 Day 4 
dose of ixazomib) 
Pre-dose, 30 min, 1 h, 2 h, 4 h, 8 h, 24 
h, 72 h, 264 h post-dose 
32 mL 
Weight 
Block 1 Day 
1 
Block 1 Day 
8 
Block 1 Day 
11 
Block 2 Day 
1 
Block 2 Day 
15 
Block 2 Day 
18 
Volume/30 
days 
<20 kg 
72 h post-
dose (to be 
collected 
prior to the 
Block 1 Day 
4 dose of 
ixazomib) 
Pre-dose 
Pre-dose, 
72 h post-
dose (Block 
1 Day 14) 
- 
- 
- 
8 mL 
≥20 kg 
72 h post-
dose (to be 
collected 
prior to the 
Block 1 Day 
4 dose of 
ixazomib) 
Pre-dose 
Pre-dose, 
30 min, 2 h, 
4 h, 72 h 
post-dose 
(Block 1 
Day 14) 
Pre-dose 
 
Pre-dose 
 
Pre-dose 
 
20 mL 
 

 
 
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Preparation of Plasma Pharmacokinetic Samples 
 
1. Draw blood into labeled and chilled 2-mL lavender top K2EDTA 
vacutainer tube.  
 
2.  Mix the blood with the anticoagulant by gently inverting the tube 8-10 
times and immediately place on wet ice.   
 
3. Centrifuge the blood samples for 10 minutes at 1000 x g at 4º C in a 
refrigerated centrifuge within 10 minutes of sample collection.  
 
4.  Immediately following centrifugation, gently remove the plasma from the 
packed cells and aliquot into transfer vials filled with lyophilized citric acid. 
Each aliquot should contain exactly 0.5 mL of plasma. 
 
5. Vortex split tubes thoroughly. Any remaining plasma post-split 1/split 2 
sample aliquots should be discarded following appropriate biohazard 
disposal procedures. 
 
NOTE: If < 0.5 mL plasma is obtained post centrifugation, do not process or store 
split 1 or split 2, record split 1: ISV (Insufficient Sample Volume), split 2: ISV. If < 
1.0 mL plasma is obtained post centrifugation, process and store split 1 
according to procedure; do not process or store split 2, record split 2: ISV. 
Discard remaining plasma using appropriate biohazard waste disposal 
procedures. 
 
6. Replace cap on tube and freeze the samples immediately at -70°C. 
 
Note:  No more than 60 minutes should elapse between blood collection and 
freezing the plasma samples. 
 
7. Keep samples frozen at -70°C or lower until shipment. 
 
Note:  Wet ice is defined as a mixture of ice and water. 
 
Specimen Labeling: 
Each tube must be labeled with the study ID number, along with the date and 
time of when the sample was obtained. No personal identifying patient 
information should be included in the specimen or transmittal form. 
Specimen Packaging and 
Shipping: 
Covance Clinical Laboratory Services 
8211 Scicor Drive, Indianapolis, IN 46214 USA 
 
 
Document the exact dates and times of ixazomib administration and sample collection on the 
Pharmacokinetics Study Form (Appendix III) and in the eCRF. Ensure that any information requested on 
the tube label is completely filled out and legible.   
  
 
8.4 
Additional Information for Correlative Studies  
 
The following correlative studies will be performed on patients with ALL who consent to participate.  
Peripheral blood samples will be collected prior to the start of treatment (Proteasome assay) and on Day 

 
 
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1 of treatment at hour 0, at 4-6 hours, and 24 hours (in patients ≥ 12 kg) following the first dose of 
ixazomib (Protein microarray). 
 
8.4.1 
Proteasome activity 
The activity of the 26S constitutive and immunoproteasome subunits (β5, iβ5, β1 and iβ1) will be 
performed on peripheral blood for patients with at least 1000 cell/uL absolute blast count. Work 
will be done through the Horton laboratory in collaboration with Jaqueline Cloos, VU Medical 
Center, Amsterdam, the Netherlands. 
 
8.4.2  
Protein microarray:  
Protein expression in malignant lymphoblasts will be analyzed using capillary electropheresis 
and/or reverse-phase protein lysate arrays in Dr. Horton’s laboratory. RPPA analysis will have 
higher priority since many more proteins can be assessed using small amounts of material 
(200,000 cells). RPPA will be performed as previously described.55 Capillary electrophoresis will 
be performed according to the manufacturer’s directions using commercially available antibodies. 
The investigators (Horton and Kornblau labs) have extensive experience with their respective 
techniques.56  
 
8.4.3  
Banking:  
Peripheral blood samples remaining after RPPA and immunoblot will be banked for future 
proteomic studies. If the patient consents to banking, any excess lymphoblasts, non-malignant 
lymphocytes and plasma leftover from research tests will be banked for future TACL biology 
studies and stored within the TACL Central Biological Repository under the TACL T2016-005 
study. Samples will remain linked to their TACL identification number. 
 
9.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY, OFF STUDY CRITERIA AND STUDY 
TERMINATION 
 
9.1 
Criteria for Removal from Protocol Therapy 
 
 
 
Response evaluable patients will be followed for a duration of a minimum of four months and 
maximum 2 years; toxicity evaluable but not response evaluable patients will be followed for one 
month after discontinuation of study therapy. 
a. Patient is not CNS 1 or 2 after the first course of therapy (this excludes patients who are CNS 3 due to 
chloromas or cranial nerve involvement with evidence of improvement).  
b. Relapse in any site following remission 
c. Progressive disease 
d. Completion of protocol therapy 
e. Second malignant neoplasm 
f. 
Patient/parent withdrawal or refusal after beginning protocol therapy 
g. Patient off treatment for other complicating disease 
h. Non-compliance with protocol regimen and procedures 
i. 
Investigator determination 
j. 
Female patient becomes pregnant or begins breast-feeding 
 
9.2 
Off Study Criteria 
a. Death 
b. Patient Lost to follow-up 
c. Patient withdraws consent, refuses follow-up 
 

 
 
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9.3 
Termination of the Study by TACL 
The TACL Consortium may terminate this study prematurely, either in its entirety or at an investigative 
site, for reasonable cause provided that written notice is submitted in advance of the intended 
termination.  Advance notice is not required if the study is stopped due to safety concerns.   
 
 
 

 
 
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10.0 
STATISTICAL CONSIDERATIONS 
 
10.1 
Design Overview 
 
This is a Phase 1/2 study that comprises two strata.   
 
• 
Stratum A (primary) includes all eligible patients who are ≥ 1 year of age and who do not have 
Down syndrome (DS).  
 
• 
Stratum B (secondary) includes all eligible patients who are either < 1 year of age or who have 
DS. 
 
The primary dose finding (Phase 1) and response evaluation expansion (Phase 2) will occur in Stratum A.  
A modified dose escalation, as described below, will occur in Stratum B. Down syndrome patients 
enrolled in Stratum B will receive 1.6 mg/m2 in Phase 2, which is one dose level below for the non-DS 
patients. 
  
10.1.1 Phase 1 
 
The phase 1 portion is a 3+3 dose escalation study to determine the MTD/RP2D of PO ixazomib 
in combination with VXLD therapy. This design targets DLT rates on the order of 15-20%, which 
is considered acceptable for this regimen.  
 
Enrollments are planned in groups of up to three patients, with doses escalated or de-escalated 
according to the rules of the 3+3 dose-escalation design, as follows:  
 
• 
Up to 3 patients are entered at the starting dose level 
• 
If 0 of 3 patients experiences DLT at a given dose level, then the dose is escalated to the 
next higher level, if a higher dose level exists, and up to three patients are enrolled.  If a 
higher dose level does not exist, up to three additional patients are accrued at the same dose 
level. 
• 
If 1 of 3 patients experiences DLT at current dose, then up to three additional patients are 
accrued at the same dose level. 
• 
If 2 or more DLTs are observed at a given dose level, then the MTD has been exceeded, 
dose escalation and accrual to the current dose level will be stopped, and up to three 
additional patients will be enrolled at the next lower dose level, if a lower dose level exists, 
unless six patients have already been treated at that lower dose. 
 
The MTD is the highest dose level tested at which 0/6 or 1/6 patients experience DLT with at 
least two patients encountering DLT at the next higher dose.  If the highest specified dose level is 
reached with 0/6 or 1/6 patients experiencing DLT, i.e., the MTD has not been reached, this dose 
level will be referred to as the Highest Tested Dose (HTD).  The MTD or HTD will be the 
recommended Phase 2 dose (RP2D). If at least two patients encountering DLT at the lowest 
dose, then no MTD exists.  
 
For Stratum A patients, the starting dose will be 1.6mg/m2/day (see Section 4.5).  Escalation/de-
escalation decisions will be based on the DLTs that occur during the first block of treatment.  
Stratum B patients will not be included in the primary DLT or response evaluation due to their 
unique biology and toxicity profile. To ensure the safety of these patients, they will be entered at 

 
 
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one dose level below a determined safe dose level in older children (which is defined as a dose at 
which 0/3 or ≤ 1/6 patients have experienced a DLT), and will follow a 3+3 dose escalation design 
for safety, although there is no expectation that this dose escalation will be completed.  At no time 
will the dose given to infants or Down syndrome patient exceed the currently established safe 
dose in non-infant/non-Down patients.   
Accrual: In Stratum A, the phase 1 portion will require a minimum of 4 and maximum of 18 DLT 
evaluable. Likely accrual is  9-12 DLT evaluable patients if an RP2D is determined,  requiring 12-
18 months. A small number of additional patients will be enrolled in Stratum B. 
During Phase 1, enrollment will be restricted initially to patients < 18 years of age until a 
minumum of 9 such patients have been enrolled.   
 
10.1.2 Phase 2  
 
If an RP2D is established for Stratum A, a phase 2 expansion will be performed at the RP2D in 
Stratum A and one dose below the RP2D in patients with Down syndrome or less than 1 year of 
age.  Stratum A patients satisfying the phase 2 eligibility criteria will be enrolled and treated at the 
RP2D until 18 response evaluable patients have been treated at the RP2D or until a total of 24 
evaluable patients (including both phase 1 and 2 enrollments) are enrolled, whichever occurs 
first. Response-evaluable Stratum A patients treated at the PO RP2D in phase 1 will be included 
in the phase 2 analysis and be counted toward the 18 response evaluable patients. 
 
Interim analysis.  There will be no interim analyses for futility or efficacy during phase 2. 
 
Accrual.  A minimum of 6 and a maximum of 12 response evaluable patients will be enrolled in 
Stratum A during the phase 2 expansion, for a total of 12-18 response evaluable patients accrued 
for analysis.  Stratum B patients with Down syndrome or less than 1 year of age can be enrolled, 
but will not be counted toward the target accrual and not included in the primary response analysis. 
During the phase 2 expansion, Stratrum A enrollment will be restricted initially to patients < 18 
years of age until a minumum total of 6 such patients have been enrolled at the RP2D. The 
estimated time to complete phase 2 accrual is 12-18 months. Assuming a maximum non-
evaluability rate of 10%, a maximum of 26-27 patients in Stratum A will be required to complete 
both phase 1 and phase 2.   
10.2 
Endpoints 
 
Primary Endpoints:   
o 
Phase 1: Dose limiting toxicity (DLT) during  block 1 of chemotherapy 
o 
Phase 1: PK parameters of ixazomib during  block 1 of chemotherapy 
o 
Phase 1: CTCAE toxicities during block 1 of chemotherapy 
o 
Phase 2: Response (CR+ CR MRD-, and CR + CR MRD- + CRi) after block 1 chemotherapy 
Secondary Endpoint:   
o 
CTCAE toxicities during block 2 chemotherapy 
o 
Palatibility study of ixazomib 
Exploratory Endpoints: 
o 
Proteasome activity and cell stress protein in peripheral blasts. 
o 
CTCAE toxicities during maintenance therapy 

 
 
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o 
Response (CR+ CR MRD-, and CR + CR MRD- + CRi) after block 2 re-induction chemotherapy 
o 
Event-free survival (EFS), defined as the time from study entry to the earliest occurrence of 
failure to respond to block 1 of treatment, disease progress, disease relapse, or death from any 
cause. 
o 
Overall survival (OS), defined as the time from study entry to death from any cause. 
o 
MRD status after block 1 and block 2 therapy 
 
10.3 
Patient Evaluability and DLT Definition 
 
10.3.1  Definition of a patient evaluable for dose limiting toxicity (DLT) 
 
Patients are evaluable for DLT if, during the first block of therapy, they receive at least one dose 
of Ixazomib and they terminate treatment for toxicity or intolerability, they experience a DLT, or 
they receive at least 75% of the required dose of ixazomib without DLT.  The required dose of 
Ixazomib is defined as the total nominal dose during the block per sections 4.1, 4.2, or 4.3, 
adjusted for any dose modifications due to renal or hepatic impairment as per sections 4.7.1.2 
and 4.7.1.3.  During phase 1, patients who do not satisfy one of these conditions are not 
evaluable for toxicity and will be replaced 
 
10.3.2  Definition of a patient evaluable for response 
 
A patient will be considered evaluable for response if the patient receives all or part of protocol 
therapy and the patient is under follow-up for a sufficient period to evaluate the disease at the end 
of the block 1. A patient will also be considered evaluable for response if the patient meets the 
definition of progressive disease or dies as the result of a DLT. A patient who dies as a result of a  
DLT after receiving all or part of protocol therapy will be considered a non-responder. Patients who 
are not considered evaluable for response will be replaced.  
 
 
10.4  
Interim Monitoring of Toxic Death  
 
The occurrence of toxic death (TD, defined as treatment related mortality) at any time during protocol 
therapy, or until 30 days following the last dose of study therapy, will be a primary endpoint for safety 
monitoring. A population toxic death rate that exceeds p0=0.10 will be considered unacceptable. A 
Bayesian monitoring rule based on a pessimistic Beta (1,3) prior distribution on the parameter p0 will be 
used to judge the evidence that the population toxic death rate exceeds this quantity. This prior has mean 
0.25, median 0.21, and 90% of support under 0.54.  A posterior probability of greater than 80% that p0>0.10 
will be considered statistical evidence that the population toxic death rates may exceed 0.10.  Operationally, 
this criterion will be satisfied if the following fractions of TDs out of total patients treated are exceeded:  
≥1/5, ≥2/12, ≥3/20, ≥4/28, and so on as dictated by this rule.  If this criterion is satisfied at any time the 
cause and circumstances of these deaths will be reviewed with the study committee and with the Data and 
Safety Monitoring Committee to determine whether modifications to or termination of the study is warranted. 
 
10.5 
Analysis of primary and secondary endpoints  
 
Analysis of DLT. Analysis of DLT will be in the context of the dose escalation design described above.   
 
Analysis of Toxicity. CTCAE grade 3+ hematologic and non-hematologic toxicities, overall and attributable 
to ixazomib, will be summarized as percents of patients experiencing these toxicities, with associated 
standard errors, for each treatment block and for the entire treatment course. 

 
 
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Analysis of Response. The analysis of the phase 2 portion will focus on estimating the response rate 
following block 1 of treatment. With a maximum sample size of 18 response evaluable patients, the standard 
error (SE) of the overall estimate of response rate will be at most 0.12,.  The minimum sample size of 12 
response evaluable patients corresponds to a SE of at most 0.14. 
 
Analysis of PK. For patients enrolled in the phase 1 portion, PK parameters will be summarized descriptively 
as permitted by the data..  If sample size permits, the relationship between ixazomib dose and ixazomib PK 
parameters may be examined to assess dose linearity. 
 
The PK data collected in the phase 1 and phase 2 portions will contribute to population PK analyses of 
ixazomib and may also be used to examine the exposure-efficacy and exposure-safety relationships for 
ixazomib. These analyses will be reported separately. 
 
 
10.6 
Analysis of exploratory endpoints 
 
The analysis of ixazomib PD, post block 1 and block 2 MRD, and other exploratory endpoints will be 
primarily descriptive, but will comprise at minimum summarizing these difference measures as means, 
proportions, or in the case of EFS and OS, the 4-month and two-year EFS and OS probability as estimated 
via the product limit estimator, with associated standard errors. 
 
10.7 
Inclusion of Women and Minorities 
 
The study is open to all participants regardless of gender or ethnicity.  Review of accrual to past studies of 
new agents demonstrates the accrual of both genders and all NIH-identified ethnicities to such studies. The 
small number of patients entered into this trial will obviate any analysis of variation in response rate with 
gender or ethnicity. 
 
11.0 
RESPONSE CRITERIA 
 
11.1 
Bone Marrow Response Criteria for patients with leukemia 
 
11.1.1 Complete Remission (CR) 
• 
A bone marrow with <5% blasts by morphology; and  
• 
No evidence of circulating blasts or extramedullary disease; and 
• 
Recovery of peripheral counts (ANC > 500/µL and PLT count > 20,000/µL, platelet infusion 
independent).  
 
11.1.2 Complete Remission, MRD negative (CR MRD-) 
• 
A bone marrow with <5% blasts by morphology; and  
• 
MRD <0.1% by flow or molecular testing (e.g. PCR); and 
• 
No evidence of circulating blasts or extramedullary disease; and 
• 
Recovery of peripheral counts (ANC > 500/µL and PLT count > 20,000/µL, platelet infusion 
independent).  
• 
Qualifying marrow and peripheral counts should be performed within 1 week of each other 
 
11.1.3 Complete Response with Incomplete Count Recovery (CRi) 
• 
A bone marrow with <5% blasts by morphology; and  
• 
No evidence of circulating blasts or extramedullary disease; and  

 
 
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• 
Insufficient recovery of absolute neutrophil counts (ANC <500/µL), and/or insufficient recovery 
of platelets (PLT counts <20,000/µL, platelet infusion independent),  
 
11.1.4  Partial Response (PR) 
• 
Complete disappearance of circulating blasts and one of the following:  
• 
A decease of at least 50% of blasts in the bone marrow with ≥5% and < 25% blasts by 
morphology with recovery of peripheral counts (ANC > 500/µL and PLT count > 20,000/µL, 
platelet infusion independent) 
Note: only patients who entered the study with > 25% blasts in the marrow may be assessed 
as PR 
• 
Attainment of a bone marrow CR (<5% blasts by morphology) with proven persistence of 
extramedullary disease qualifies as a PR 
 
11.1.5 Stable Disease (SD) 
Patient does not satisfy the criterion for either CR, CR MRD-, CRi, PR or disease progression. 
 
11.1.6 Progressive Disease (PD) 
An increase of at least 25% (with a minimum increase of of 5000 cell/μL) in the absolute number 
of bone marrow or circulating leukemic cells, development of new sites of extramedullary disease, 
or other laboratory or clinical evidence of progression of disease. 
 
11.1.7  Non-responder (NR)   
A patient who dies from a DLT will be considered as a non-responder, regardless of the disease 
assessment. 
 
11.1.8 Not evaluable (NE) 
Aplastic or severely hypoplastic marrow with any blast percentage. Bone marrow 
aplasia/hypoplasia is defined as overall marrow cellularity less than 10-20%. In this instance, 
marrow evaluation should be repeated every 1-2 weeks until response determination can be made 
or patient meets criteria for a DLT of prolonged myelosuppression (as defined in section 4.4). 
 
11.1.9 Relapse 
After documentation of remission, one bone marrow aspirate and/or biopsy showing ≥5% leukemic 
blasts or pathological evidence of extramedullary disease. 
 
11.2 
CNS Response Criteria 
 
11.2.1 CNS  Status Definitions for Patients with ALL 
 
CNS 1: In cerebral spinal fluid (CSF), absence of blasts on cytospin preparation, regardless of the 
number of white blood cells (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 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 (formula below). 
 

 
 
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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 (formula below). 
CNS 3c: Clinical signs of CNS leukemia (such as facial nerve palsy, brain/eye involvement or 
hypothalamic syndrome). 
 
11.2.2 Method of Evaluating Initial Traumatic Lumbar Punctures: 
 
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 
 
CSF WBC > 2X  Blood WBC 
CSF RBC           Blood RBC 
 
A patient with CSF blasts, whose CSF WBC/RBC is 2X greater than the blood WBC/RBC ratio, has 
CNS disease at diagnosis.  
 
Example: CSF WBC = 60/μL; CSF RBC = 1500/μL; blood WBC = 46000/μL; blood RBC = 3 X 
106/μL: 
60/1500 = 0.04 > 2X 4600/3x106 = 0.015 
 
 
 
Therefore this patient has CNS disease because 0.04 > 2X 0.015 
 
11.3 
Response Criteria for Patients with Lymphoma  
 
Response and progression will be evaluated in this study using the revised Response Evaluation 
Criteria in Solid Tumors (RECIST) guideline (version 1.1).57 Key points are that 5 target lesions 
are identified and that changes in the largest diameter (unidimensional measurement) of the 
tumor lesions but the shortest diameter of malignant lymph nodes are used in the RECIST v 1.1 
criteria. 
 
11.3.1  Definitions 
 
Evaluable for objective response:  
 
Patients who exhibit objective disease progression prior to the end of block 1 will be considered 
evaluable for response. For all other patients, only those patients who have measurable disease 
present at baseline, have received at least one block of therapy, and have had their disease re-
evaluated will be considered evaluable for response.  
 
Evaluable Non-Target Disease Response:  
 
Patients who have lesions present at baseline that are evaluable but do not meet the definitions 
of measurable disease, have received at least one block of therapy, and have had their disease 
re-evaluated will be considered evaluable for non-target disease.  The response assessment is 
based on the presence, absence, or unequivocal progression of the lesions.  
 
11.3.2  Disease Parameters 
 
 
Measurable disease:  

 
 
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Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with CT 
scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  If the investigator thinks it appropriate to include them, the conditions 
under which such lesions should be considered must be defined in the protocol. 
 
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 (CT scan slice thickness no greater than 5 mm).  At 
baseline and in follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease:  
 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered non-measurable 
disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed 
by CT or MRI), are considered as non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
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 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. 
 
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.  
 
11.3.3.  Methods for Evaluation of Measurable Disease 
 
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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. 
 
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (e.g. for body scans). Ideally, the same type of 
scanner should be used and the image acquisition protocol should be followed as closely as 
possible to prior scans.  
 
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if the 
site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to 
a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time.  Note, however, that the PET portion of the CT introduces 
additional data which may bias an investigator if it is not routinely or serially performed.   
 
Cytology should be obtained if an effusion appears or worsens during treatment when the 
measurable tumor has met criteria for response or stable disease. 
 
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 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. 
 
11.3.4 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 to <10 mm..   
 

 
 
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Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters 
 
Progressive Disease (PD): At least a 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 PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study 
 
11.3.5  Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions.  All lymph nodes must be 
non-pathological in size (<10 mm short axis) 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s). 
 
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.   
   
Overall Best Response Assessment: Each patient will be classified according to his “best 
response” for the purposes of analysis of treatment effect.  Best response is determined as 
outlined in Section 11.5 from a sequence of overall response assessments. 
 
11.3.6  Response Criteria for Patients with Lymphoma and Evaluable (but not Measurable) Disease 
 
Evaluable Disease: The presence of at least one lesion, with no lesion that can be accurately 
measured in at least one dimension.  Such lesions may be evaluable by nuclear medicine 
techniques, immunocytochemistry techniques, tumor markers or other reliable measures.  
Complete Response: Disappearance of all evaluable disease. 
Partial Response: Partial responses cannot be determined in patients with evaluable disease 
Stable Disease: That which does not qualify as Complete Response (CR), or Progressive 
Disease. 
Progressive Disease: The appearance of one or more new lesions or evidence of laboratory, 
clinical, or radiographic progression. 
Overall Best Response Assessment: Each patient will be classified according to his “best 
response” for the purposes of analysis of treatment effect.  Best response is determined as 
outlined in Section 11.5 from a sequence of overall response assessments. 
 
11.3.7  Best Response 
 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 

 
 
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measurements recorded since the treatment started).  The patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 
 
Table 3: For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>28 days Confirmation** 
CR 
Non-
CR/Non-PD 
No 
PR 
 
>28 days Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
documented at least once 
>28 days from baseline** 
PD 
Any 
Yes or 
No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
*   See RECIST 1.1 manuscript for further details on what is evidence of a new 
lesion. 
**   Only for non-randomized trials with response as primary endpoint. 
*** In exceptional circumstances, unequivocal progression in non-target lesions 
may be accepted as disease progression. 
Note: 
Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
Table 4: For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease 
since SD is increasingly used as an endpoint for assessment of efficacy in 
some trials so to assign this category when no lesions can be measured is 
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Table 5.  Sequences of overall response assessments with corresponding best response. 
  1st Assessment 
  2nd Assessment 
  Best Response 
Progression 
 
Progressive disease 
Stable, PR, CR 
Progression 
Progressive disease 
Stable 
Stable 
Stable 
Stable  
PR, CR 
Stable 
Stable  
Not done 
Not RECIST classifiable 
PR 
PR 
PR 
PR 
CR 
PR 
PR, CR 
Not done 
Not RECIST classifiable 
CR 
CR 
CR 
 
12.0 
ADVERSE EVENT REPORTING REQUIREMENTS  
 
12.1 
Definitions 
 
Adverse Event: An adverse event means any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related. 
 
Suspected Adverse Reaction (SAR): Any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event.  Reasonable possibility means there is evidence to suggest a causal 
relationship between the drug and the adverse event. 
 
Unexpected Adverse Event or Unexpected Suspected Adverse Reaction: An adverse event or 
suspected adverse reaction is considered “unexpected” if it is not listed in the investigator brochure or is 
not listed at the specificity or severity that has been observed; or, if an investigator brochure is not available, 
is not consistent with the risk information described in the general investigational plan. 
 
Serious Adverse Events (SAE) or Serious Suspected Adverse Reactions (SSAR): An adverse event 
or suspected adverse reaction is considered serious if, in the view of either the investigator or sponsor, it 
results in any of the following outcomes: 
 
Death of Patient 
An event that results in the death of a patient. 
Life-Threatening 
An event that, in the opinion of the investigator, would have resulted in immediate 
fatality if medical intervention had not been taken.  This does not include an event that 
would have been fatal if it had occurred in a more severe form. 
Hospitalization 
An event that results in an admission to the hospital for any length of time.  This does 
not include an emergency room visit or admission to an outpatient facility. 
Prolongation of 
Hospitalization 
An event that occurs while the study patient is hospitalized and prolongs the patient’s 
hospital stay. 
Congenital 
Anomaly 
An anomaly detected at or after birth or any anomaly that results in fetal loss. 

 
 
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Persistent or 
Significant 
Disability/ 
Incapacity 
An event that results in a condition that substantially interferes with the activities of 
daily living of a study patient.  Disability is not intended to include experiences of 
relatively minor medical significance such as headache, nausea, vomiting, diarrhea, 
influenza, or accidental trauma (e.g., sprained ankle). 
Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome 
An important medical event that may not be immediately life-threatening or result in 
death or hospitalization, but based on medical judgment may jeopardize the patient 
and may require medical or surgical intervention to prevent any of the outcomes listed 
above (i.e., death of patient, life-threatening, hospitalization, prolongation of 
hospitalization, congenital anomaly, or persistent or significant disability/incapacity). 
Examples of such 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. 
 
12.2 
Data Collection 
 
Adverse events and suspected adverse reactions (CTCAE v5.0 grades 1-5)  will be collected and reported 
on the electronic CRFs beginning with the first dose of study therapy until 30 days following the last dose 
of study therapy. The investigator will evaluate all adverse events and suspected adverse reactions as to 
their severity and relationship to ixazomib as well as the regimen as a whole. Serious adverse events and 
suspected adverse reactions will require expedited reporting to the TACL Operations Center as 
described below.  
12.3 
Reporting Serious Adverse Events or Serious Suspected Adverse Reactions 
 
12.3.1 The following serious adverse events or serious suspected adverse reactions requires expedited 
reporting: 
 
All Grade 5 events regardless of causality. 
 
All Grade 4 & 3 events unexpected & expected that are possibly, probably or definitely related to 
ixazomib or the regimen as a whole.  Exclude reporting of hematologic toxicity as a serious adverse 
event unless the event meets the criteria of hematologic dose limiting toxicity per protocol section 
4.6:  Bone marrow aplasia: > 49 days from Day 1 of therapy will be a DLT. Aplasia is defined as 
the failure to recover a peripheral ANC of ≥ 500/µL and PLT ≥ 20,000/µL in the absence of 
persistent leukemia. 
 
12.3.2 Steps for Reporting 
 
Step 1: Identify the adverse event or suspected adverse reaction using the NCI Common 
Toxicity Criteria (CTC), version 5.0.    
 
The CTC provides descriptive terminology and a grading scale for each adverse event listed.  A 
copy of the CTC can be downloaded at: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Ref
erence_5x7.pdf#search=%22CTCAE%22.   
 
Step 2: Grade the event using the NCI CTCAE version 5.0. 
 
Step 3: Determine if the adverse event or suspected adverse reaction meets the criteria of 
being “serious”. 

 
 
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Step 4: Determine the relationship of DRUG and the regimen as a whole to the event 
The investigator will assess the causal relationship between the investigational product and the 
regimen as a whole and the adverse event.  The investigator will use his/her clinical expertise and 
judgment to select the attribution category below that best fits the circumstances of the AE. 
 
Unrelated: The event is clearly related to other factors such as the participant’s clinical 
state, other therapeutic interventions or concomitant drugs administered to the participant. 
 
Unlikely: The event is doubtfully related to investigational agent(s). The event was most 
likely related to other factors such as the participant’s clinical state, other therapeutic 
interventions, or concomitant drugs. 
 
Possible: The event follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by other factors such as the participant’s 
clinical state, other therapeutic interventions or concomitant drugs. 
 
Probable: The event follows a reasonable temporal sequence from the time of drug 
administration, and follows a known response pattern to the study drug. The event cannot 
be reasonably explained by other factors such as the participant’s clinical state, therapeutic 
interventions or concomitant drugs. 
 
Definite: The event follows a reasonable temporal sequence from the time of drug 
administration, follows a known response pattern to the study drug, cannot be reasonably 
explained by other factors such as the participant’s condition, therapeutic interventions or 
concomitant drugs; AND occurs immediately following study drug administration, improves 
upon stopping the drug, or reappears on re-exposure.  
 
Step 5: Determine if the adverse event or suspected adverse reaction is “unexpected”.  
 
Step 6: Notify the TACL Operations Center by email 
 
The following information should be submitted within 24 hours of event notification by email 
tacl@chla.usc.edu. 
 
1. Patient TACL study ID and initials 
2. Event description 
3. Severity (NCI Grade) 
4. Onset date 
5. Reason event is considered serious 
6. Dose of study drug and dates of administration 
7. Investigator opinion of relationship to DRUG and the regimen as a whole 
8. Name and phone number of physician in charge of the case 
9. Name and phone number of CRA or Research nurse working with the case 
 
Step 7: Submit a written report to the TACL Operations Center 
 
Complete the TACL SAE Notification Form within 72 hours of learning of the event.  The completed 
form is email to tacl@chla.usc.edu. The form may also be faxed to (323) 361-4505. A follow-up SAE 

 
 
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Notification Form must be submitted upon resolution of the event. Please confirm via email or phone 
that the TACL Operations Center has received this notification.   
 
Step 8: TACL Operations to provide notification to Takeda 
 
Upon review of notification and outcome of SAE by TACL Study Chair/Vice Chair, submission of  
documents will be provided toTakeda. 
 
12.4 
Institutional Reporting to the IRB 
 
All SAE’s should be reported to the treating institutions IRB or Ethics board. The TACL Operations Center 
will also report all SAE’s to the CHLA IRB. The TACL Operations Center will distribute SAE’s to all TACL 
sites as appropriate for submission to their own IRB’s.  
 
13.0 
DATA AND SAFETY MONITORING 
 
13.1 
Data Submission 
 
All study data will be submitted via electronic data capture forms using the iMedidata/TACL Website.  
Please refer to the TACL web site (https://tacl.chla.usc.edu) for Medidata user manual or contact the TACL 
Operations Center at (323) 361-5132 if you need assistance.   
 
The following are required to be submitted to the Operations Center for all patients entered: 
Paper copy of following:  Roadmaps and Bone Marrow Reports (include both aspirate and biopsy reports). 
These forms are to be e-mailed (tacl@chla.usc.edu) or faxed to the TACL Operations Office at (323) 361-
4505 at the end of each course during which the bone marrows are done. 
 
 
 
13.2 
Weekly Safety Review 
 
The TACL Operations Center (TOC) conducts weekly (as needed) patient safety and review meetings with 
the protocol chair, protocol vice-chair, research coordinators and other administrative TACL team members 
to review all data submitted, non-serious adverse events and other correspondence pertaining to patients.  
Serious adverse events will be immediately evaluated by the study team and determination regarding 
notification of participating sites will be made.  All serious adverse events will be sent to the CHLA CCI and 
DSMC if required.  Any interim results that would affect patient safety would be immediately communicated 
to all participating TACL sites. All correspondence with sites will be done via email, with all information also 
being posted on a member’s only section of the TACL website. 
 
13.3 
Data Safety and Monitory Committee 
 
DSMC meetings will occur every 6 months. Every 6 months, a DSMC report for each protocol will be 
prepared by the study statistician and study PI detailing patient accrual, toxicities, deaths on study, current 
study status, responses (responses will be blinded until study completes accrual), summary of amendments 
to protocol/consent, lists of any publications from study, and plans for study in coming year.  Any 
publications from the study (abstract or manuscript) will be attached to the DSMC report.  After DSMC 
review, the DSMC will issue a confidential report for each study to the study PI and TACL Operations 
Center. 
 

 
 
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Not more than 8 weeks after the DSMC meeting, a DSMC public review report will also be created for each 
protocol after approval of the confidential report and resolution of any issues by the PI The public report will 
then be emailed to the participating sites for each study.  These can be filed at the IRB at each site if 
required per local IRB guidelines. 
 
 
 

 
 
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14.0 
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Horton, T.M., et al. Bortezomib interactions with chemotherapy agents in acute leukemia in vitro. Cancer 
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Lee, E.C., et al. Antitumor activity of the investigational proteasome inhibitor MLN9708 in mouse models of 
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Rajkumar, S.V., Richardson, P.G., Hideshima, T. & Anderson, K.C. Proteasome inhibition as a novel 
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Niewerth, D., et al. Higher ratio immune versus constitutive proteasome level as novel indicator of sensitivity 
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Ravi, D., et al. Proteasomal Inhibition by Ixazomib Induces CHK1 and MYC-Dependent Cell Death in T-cell 
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Smith, D.C., et al. Phase 1 study of ixazomib, an investigational proteasome inhibitor, in advanced non-
hematologic malignancies. Investigational new drugs 33, 652-663 (2015). 
25. 
Richardson, P.G., et al. Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in 
relapsed/refractory multiple myeloma patients. Blood 124, 1038-1046 (2014). 

 
 
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Kumar, S.K., et al. Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with 
lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label 
phase 1/2 study. The Lancet. Oncology 15, 1503-1512 (2014). 
27. 
Parker, C., et al. Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic 
leukaemia (ALL R3): an open-label randomised trial. Lancet 376, 2009-2017 (2010). 
28. 
Rheingold, S.R., et al. A phase 1 trial of temsirolimus and intensive re-induction chemotherapy for 2nd or 
greater relapse of acute lymphoblastic leukaemia: a Children's Oncology Group study (ADVL1114). British 
journal of haematology 177, 467-474 (2017). 
29. 
Burke, M.J., Brown, P., Sposto, R., Gore, L. & Wayne, A.S. Pilot Study of Decitabine and Vorinostat with 
Chemotherapy for Relapsed ALL: A Report from the Therapeutic Advances in Childhood Leukemia &amp; 
Lymphoma (TACL) Consortium. Blood 128, 2781-2781 (2016). 
30. 
Messinger, Y., et al. Phase I study of bortezomib combined with chemotherapy in children with relapsed 
childhood acute lymphoblastic leukemia (ALL): a report from the therapeutic advances in childhood 
leukemia (TACL) consortium. Pediatric blood & cancer 55, 254-259 (2010). 
31. 
Messinger, Y.H., et al. Bortezomib with chemotherapy is highly active in advanced B-precursor acute 
lymphoblastic leukemia: Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study. Blood 
120, 285-290 (2012). 
32. 
Salzer, W.L., et al. Decreased induction morbidity and mortality following modification to induction therapy 
in infants with acute lymphoblastic leukemia enrolled on AALL0631: a report from the Children's Oncology 
Group. Pediatric blood & cancer 62, 414-418 (2015). 
33. 
Le Tourneau, C., Lee, J.J. & Siu, L.L. Dose escalation methods in phase I cancer clinical trials. Journal of 
the National Cancer Institute 101, 708-720 (2009). 
34. 
Niewerth, D., et al. Proteasome subunit expression analysis and chemosensitivity in relapsed paediatric 
acute leukaemia patients receiving bortezomib-containing chemotherapy. Journal of hematology & 
oncology 9, 82 (2016). 
35. 
Kornblau, S.M., et al. Functional proteomic profiling of AML predicts response and survival. Blood 113, 154-
164 (2009). 
36. 
Horton, T.M., Qiu, Y., Jenkins, G. & Kornblau, S.M. Protein Expression Clusters Can Differentiate Leukemia 
Subtypes in Pediatric Leukemia. Blood 124, 3784-3784 (2014). 
37. 
Hoff, F.W., et al. Recurrent Patterns of Protein Expression Signatures in Pediatric Acute Lymphoblastic 
Leukemia: Recognition and Therapeutic Guidance. Blood 128, 4089-4089 (2016). 
38. 
Hoff, F.W., et al. Recognition of Recurrent Protein Expression Patterns in Pediatric Acute Myeloid Leukemia 
Suggests New Therapeutic Targets. Blood 128, 1712-1712 (2016). 
39. 
Pigneux, A., et al. Proteasome inhibition specifically sensitizes leukemic cells to anthracyclin-induced 
apoptosis through the accumulation of Bim and Bax pro-apoptotic proteins. Cancer biology & therapy 6, 
603-611 (2007). 
40. 
Mistry, P., Batchelor, H. & project, S.P.-U. Evidence of acceptability of oral paediatric medicines: a review. 
The Journal of pharmacy and pharmacology 69, 361-376 (2017). 
41. 
Van Riet-Nales, D.A., et al. Paediatric Drug Development and Formulation Design-a European Perspective. 
AAPS PharmSciTech 18, 241-249 (2017). 
42. 
Davies, E.H. & Tuleu, C. Medicines for children: a matter of taste. The Journal of pediatrics 153, 599-604, 
604 e591-592 (2008). 
43. 
Mulla, H., et al. 'Acceptability' of a new oral suspension formulation of mercaptopurine in children with acute 
lymphoblastic leukaemia. Journal of oncology pharmacy practice : official publication of the International 
Society of Oncology Pharmacy Practitioners 22, 387-395 (2016). 
44. 
Nagorsen, D., Kufer, P., Baeuerle, P.A. & Bargou, R. Blinatumomab: a historical perspective. Pharmacology 
& therapeutics 136, 334-342 (2012). 
45. 
Gupta, N., et al. Population Pharmacokinetic Analysis of Ixazomib, an Oral Proteasome Inhibitor, Including 
Data from the Phase III TOURMALINE-MM1 Study to Inform Labelling. Clinical pharmacokinetics (2017). 
46. 
Gupta, N., et al. A pharmacokinetics and safety phase 1/1b study of oral ixazomib in patients with multiple 
myeloma and severe renal impairment or end-stage renal disease requiring haemodialysis. British journal 
of haematology 174, 748-759 (2016). 

 
 
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47. 
Gupta, N., et al. Pharmacokinetics of ixazomib, an oral proteasome inhibitor, in solid tumour patients with 
moderate or severe hepatic impairment. British journal of clinical pharmacology 82, 728-738 (2016). 
48. 
Gupta, N., et al. Pharmacokinetics and safety of ixazomib plus lenalidomide-dexamethasone in Asian 
patients with relapsed/refractory myeloma: a phase 1 study. Journal of hematology & oncology 8, 103 
(2015). 
49. 
Suzuki, K., et al. Phase 1 study of ixazomib alone or combined with lenalidomide-dexamethasone in 
Japanese patients with relapsed/refractory multiple myeloma. International journal of hematology 105, 445-
452 (2017). 
50. 
Gupta, N., et al. The Effect of a High-Fat Meal on the Pharmacokinetics of Ixazomib, an Oral Proteasome 
Inhibitor, in Patients With Advanced Solid Tumors or Lymphoma. Journal of clinical pharmacology 56, 1288-
1295 (2016). 
51. 
Custodio, J.M., Wu, C.Y. & Benet, L.Z. Predicting drug disposition, absorption/elimination/transporter 
interplay and the role of food on drug absorption. Advanced drug delivery reviews 60, 717-733 (2008). 
52. 
Palumbo, A. & Anderson, K. Multiple myeloma. The New England journal of medicine 364, 1046-1060 
(2011). 
53. 
Herndon, T.M., et al. U.s. Food and Drug Administration approval: carfilzomib for the treatment of multiple 
myeloma. Clinical cancer research : an official journal of the American Association for Cancer Research 
19, 4559-4563 (2013). 
54. 
Bross, P.F., et al. Approval summary for bortezomib for injection in the treatment of multiple myeloma. 
Clinical cancer research : an official journal of the American Association for Cancer Research 10, 3954-
3964 (2004). 
55. 
Tibes, R., et al. Reverse phase protein array: validation of a novel proteomic technology and utility for 
analysis of primary leukemia specimens and hematopoietic stem cells. Molecular cancer therapeutics 5, 
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56. 
Horton, T.M., et al. A phase 1 study of the proteasome inhibitor bortezomib in pediatric patients with 
refractory leukemia: a Children's Oncology Group study. Clinical cancer research : an official journal of the 
American Association for Cancer Research 13, 1516-1522 (2007). 
57. 
Eisenhauer, E.A., et al. New response evaluation criteria in solid tumours: revised RECIST guideline 
(version 1.1). European journal of cancer 45, 228-247 (2009). 
58.  
Angiolillo AL, Schore RJ, Devidas M, et al. Pharmacokinetic and pharmacodynamic properties of 
calaspargase pegol Escherichia coli L-asparaginase in the treatment of patients with acute lymphoblastic 
leukemia: results from Children's Oncology Group Study AALL07P4. J Clin Oncol. 2014; 32(34): 3874-
3882. 
59. 
Vrooman LM, Blonquist TM, Stevenson KE, et al. Efficacy and Toxicity of Pegaspargase and Calaspargase 
Pegol in Childhood Acute Lymphoblastic Leukemia: Results of DFCI 11-001. J Clin Oncol. 2021; 39(31): 
3496-3505. 
60. 
Hunger SP and Raetz EA.  How I treat relapsed acute lymphoblastic leukemia in the pediatric population.  
Blood, 2020 Oct 15; 136(16): 1803-1812. doi: 10.1181/blood.2019004043. PMID: 32589723 
 
 
 
 
 
 

 
 
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15.0 
SAMPLE INFORMED CONSENT 
 
SAMPLE INFORMED ASSENT*/CONSENT DOCUMENT / PARENTAL PERMISSION FOR PARTICIPATION IN 
RESEARCH 
*Assent for patients >14 years of age 
*Assent for patients <14 years of age should be written per institutional guidelines 
 
TACL Protocol  
A TACL Phase 1/2 Study of PO Ixazomib in Combination with Chemotherapy for 
Childhood Relapsed or Refractory Acute Lymphoblastic Leukemia and Lymphoblastic 
Lymphoma  
 
Subject Name: 
 
Medical Record #  
 
Physician: 
 
 
 
KEY INFORMATION  
(1) The information in this form is being used to seek your consent for a research study. Participation in the 
study is completely voluntary. 
(2) This research is being done to find the optimal dose of Ixazomib with intensive chemotherapy and to 
know the side effects (good/bad) that it may cause. Participation will last up to 24 months. Study 
procedures for this research are:  
• 
Take a study drug, Ixazomib, on various days by mouth along with other chemotherapy drugs 
that will be given to you by various methods (such as injections). 
• 
Allow to collect blood samples from you by inserting a needle into a vein or by using your 
peripheral or central line. 
• 
Complete a questionnaire about the smell and taste of the study drug.  
• 
Participate in optional biology studies allowing us to collect additional bone marrow and blood 
specimens and storing those leftover specimens for use in future research studies. 
• 
Allow the research team to review and record information from your medical record. 
(3) The most likely risks to you of the research are:  
• 
Chemotherapy side effects, such as feeling tired, anemia, and easily bruised, loss of appetite,  
shortness of breath, headaches, or nerve pain, or allergic reactions. 
Please see the POTENTIAL RISKS AND DISCOMFORTS section for a complete list of expected risks. 
(4) The most likely benefits to you of the research are: Researchers believe this therapy may stop your 
leukemia or lymphoma to stop growing or go into remission for a period of time. 
(5) If you decide to not be in the research, your choices are:  
• 
Receive other combinations of chemotherapy 
• 
Decide not to receive additional chemotherapy for your condition. 
 
 
 
Local IRB changes to this document are allowed. Changes within the document should not substantially 
alter the meaning or intent of the consent document. If the institution or IRB insists on making deletions or 
more substantive modifications to the consent, especially in the risks sections, they should be reviewed 
and approved by the TACL Operations Center.  

 
 
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When we say “you” in this consent form, we mean you or your child; “we” means the doctors and other 
staff. 
 
This is a clinical trial, a type of research study. Your study doctor will explain the clinical trial to you. Clinical trials 
include only people who choose to take part. Please take your time to make your decision about taking part.  You 
may discuss your decision with your friends and family.  You can also discuss it with your health care team.  If you 
have any questions, you can ask your study doctor for more explanation.  
 
This study is being carried out by the Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) 
Consortium. TACL is a group of Universities and Children’s Hospitals that are working together to find treatments 
for children with leukemia and lymphoma. Funding for this research is provided by Takeda Pharmaceuticals 
Company Limited, or its affiliates (Takeda). 
 
You are being asked to take part in this research study because your ALL or Lymphoblastic Lymphoma (LLy) has 
come back (relapsed) or didn’t respond to the standard therapy.  
 
This is a phase 1/2 study of a drug called Ixazomib in combination with cytotoxic chemotherapy consisting of 
Vincristine, Dexamethasone, Asparaginase, and Doxorubicin (VXLD) during Blocks 1, 2, and Maintenance phase. 
Ixazomib is considered experimental because it has not been proven to work in a situation like yours. It is a drug 
given orally. Ixazomib taken with lenalidomide and dexamethasone is approved by the Federal Drug Administration 
for the treatment of patients with multiple myeloma who have received at least one prior treatment for their multiple 
myeloma. It is not known if ixazomib is safe and effective in children. We are studying whether adding ixazomib to 
the chemotherapy we routinely used to treat your cancer can increase response to the therapy. This is called a 
Phase 1/2 study because the goal is to find the optimal dose of Ixazomib that we can give safely in combination 
with intensive chemotherapy, and whether this combination could improve the response rate of the chemotherapy. 
 
It is important for you to know why this study is being done before you decide to take part in this research study. 
This consent will tell you about the study. This consent will also tell you about risks and side effects that might 
happen to you if you take part in this study. You also need to know you do not have to take part in this study. You 
can talk to your doctor about other cancer treatments. Because all of the drugs used in this study are each available 
to doctors, it is possible for you to receive these drugs without taking part in this study. Taking part in this study is 
voluntary. 
 
Why is this study being done? 
 
We are testing new experimental drug combinations such as the combination of Ixazomib with cytotoxic 
chemotherapy consisting of Vincristine, Dexamethasone, Asparaginase, and Doxorubicin (VXLD) during Blocks 1, 
2, and Maintenance phase in the hopes of finding a drug combination that may be effective against relapsed 
leukemia and lymphoma. 
 
The goals of this study are: 
 
• 
To find the optimal dose of Ixazomib that can be given with intensive chemotherapy without causing severe 
side effects; 
• 
To learn what kind of side effects Ixazomib can cause; 
• 
To learn more about the pharmacology (how your body handles the drug) of Ixazomib; 
• 
To learn how Ixazomib affects specific molecules on leukemia and lymphoma cells;   
To determine whether Ixazomib, combined with intensive chemotherapy is a beneficial treatment for your ALL or 
LLy. 
 

 
 
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How many people will take part in this study? 
It is expected that approximately 27 children and young adults will take part in this study. 
 
 
What will happen if I take part in this research study? 
 
Before you begin the study… 
 
You will need to have the following exams, tests or procedures to find out if you can be in the study. These exams, 
tests or procedures are part of your regular cancer care and may be done even if you do not join the study.  If you 
have had some of them recently, they may not need to be repeated. The results of these tests will be reviewed.  It is 
possible that after these tests are reviewed, you will not be able to take part in the study.  If you are not able to take 
part in the study, your doctor will discuss with you the reasons why. 
 
• 
A medical history 
• 
Physical exam with vital signs 
• 
Bone marrow test to check your cancer (see Tests on the Bone Marrow, below) 
• 
Lumbar puncture to test the fluid in your spinal cord (see Lumbar Punctures, below) 
• 
Various blood tests to check your organ function 
• 
Tests to make sure you are not pregnant (if you are a female and old enough to become pregnant) 
• 
Echocardiogram (ECHO) which uses sound waves to test heart function 
• 
CT / PET or Gallium Scans to check your cancer (for some patients) 
• 
Neurological exam 
 
Tests on the Bone Marrow 
Examinations of the bone marrow will be performed routinely and may be done at the discretion of your study doctor. 
You have already had many tests of your bone marrow for your previous treatment of  ALL or LLy.                    
Many children receive some form of sedation or anesthesia during this procedure. A small area over your hip bone 
on the back will be cleaned and numbed with lidocaine and/or with an anesthetic cream. Approximately a little less 
than 3 teaspoons of bone marrow will be withdrawn through a needle inserted into the bone. The test is painful, 
especially when the bone marrow is withdrawn. There is also a small risk of bleeding or infection from this procedure.   
 
Lumbar Punctures (“L.P.s”, “spinal taps”) 
You are familiar with spinal taps since they were done during your initial therapy for leukemia or lymphoma ALL or 
LLy. Whether you decide to participate or not in this study, spinal taps will need to be done to give medicines, which 
are necessary to prevent the leukemia from spreading to the spinal fluid. Participating on the study doesn’t require 
additional spinal taps. Your doctor will decide what medication(s) to be injected into your spine while you are having 
a lumbar puncture. This way of giving medicine is called “intrathecal” or IT. Many children receive some form of 
sedation or anesthesia during this procedure. Spinal taps are painful and may cause headaches. The skin at the 
site of needle insertion is usually numbed with an anesthetic cream or lidocaine before the procedure is performed. 
Approximately a little less than a teaspoon of spinal fluid will be withdrawn prior to injection of the medicine. 
 
 
During the study… 
 
If the exams, tests and procedures show that it is safe for you to be enrolled on the study you will receive treatment 
courses detail below.  
 
Various methods will be used to give drugs: 

 
 
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• 
IV – Drug is given using a needle or tubing inserted into a vein,  It can be given by IV push over several 
minutes or by infusion over minutes to hours 
• 
PO-Drug is given by capsule or liquid swallowed through the mouth 
• 
IM- Drug is given using a needle for single injection into the muscle. 
• 
IT – Drug used to treat the brain and spinal cord is given using a needle inserted into the spinal canal 
 
Block 1 will consist of the following medications: Ixazomib by mouth on days 1, 4, 8, and 11. Vincristine will be given 
by intravenous (IV) infusion on days 1, 8, 15, and 22. Dexamethasone will be given by intravenous (IV) infusion or 
by mouth on days 1 – 14. Pegaspargase will be given by IV injection on day 2 and 15. Doxorubicin will be given via 
IV on day 1. You will then recover from the combined therapy. After block 1 therapy, based on your response, your 
doctor will discuss with you about the options of moving onto block 2 therapy, going directly to maintenance therapy 
up to 4 cycles, and/or going off protocol therapy.  
 
We highly recommend you remain in the hospital during the block 1 from the time you start the therapy (or from 
Day 1) until blood work and your medical team determine it is safe for you to be sent home. It will be mandatory 
that you are started on preventative antibiotics and anti-fungal while you are hospitalized. 
 
Treatment 
 
Block 1 
Days 
1 
2 
4 
8 
9 
11 
14 
15 
16 
18 
22 
23 
29 
30 
Ixazomib* 
● 
 
● 
● 
 
● 
 
 
 
 
 
 
BM 
 
Vincristine IV (1.5mg/m2) 
● 
 
 
● 
 
 
 
● 
 
 
● 
 
 
Dexamethasone IV/PO (10mg/m2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pegaspargase IV/ IM (2500 IU/m2) √ ± 
 
● 
 
 
 
 
 
● 
 
 
 
 
 
OR Calaspargase IV (2500 IU/m2) √ ± 
 
● 
 
 
 
 
 
 
 
 
 
 
 
Doxorubicin (60mg/m2) 
● 
 
 
 
 
 
 
 
 
 
 
 
 
Initial IT chemotherapy 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
CNS 1/2: IT Methotrexate 
 
 
 
 
 
 
 
● 
 
 
 
 
●‡ 
 
CNS 3: IT Triple 
 
 
 
● 
 
 
 
● 
 
 
● 
 
●‡ 
 
Leucovorin IV/PO (5 mg/m2 at hr 24 
and 30 post-ITs)^ 
 
● 
 
 
● 
 
 
 
● 
 
 
● 
 
● 
‡ IT therapy assigned to be given on Day 29 may be moved such that it may be given at the time of the end of Block 
1 bone marrow/disease evaluation. 
 
√ Either Pegaspargase OR Calaspargase will be administered according to current approved labeling based on age 
and regional availability. Patients who start on either Pegaspargase or Calaspargase must continue the same 
treatment throughout the treatment cycle and are not to be used interchangeably. Patients receiving Calaspargase 
will only receive one dose in this cycle 
 
± crisantapase (Erwinase®) or asparaginase Erwinia chrysanthemi (recombinant)-rywn (Rylaze®) may be 
substituted for allergy to Pegaspargase or Calaspargase. If reaction to Day 2 calaspargase requires Erwinia 
replacement, 2 courses of Erwinia (beginning at or around Day 2 and at or around Day 15) should be administered 
(i.e. 12 total Erwinia doses). 
 
Block 2 
Days 
1 
3 
4 
5 
8 
9 
10 
11 
15 
18 
19 
21 
Ixazomib* 
● 
 
● 
 
● 
 
 
 
● 
● 
 
 
Dexamethasone IV/PO (6mg/m2) 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Vincristine IV (1.5mg/m2) 
 
● 
 
 
 
 
 
 
 
 
 
 
Methotrexate IV (1000mg/m2) 
 
 
 
 
● 
 
 
 
 
 
 
 
Pegaspargase IV / IM (2500 IU/m2) √  ± 
 
 
 
 
 
● 
 
 
 
 
 
 
OR Calaspargase IV (2500 IU/m2) √ ± 
 
 
 
 
 
● 
 
 
 
 
 
 
Cyclophosphamide IV (440mg/m2) 
 
 
 
 
 
 
 
 
 
 
 
 
Etoposide IV (100mg/m2) 
 
 
 
 
 
 
 
 
 
 
 
 
CNS 1/2: IT Methotrexate 
 
 
 
 
● 
 
 
 
 
 
 
 
CNS 3: IT Triple 
 
 
 
 
● 
 
 
 
 
 
 
 
Leucovorin IV/PO (15 mg/m2)^ 
 
 
 
 
 
 
● 
 
 
 
 
 
√ Either Pegaspargase OR Calaspargase will be administered according to current approved labeling based on age 
and regional availability. Patients who start on either Pegaspargase or Calaspargase must continue the same 
treatment throughout the treatment cycle and are not to be used interchangeably.  
 
± crisantapase (Erwinase®) or asparaginase Erwinia chrysanthemi (recombinant)-rywn (Rylaze®) may be 
substituted for allergy to Pegaspargase or Calaspargase. Six doses of replacement Erwinia should be given to 
replace either pegaspargase or calaspargase during Block 2 
 
Optional Standard Maintenance 
Days 
1 
2 
5 
8 
11 
15 
18 
22 
28 
Ixazomib* 
● 
 
 
● 
 
● 
 
 
 
Vincristine IV (1.5mg/m2) 
● 
 
 
 
 
 
 
 
 
Prednisone (20mg/m2/dose BID) 
 
 
 
 
 
 
 
 
 
Mercaptopurine (75mg/m2/day) 
 
 
 
 
 
 
 
 
 
Methotrexate 20mg/m2/week 
● 
 
 
● 
 
● 
 
● 
● 
IT Methotrexate# 
● 
 
 
 
 
 
 
 
 
Leucovorin IV/PO (5 mg/m2 at hr 
24 and 30 post-IT)^ 
 
● 
 
 
 
 
 
 
 
 
 
# Optional per treating physician; or Triple IT: optional for CNS 3 patients only 
*Ixazomib is a capsule that will be given orally. If you can’t swallow a capsule, you will be given a liquid solution. 
Ixazomib will be given at different doses. The table below shows the doses of ixazomib planned in this study. Your 
doctor will discuss with you which dose of ixazomib will be administered. 
^For patients with DS only (based on dates when IT MTX or ITT given) 
 
 
Level 
Patients ≥ 1 year of 
age 
Dose 
Patients < 1 year of 
age 
Dose 
-1 
1.2 mg/m2/day 
0.04 mg/kg/day 
1 
1.6 mg/m2/day 
0.05 mg/kg/day 
2 
2 mg/m2/day 
0.07 mg/kg/day 
 
Each treatment will last 4 weeks. At the end of each treatment course, you will have an evaluation to see how your 
leukemia is responding to therapy. Additional therapy is recommended after completion of this treatment and your 
doctor will discuss those options with you.  
 

 
 
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Medical Tests During Treatment 
Whether you are on this study or not the following medical tests will be done to monitor for response to treatment 
as well as side effects related to treatment. You will have regular medical appointments throughout treatment. The 
timing of the appointments will be the same regardless if you participate in the research study. These include: 
• 
Physical exams with vital signs 
• 
Neurological Exams 
• 
Blood tests to check your organ function including 
– 
CBC to look at your blood cells 
– 
Chemistries to look at elements and minerals in your blood 
– 
Blood tests to look at your liver and kidney function 
• 
Bone Marrow Tests (including test for minimal residual disease) 
• 
Lumbar Punctures 
• 
Radiology scans such as a CT, MRI, or X-ray, if indicated 
 
Tests for Research Purposes: 
In addition to the routine tests listed above, we would like to do other tests while you are enrolled on the study.   
 
We would also like to do some extra tests called biologic studies. These tests will help us learn more about Ixazomib 
on leukemia cells and may help children who receive this drug in the future. The information learned would not change 
the way you are treated, and the results of these tests will not be returned to you. Some of these tests are required 
and others are optional.  Although these tests are very important part of how we will better learn to use this drug, it is 
your decision as to whether or not you agree to participate.  
 
Biology Studies using Bone Marrow and Blood Samples (Optional) 
When bone marrow testing is being done as part of your standard evaluation(s) before you begin therapy and 
during the first 24 hours of receiving Investigational Product (blood sample only), we would like to request extra 
samples (approximately ½ teaspoon bone marrow and 4 teaspoon of blood)  at different  time points to evaluate 
the effect of Ixazomib on your cells in the bone marrow and if sample permits to grow your cancer in a mouse to 
further study the effect of Ixazomib and intensive reinduction chemotherapy on proteins in those cells. Cells 
leftover from the research studies above will be stored for future proteomics research and TACL biology studies.  
 
Upon the completion of this study, any leftover bone marrow and blood samples (including cells) and data from 
testing done on your samples will be stored within the TACL Central Biological Repository under the TACL 
T2016-005 study for use in future research studies.   
 
Your leftover research samples (including cells) and data from testing done on your research samples being 
stored at Baylor College of Medicine and in the TACL Central Biorepository will be “coded.”  “Coded” means that 
your leftover research samples and data will be assigned a unique code. Your leftover samples and data will not 
include your name or any other identifying information about you. The code that could be linked back to your 
identifying information will be kept separate from your research samples and data.  
 
Your leftover research samples (including cells) and data being stored at Baylor College of Medicine and in the 
TACL Central Repository may be used by the researcher conducting this study or other researchers (at CHLA or 
elsewhere) for future research projects that are unrelated to the purpose of this study. This future research may 
be done without consulting you or obtaining consent (permission) for this additional use. Future TACL biology 
studies on samples stored in the TACL Central Repository might include whole genome sequencing. 
 
Your coded leftover research samples (including cells) stored at Baylor College of Medicine and in the TACL 
Central Biorepository may also be used for commercial research.  There are no plans for you to share in any 
profits generated for any discoveries made as a result of this research.  
 
Information about Genetic Testing 

 
 
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Inside each cell in the human body, there are long and complex molecules called DNA. DNA stores the 
information that directs all cells in the body how to work. DNA is made up of many genes. Genes direct specific 
things like hair color or height.  
 
When scientists look at the whole length of all your DNA molecules, this is called “whole genome” or “whole 
exome” testing. “Whole genome” or “whole exome” tests result in a unique set of genetic blueprints that can be 
used to identify you (like a fingerprint) and possibly your near blood relations.  
 
If whole genomic sequencing is done on your leftover research samples stored in the TACL Central Biological 
Repository, the risks related to genetic analyses can be to individuals or groups. These harms include 
stigmatization and insurability. There is also a possibility that the results of the genetic testing could reveal both 
your risk of certain genetic disorders, and also suggest the risk of disease of close family. To reduce these risks, 
your samples will be stored and labeled with a code number as designed above. If the results are used in future 
research, the researchers will not be able to identify you. Information will not be recorded in your medical record. 
 
There is a Federal law, called the Genetic Information Nondiscrimination Act (GINA), which generally makes it 
illegal for health insurance companies, group health plans, and most employers to discriminate against you based 
on your genetic information. This law may protect you in the following ways: 
 
• 
Health insurance companies and group health plans may not request your genetic information that we get 
from this research. 
• 
Health insurance companies and group health plans may not use your genetic information when making 
decisions regarding your eligibility or premiums. 
• 
Employers with 15 or more employees may not use your genetic information that we get from this research 
when making a decision to hire, promote, or fire you or when setting the terms of your employment. 
 
This Federal law does not protect you against genetic discrimination by companies that sell life insurance, 
disability insurance, or long-term care insurance. 
 
There may be other risks that are not known at this time. Tell the study investigator or study staff right away if you 
have any problems. 
 
We will ask you about your decision about this optional procedure(s) at the end of this form. If you choose not to 
participate in the optional procedure(s), the data and specimens collected in this study will not be stored and used 
in future research studies. 
 
PK Samples (Mandatory) 
Doctors have developed test to study the levels of Ixazomib in the body. During therapy, researchers would like to 
draw additional blood at various time points. Any leftover blood that is not used for this test will be destroyed. Blood 
samples will be collected from all subjects during the study, the amount of the blood draw will be based upon your 
weight. Your doctor will discuss with you how much blood is required.  
 
Phase 1:  
Patients that are <20 kg will have 5 additional blood draws (approx.10mL, a little over 2 teaspoons), while patients 
≥20 kg will have 16 additional blood draws during Block 1 (approx.32mL, a little over 2 tablespoons). 
 
Phase 2: 
Patients that are <20 kg will have 4 additional blood draws (approx. 8mL, about a teaspoon and half) while patients 
≥20 kg will have 10 additional blood draws between Block 1 & Block 2 of treatment (approx.20mL, a little over 1 
tablespoon).   
 
Palatability Test 

 
 
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During the first block of treatment, a questionnaire will be completed after each dose of Ixazomib to gauge the smell 
and taste, using a 5-point facial scale. 
 
Final Study Visit 
Within 30 days after you finish the last dose of study drugs, your doctor will need to check to see how you are doing. 
The doctor will ask you how you feel, if you have trouble doing your daily routine, and what drugs you are taking. 
You will also have the following tests done:  
• 
Physical exam, weight and vital signs 
• 
CBC and chemistry blood tests 
 
Follow-up Tests 
After completing the treatment on this study we would like to continue to collect some medical information about 
how you are doing for as long as you are willing to let us or until the study is completely closed. We will collect 
information on how your ALL or LLy is doing, what kind of therapy you may be getting and if you have any long term 
side effects.   
 
 
What are my responsibilities? 
 
• 
During the study you will be asked to take all your chemotherapy drugs as prescribed. It is very important that 
you follow your doctor’s instructions regarding when and how to take your study medications.  Be sure to ask 
your study doctor or nurse if you have any questions about taking your study medications.   
 
• 
If you experience any unusual side effects as explained by your study doctor, you should contact the study 
center immediately. You should also contact your study doctor if you are hospitalized for any reason during the 
study or within 30 days after completion of therapy. 
 
  
How long will I be in the study?   
 
You will be in the study to receive at least one course of therapy. After completing the study therapy, your doctor 
will discuss with you the options for additional treatment. These options will vary depending on whether or not your 
leukemia responded to the therapy. You will remain in study for approximately 24 months.  
 
 
After completing the treatment on this study we would like to continue to collect some medical information about 
how you are doing for as long as you are willing to let us.  We will collect information on how your ALL or Lymphoma 
is doing, what kind of therapy you may be getting and if you have any long term side effects.   
 
 
Can I stop being in the study? 
 
Yes. You can decide to stop at any time. Your clinical care will not be affected by your decision to withdraw.  Tell 
your doctor if you are thinking about stopping or decide to stop.  He or she will tell you how to stop safely.  You will 
be asked to visit the hospital or clinic for some follow-up tests to make sure all the side effects you may have 
experienced have gone away. 
 
It is important to tell your doctor if you are thinking about stopping so any risks of the study treatment and 
chemotherapy drugs can be evaluated by your doctor.  Another reason to tell your doctor that you are thinking about 
stopping is to discuss what follow-up care and testing could be most helpful for you. 

 
 
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Your doctor may stop you from taking part in this study at any time without your permission if he/she believes it is 
in your best interest; if you do not follow the study rules; if you become pregnant or begin to breast feed; or if the 
study is stopped. 
 
 
What side effects or risks can I expect from being in the study?  
 
All people who receive cancer treatment are at risk of having side effects.  In addition to killing leukemia cells, 
chemotherapy drugs can damage normal tissues and produce side effects.  Side effects are usually reversible when 
the medication is stopped, but occasionally can persist and cause serious complications or death. The therapy used 
in this clinical trial is intensified so that it can kill cancer cells quickly before they can become resistant to treatment. 
Protocols used to treat relapsed leukemia are more intense than are those to treat newly diagnosed disease. It is 
not possible to predict whether the side effects listed below, or other rare side effects may occur.  Side effects can 
be increased when chemotherapy drugs are combined.  
 
Common side effects include nausea, vomiting, hair loss and fatigue. Chemotherapy causes temporary bone 
marrow depression. Bone marrow depression results in a decreased production of red cells causing anemia; 
decreased platelet production causing bruising and an increased chance of bleeding; and decreased white cell 
production, causing a risk of serious and potentially life threatening infections. Red blood cell and platelet 
transfusions may be required. 
 
Risks of having the bone marrow procedure include bleeding, chance of an infection and long lasting pain at the 
place where the needle is inserted into the bone.  
 
Each drug will have a unique set of side effects.  Side effects related to drugs occur in people at different rates or 
frequencies.     
 
STUDY DRUG 
 
There are risks to taking part in any research study.  During the study, you may have problems or discomforts  
and  risks  from  Ixazomib,  Ixazomib   and  other  drug  combinations,  and/or  study procedures.   The more 
commonly occurring discomforts and risks are listed below, as are the rare but serious discomforts and risks.  
You should discuss these with your study doctor. There is always the possibility that unknown risks may occur, 
however your doctor will watch closely for problems or discomforts and risks.  Many discomforts and risks go 
away shortly after treatment is stopped or with treatment for the discomforts and risks, but in some cases 
discomforts and risks may be serious, long- lasting or permanent and may even result in hospitalization or death. 
If any discomforts and risks occur, you must tell your study doctor or study staff, even if you do not 
think they are related to the study drug. 
 
POTENTIAL DISCOMFORTS AND RISKS OF IXAZOMIB 
Based on studies of Ixazomib it is possible to predict some of the discomforts and risks. However, it is possible 
that Ixazomib may cause risks that have not yet been observed in patients.  The following risks might be seen: 
 
 
• 
Low platelet count which may increase the chance of bleeding  
• 
Skin rash which may range from some red areas, small flat spots, or small raised  bumps 
that may or may not be itchy in a few areas or all over the body Nausea  

 
 
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• 
Vomiting  
• 
Diarrhea  
• 
Numbness or tingling or pain feelings in hands and feet  
• 
Swelling or fluid buildup in the arms or legs 
• 
Flu-like symptoms and other upper respiratory tract infections 
• 
Arthralgia or joint pain 
• 
Lung infections including pneumonia, bronchitis, or pneumonitis 
• 
Herpes Zoster that can sometimes cause local pain that may last after recovery from the 
skin rash and does not go away from some time 
 
Other discomforts and risks reported in studies with Ixazomib, which may have been due to the patient’s disease, 
Ixazomib, other medications, or some combination of these include: 
• 
Not feeling like eating  
• 
Electrolyte imbalance (blood chemical imbalance)  
• 
Loss of water from the body (dehydration; because of vomiting and/or loose stools 
• 
High blood creatinine and renal failure which means your kidneys are having trouble 
working well; Patients who had lost body water (dehydration) because of vomiting and/or 
loose stools have had high levels of creatinine indicating that the kidneys were failing to 
function adequately. In some severe situations, less kidney function may require 
temporary treatment with a machine that supports the function of the kidney (dialysis) 
• 
Feeling short of breath or difficulty breathing  
• 
Feeling tired or weak 
• 
Chills  
• 
Cough 
• 
Fever 
• 
Headache 
• 
Pain in the abdomen or back   
• 
Muscle weakness  
• 
Feeling dizzy or dizziness 
• 
Lowered blood pressure that can commonly cause you to feel light headed, faint or pass 
out when you stand up  
• 
Lowered white blood cells called lymphocytes  
• 
Lowered red cells or anemia which may make you feel tired 
• 
Lowered white blood cells called neutrophils that may increase your risk of infection and 
may be associated with fever 
• 
Constipation 
• 
Pain (muscular) in extremities   
• 
Distortion of the sense of taste i.e. an abnormal or impaired sense of taste 
• 
Trouble falling asleep, staying asleep or both 
 
Some discomforts and risks occur with lesser frequency (<1%) than those mentioned above, should be noted 
because they are severe, life-threatening or fatal.  With limited experience and because these events occurred 
while patients were receiving other drugs as well, we do not know if ixazomib causes such problems.  Severe, life-
threatening or deadly conditions that may involve rash, blistering, skin peeling and mouth sores including Stevens-
Johnson Syndrome, Toxic Epidermal Necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS 
syndrome), acute febrile neutrophilic dermatosis (Sweet’s syndrome) and pemphigus vulgaris, have been 
reported in  ixazomib studies when given in combination with other drugs.  These rashes are disorders of the 
immune system, which differ from regular skin rashes and are generally more severe. 

 
 
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In addition, two rare neurological conditions have been reported in patients on ixazomib (frequency <1%). Posterior 
reversible encephalopathy syndrome (PRES) which affects the brain and may cause headaches, changes in your 
vision, changes in your mental status, or seizures (fits), but is usually reversible.. Transverse myelitis, also a rare 
condition (<1%), is an inflammatory disease causing injury to the spinal cord which has been reported in a patient 
receiving ixazomib. This condition may cause varying degrees of muscle weakness, reduced movement in legs, 
changes in the feelings of the toes and feet, unusual muscle tightness, feelings of pain, changes in bowel 
(constipation) or urinary (loss of control) function or loss of leg movement.  In general, recovery may be partial, 
complete, or not at all but most patients experiencing transverse myelitis have good to fair recovery of symptoms. 
We do not know whether Ixazomib causes transverse myelitis, however, as it happened to a patient receiving 
ixazomib, we are not able to exclude the possibility that ixazomib may have contributed to transverse myelitis. 
 
Progressive multifocal leukoencephalopathy (PML) is a rare, serious infection of the brain that is caused by a 
virus. Persons with a weakened immune system may develop PML. PML can result in death or severe disability. 
PML has been observed rarely (<0.1 %) in patients taking ixazomib.  It is not known whether ixazomib may 
contribute to the development of PML. 
 
Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenia purpura (TTP) and hemolytic uremic 
syndrome (HUS), are rare, serious blood disorders that cause low levels of platelets and red blood cells, and 
result in blood clots in small vessels. Symptoms may include fatigue, fever, bruising, nose bleeds, and decreased 
urination. These disorders can occasionally be fatal. TMA, TTP, and HUS have been seen rarely (<0.1%) in 
patients treated with ixazomib.  
Overdose has been reported in patients taking Ixazomib.  Reports of accidental overdose have been associated 
with risks such as nausea, lung infections including aspiration pneumonia, multiple organ failure, and death.  It is 
important to take only one dose of Ixazomib at a time, and only at the prescribe intervals. 
 Ixazomib should not be taken if you have ever had an allergic reaction to the active substance or any of the 
inactive ingredients using in its formulation. 
 
The following side effects may also be a risk with ixazomib because they have been reported with another 
proteasome inhibitor, bortezomib (Velcade), in patients with diseases requiring this type of treatment, or in 
patients who receive ixazomib in combination with other drugs for cancer treatment: 
 
• 
Rapid death of cancer cells that may let large amounts of the cells into the blood that injure organs, such 
as kidneys (this is referred to as tumor lysis syndrome); 
 
• 
Worsening of your heart function (congestive heart failure) that may require additional drugs for treatment 
or hospitalization; 
 
• 
Disorders of your lung that could be serious enough to result in death 
 
Other drugs and supplements may affect the way ixazomib works. Tell your doctor about all drugs and 
supplements you are taking while you are in this study. 
RISK TO THE UNBORN CHILD (MEN AND WOMEN) 
Female Subjects: We do not know if the study drug Ixazomib will affect mother’s milk or an unborn child. 
Therefore, breast-feeding and pregnancy women are not allowed to take part in the study. Due to unknown risks 
and potential harm to the unborn child/infant, you should not become pregnant or nurse a baby while on this 
study. 
You must have a negative pregnancy test prior to enrolling in the study 

 
 
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Protocol Amendment #1 Version Date: 
 Protocol Amendment #2 Version Date:  
 Protocol Amendment #3 Version Date:  
 Protocol Amendment #4 Version Date:  
 Protocol Amendment #5 Version Date: 
 Protocol Amendment #6 Version Date 
 Protocol Amendment #7 Version Date: 
 
19December2019 
16September2020 
11May2021 
24January2022 
26October2022 
20July2023 
07September2023 
Unless you cannot have children because of surgery or other medical reasons (you had an effective tubal ligation: 
you had the ovaries or the uterus removed; or you are post-menopausal), you must use two effective methods of 
birth control from the time of signing the information consent form, for the entire study drug treatment period 
(including interruptions in treatment), and for 6 months after completing study drug treatment. It is strongly 
recommended that at least one of these two methods be highly effective (see example below). 
 
Highly effective methods 
Other effective methods (barrier) 
Intra-uterine devices (IUD) 
Latex or non-latex condom with or without a 
spermicidal agent 
Hormonal (birth control pills/oral contraceptives, 
injectable contraceptives, contraceptive patches, or 
Diaphragm with spermicide; Cervical cap with a 
spermicide; Sponge with a spermicide 
If one of the highly effective methods cannot be used, using two effective methods at the same time are 
recommended. 
 
You must us birth control methods as directed above, unless you completely avoid having heterosexual 
intercourse. 
Male subjects: We do not know if using ixazomib will affect sperm, Therefore, due to potential risk, you should 
not get your partner pregnant during the study drug treatment period (including interruptions in treatment). Even if 
you are surgically sterilized (i.e. have had a vasectomy) you must agree to use an appropriate method of barrier 
contraception (latex or non-latex condom with or without a spermicidal agent) during the entire study drug 
treatment period, and for 6 months after completing study drug treatment, Or, you should completely avoid having 
heterosexual intercourse. 
Highly effective methods 
Other effective methods (barrier) 
Vasectomy 
Latex or non-latex condom with or without a 
spermicidal agent 
 
Diaphragm with spermicide; Cervical cap with a 
spermicide; Sponge with a spermicide 
If one of the highly effective methods cannot be used, using two effective methods at the same time are 
recommended. 
 
All subjects (male or female): If you or your partner becomes pregnant during this study, you must tell the study 
doctor immediately. The doctor will advise you of the possible risks to your unborn child and discuss options for 
managing the pregnancy with you. For female subjects who become pregnant while on this study, the study drug 
will be stopped immediately, and the pregnancy will be followed until conclusion. 
If you do not understand what any of these discomforts and risks mean, please ask the study doctor or study staff 
to explain the terms to you. 
 
Tables listed below are the additional chemotherapy drugs to be used and outlines potential risks and 
discomforts. 
 
Asparaginase (Pegaspargase OR Calaspargase): 

 
 
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 Protocol Amendment #3 Version Date:  
 Protocol Amendment #4 Version Date:  
 Protocol Amendment #5 Version Date: 
 Protocol Amendment #6 Version Date 
 Protocol Amendment #7 Version Date: 
 
19December2019 
16September2020 
11May2021 
24January2022 
26October2022 
20July2023 
07September2023 
More Likely 
Less Likely 
Rare but Serious 
• 
An increase in the level 
of ammonia that is found 
in the blood 
• 
A decrease in levels of 
factors in the blood that 
help your blood to clot 
normally 
• 
A feeling of extreme 
tiredness not relieved by 
sleep 
• 
Weakness 
• 
Diarrhea 
 
• 
Rashes, hives, swelling of the 
lips 
• 
Feeling short of breath or 
shortness of breath 
• 
Some sort of allergic reaction 
such as a rash, hives or fever 
that may require pretreatment 
with antihistamines prior to the 
injection 
• Puffiness or swelling around the 
eyes 
• Fluid build-up in the tissues or 
Fluid retention 
• High levels of sugar in the blood 
that may require treatment 
• Elevation in the blood of certain 
enzymes or bilirubin found in the 
liver which may mean liver 
irritation or damage 
• High levels of uric acid in the 
blood which could damage the 
kidneys 
• Headache 
• Dizziness 
• Chest pain 
• A fast heartbeat which may 
cause pain in the chest 
• A decrease or an increase in 
blood pressure 
• Loss of desire to eat or appetite 
• Weight loss 
• Mild nausea and/or vomiting 
• Muscle and joint aches and pains 
• Numbness and tingling in the 
fingers and toes 
• Chills and fever 
• Changes in your mood such that 
you feel depressed, irritable, 
confused or have hallucinations 
(see or hear things that are not 
there) 
• An increase in the levels of lipids 
(fats) in your blood which if 
prolonged could lead to heart 
problems later in life 
• Shakiness or tremor which may 
cause jerky movements 
• Pain in the abdomen (belly) 
• Too much gas produced in the 
intestines 
• Severe allergic reaction which 
can be life threatening with 
shortness of breath, low blood 
pressure, rapid heart rate chills 
and fever 
• Irritation of the small airways of 
your lungs that can make you 
cough and wheeze 
• Seizures 
• Coma 
• Sudden damage to the red blood 
cells (hemolytic anemia) which 
could cause a rapid decrease in 
the number of red blood cells 
such that you would be tired and 
weak and feel short of breath 
and may require a blood 
transfusion 
• Temporary decrease in blood to 
the brain which can lead to 
temporary loss of consciousness 
• A bleeding disorder that can 
lead to bleeding from many 
areas of the body or excessive 
clotting in blood vessels 
including those that lead to the 
brain 
• Damage to the bladder which 
can lead to large amounts of 
blood in the urine, pain and the 
urge to urinate frequently and 
also scarring of the bladder 
• High levels of nitrogen and/or a 
chemical (creatinine) in the 
blood which may indicate that 
the kidneys are not working as 
well as normal 
• Severe kidney damage 
• Severe damage to the liver 
which can lead to a fatty and 
enlarged liver, inflammation 
and/or scarring which could lead 
to a yellow appearing skin, and 
fluid collection in the abdomen 
(belly) which makes it look larger 
• Reduced ability of the body to 
fight infection which can lead to 
infections including severe blood 
infections which will need to be 
treated and may be life 
threatening, infections of the 

 
 
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 Protocol Amendment #2 Version Date:  
 Protocol Amendment #3 Version Date:  
 Protocol Amendment #4 Version Date:  
 Protocol Amendment #5 Version Date: 
 Protocol Amendment #6 Version Date 
 Protocol Amendment #7 Version Date: 
 
19December2019 
16September2020 
11May2021 
24January2022 
26October2022 
20July2023 
07September2023 
More Likely 
Less Likely 
Rare but Serious 
• Inflammation of the pancreas (an 
organ in the abdomen which 
produces insulin and certain 
digestive chemicals) which may 
affect the function of the 
pancreas and which may cause 
pain in the abdomen (belly)which 
can be severe and may increase 
the blood sugar 
• Elevations of certain chemicals in 
the blood which may indicate 
damage to the pancreas 
• Fewer white blood cells, red 
blood cells and platelets in the 
blood  
o 
a low number of white blood 
cells can make it easier to 
get infections 
o 
a low number of red blood 
cells can make you feel tired 
and weak 
o 
a low number of platelets 
causes you to bruise and 
bleed more easily 
valves in the heart, the bladder 
and other areas of the body 
 
 
 
 
Erwinia Asparaginase: 
If you develop an allergic reaction to asparaginase (Pegaspargase or Calaspargase), you may be treated with 
crisantapase (Erwinase®) if available.  This preparation has been given to hundreds of children over many years 
and many of the side effects are similar to those that occur with the other forms of asparaginase.  
 
Another alternative if you are not able to take Pegaspargase or Calaspargase is Erwinia chrysanthemi 
(recombinant)-rwyn (Rylaze ®) (given into the muscle). The side effects are the same as Erwinia asparaginase. 
 
 
More Likely 
Less Likely 
Rare but Serious 
 
 
• Allergic reaction by your body to 
the drug product that can occur 
immediately or may be delayed. 
The reaction may include hives, 
low blood pressure, wheezing, 
swelling of the throat, and difficulty 
breathing. 
• Allergic reaction which can be life-
threatening and potentially fatal. 
This reaction requires immediate 
medical treatment. It may include 
fever, chills and skin rash. Less 
commonly wheezing, shortness of 
breath, swelling of the throat, drop 
• Inflammation of the pancreas (an 
organ in the abdomen which makes 
insulin and certain digestive 
chemicals) which causes severe pain 
in the abdomen (belly) and back and 
may increase the blood sugar  
• Formation of blood clots that plug 
blood vessels and can lead to pain 
and swelling in the area of the clot. 
Such clots may break loose and 
travel to another area. They can 
cause damage or be life-threatening 
depending on where they go. 

 
 
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 Protocol Amendment #2 Version Date:  
 Protocol Amendment #3 Version Date:  
 Protocol Amendment #4 Version Date:  
 Protocol Amendment #5 Version Date: 
 Protocol Amendment #6 Version Date 
 Protocol Amendment #7 Version Date: 
 
19December2019 
16September2020 
11May2021 
24January2022 
26October2022 
20July2023 
07September2023 
in blood pressure, and rapid heart 
rate may occur. 
• Hives; red and sometimes itchy 
bumps on the skin. 
• Local allergic reactions including 
rashes and hives around the site 
of the injection 
 
• Excessive or uncontrolled bleeding 
which can occur in the head, stools, 
the nose, urine and other parts of the 
body. 
• Sudden and temporary loss of blood 
flow and oxygen to the brain causing 
problems with vision, dizziness, 
weakness and numbness (especially 
in one side of the body), and trouble 
speaking. Also called mini stroke. 
• A bleeding disorder in which small 
blood clots develop throughout the 
bloodstream blocking small blood 
vessels and depleting platelets and 
clotting factors needed to control 
bleeding. This condition can lead to 
bleeding from many areas of the 
body and can be life-threatening. 
• Fever 
• Abnormal control of blood sugar 
level 
• Increase in the blood level of certain 
enzymes or bilirubin (a waste 
product that passes through the 
liver) which could indicate liver 
irritation or damage 
• High blood sugar which may require 
treatment with insulin 
• An increase in the level of ammonia 
that is found in the blood 
• Vomiting 
• Nausea  
• Belly pain 
• Headache 
• Diarrhea 
• Weight loss  
• 
Seizures; sudden, uncontrolled 
muscle spasm and loss of 
consciousness resulting from 
abnormal brain function. 
 
Cyclophosphamide: 
More Likely 
Less Likely 
Rare but Serious 
• 
Loss of appetite 
• 
Nausea 
• 
Vomiting 
• 
Fewer white blood cells 
in the blood 
• 
Hair loss 
• 
Decreased ability of the 
body to fight infection 
• 
Abnormal hormone function which 
may lower the level of salt in the 
blood 
• 
Abdominal pain 
• 
Diarrhea 
• 
Fewer red blood cells and platelets in 
the blood  
• 
Heart muscle damage which 
may occur with very high 
doses and which may be fatal 
• 
Abnormal heart rhythms 
• 
Damage and scarring of lung 
tissue which may make you 
short of breath 

 
 
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Protocol Amendment #1 Version Date: 
 Protocol Amendment #2 Version Date:  
 Protocol Amendment #3 Version Date:  
 Protocol Amendment #4 Version Date:  
 Protocol Amendment #5 Version Date: 
 Protocol Amendment #6 Version Date 
 Protocol Amendment #7 Version Date: 
 
19December2019 
16September2020 
11May2021 
24January2022 
26October2022 
20July2023 
07September2023 
More Likely 
Less Likely 
Rare but Serious 
• 
Absence or decrease in 
the number of sperm 
which may be 
temporary or 
permanent which may 
decrease the ability to 
have children 
• 
Bleeding and inflammation of the 
urinary bladder 
• 
Absence or decrease monthly periods 
which may be temporary or 
permanent and which may decrease 
the ability to have children 
• 
Temporary blurred vision 
• 
Nasal stuffiness with IV infusions 
• 
Skin rash 
• 
Darkening of areas of the skin and 
finger nails 
• 
Slow healing of wounds 
• 
Infections  
• 
A new cancer or leukemia 
resulting from this treatment. 
• 
Damage or scarring of 
urinary bladder tissue 
• 
Severe allergic reaction 
which can be life threatening 
with shortness of breath, low 
blood pressure, rapid heart 
rate chills and fever 
• 
Infertility which is the inability 
to have children 
 
Doxorubicin: 
More Likely 
Less Likely 
Rare but serious 
 
Nausea 
 
Vomiting 
 
Temporary hair loss 
 
Loss of appetite 
 
Pink or red color to urine, 
sweat, tears, saliva 
 
Fewer white blood cells, red 
blood cells and platelets in the 
blood. 
• 
A low number of red 
blood cells can make 
you feel tired and 
weak 
• 
A low number of 
white blood cells can 
make it easier to get 
infections 
• 
A low number of 
platelets causes you 
to bruise and bleed 
more easily 
 
Abnormal heart rhythm that is 
unlikely to have any 
noticeable effects on your 
heart function 
 
Decreased ability of the body 
to fight infection 
 
 
Inflammation and/or sores in the 
mouth, throat and/or esophagus 
 
Diarrhea 
 
Damage to the heart muscle 
which may make you tired, weak, 
feel short of breath, and retain 
fluid 
 
Dark discoloration of the hands, 
feet and under the fingernails 
 
Rash 
 
Thickening and hardening of the 
veins through which the 
medication is given 
 
Damage to the liver 
 
Tearing and inflammation of the 
eyes 
 
Redness and burning at sites 
which have received radiation in 
the past  
 
Severe allergic reaction 
which can be life 
threatening with shortness 
of breath, low blood 
pressure and a rapid heart 
rate 
 
Ulceration of the lower 
intestinal tract 
 
An irregular heart beat 
which can be life-
threatening 
 
Severe damage to the heart 
muscle which may lead to 
severe heart failure 
 
A new cancer or leukemia 
resulting from this 
treatment. 
 
Damage to the skin if the 
medication leaks from a 
vein 
 
Etoposide: 
More Likely 
Less Likely 
Rare but Serious 
• 
Nausea and vomiting 
• 
Hair Loss 
• Loss of appetite 
• 
Damage to the liver 
• 
Severe allergic reaction which can 
be life threatening with shortness 

 
 
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Protocol Amendment #1 Version Date: 
 Protocol Amendment #2 Version Date:  
 Protocol Amendment #3 Version Date:  
 Protocol Amendment #4 Version Date:  
 Protocol Amendment #5 Version Date: 
 Protocol Amendment #6 Version Date 
 Protocol Amendment #7 Version Date: 
 
19December2019 
16September2020 
11May2021 
24January2022 
26October2022 
20July2023 
07September2023 
• 
A feeling of weakness or 
tiredness 
• 
Fewer red and white blood 
cells and platelets in the 
blood  
• 
A low number of red blood 
cells can make you feel 
tired and weak 
• 
A low number of white 
blood cells can make it 
easier to get infections 
• 
A low number of platelets 
causes you to bruise and 
bleed more easily 
 
 
• Decreased blood pressure 
during the infusion which may 
require treatment 
• rashes 
• Diarrhea 
• Pain in the abdomen 
• Mouth sores 
• Tingling sensation or loss of 
sensation in fingers or toes 
• A feeling of  extreme 
tiredness or weakness 
• The finger or toe nails may 
loosen from their nail beds 
• Inflammation of the vein 
through which the medication 
was given 
• Chest pain 
of breath, low blood pressure, 
rapid heart rate chills and fever 
• 
A new cancer or leukemia 
resulting from this treatment 
• 
Severe rashes which can result in 
loss of skin and damage to 
mucous membranes 
• 
Absence  or decrease monthly 
periods which may be temporary 
or permanent and which may 
decrease the ability to have 
children 
• 
Damage to the heart muscle 
which may make you feel tired, 
weak, feel short of breath, and 
retain fluid 
 
 
Intrathecal Triple (Methotrexate/Hydrocortisone/Cytarabine): 
More Likely 
Less Likely 
Rare but Serious 
• 
None 
• 
Headache 
• 
Abnormally high number of cells in the 
spinal fluid 
• 
Learning disability 
• 
Nausea and Vomiting 
• 
Fever 
• 
Rash  
• 
Seizures 
• 
Drowsiness 
• 
Stiff neck 
• 
Irritation of tissues in the brain/spinal 
cord 
• 
Unsteady walk 
• 
Partial paralysis 
• 
Damage to brain tissue 
• 
Increasingly poor nervous 
system function 
• 
Fewer red and white blood cells 
and platelets in the blood 
 
 
Leucovorin Calcium: 
More Likely 
Less Likely 
Rare but Serious 
• 
None 
• 
Hives 
• 
Severe allergic reaction which can be life 
threatening with shortness of breath, low blood 
pressure, rapid heart rate chills and fever 
• 
Seizure 
 
 
Intrathecal Methotrexate: 
More Likely 
Less Likely 
Rare but Serious 
 
None 
 
Headache 
 
Abnormally high number of 
cells in the spinal fluid 
 
Learning disability 
 
Vomiting 
 
Fever 
 
Seizures 
 
Partial paralysis 
 
Damage to brain tissue 
 
Increasingly poor nervous 
system function 

 
 
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Protocol Amendment #1 Version Date: 
 Protocol Amendment #2 Version Date:  
 Protocol Amendment #3 Version Date:  
 Protocol Amendment #4 Version Date:  
 Protocol Amendment #5 Version Date: 
 Protocol Amendment #6 Version Date 
 Protocol Amendment #7 Version Date: 
 
19December2019 
16September2020 
11May2021 
24January2022 
26October2022 
20July2023 
07September2023 
More Likely 
Less Likely 
Rare but Serious 
 
Rash 
 
Drowsiness 
 
Stiff neck 
 
Irritation of tissues in the 
brain/spinal cord 
 
Unsteady walk 
 
Fewer red and white blood cells 
and platelets in the blood 
• 
a low number of red 
blood cells can make 
you feel tired and weak 
• 
a low number of white 
blood cells can make it 
easier to get infections 
• 
a low number of 
platelets causes you to 
bruise and bleed more 
easily 
 
Vincristine Sulfate: 
More Likely 
Less Likely 
Rare but Serious 
 
Constipation 
 
Hair loss 
 
Reversible nerve problem 
that may affect the way 
you walk or the feelings 
in your fingers or toes 
 
Loss of deep tendon 
reflexes (such as the 
“knee jerk”) noted only on 
physical exam 
 
Jaw pain 
 
Headache 
 
Muscle Weakness 
 
Pain and bloating in your abdomen 
 
Numbness and tingling 
 
Wrist or foot drop 
 
Abnormal walk with foot slapping 
 
A drop in white blood cells, red 
blood cells and platelets in the 
blood 
 
A low number of red blood cells 
can make you feel tired and weak. 
 
A low number of white blood cells 
can make it easier to get 
infections. 
 
A low number of platelets can 
make you bruise and bleed more 
easily. 
 
Complete stoppage of your 
intestinal activity which can 
result in intestinal blockage 
 
If the drug leaks out of the vein 
when being administered it can 
cause damage to nearby tissue 
 
Seizures 
 
Vocal cord paralysis 
 
Difficulty breathing 
 
Inability to walk 
 
Decreased ability to hear 
clearly 
 
Dizziness 
 
Difficulty with urination or 
increase desire to urinate 
 
Drooping eyelids 
 
Double vision, difficulty seeing 
at night 
 
Dexamethasone: 
Likely 
Less Likely 
Rare  
• 
Overeating 
• 
Difficulty sleeping or 
falling asleep 
• 
Decreased ability of the 
body to fight infection 
• 
Personality changes with 
mood swings 
• 
Changes in hormone 
production that cause 
weight gain especially 
around the abdomen 
and shoulders, puffy 
cheeks, muscle 
• 
Upset and irritated stomach with 
heartburn 
• 
High blood sugar which may require 
treatment 
• 
Red face 
• 
Poor wound healing  
• 
Infections 
• 
Fluid retention 
• 
Stretch marks and easy bruising of 
the skin 
• 
Muscle weakness 
• 
Abnormal amounts of 
uric acid in the blood 
• 
Inflammation of the 
pancreas 
• 
Increased pressure in the 
eyes High blood 
pressure 
• 
Serious changes in 
mood, personality and/or 
severe depression  
• 
Dizziness  
• 
Headache 

 
 
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Protocol Amendment #1 Version Date: 
 Protocol Amendment #2 Version Date:  
 Protocol Amendment #3 Version Date:  
 Protocol Amendment #4 Version Date:  
 Protocol Amendment #5 Version Date: 
 Protocol Amendment #6 Version Date 
 Protocol Amendment #7 Version Date: 
 
19December2019 
16September2020 
11May2021 
24January2022 
26October2022 
20July2023 
07September2023 
Likely 
Less Likely 
Rare  
weakness and make 
your body less able to 
deal with stress 
• 
Pimples 
• 
Lessening of calcium in the bones 
making them more susceptible to 
fracture 
• 
Cataracts which are usually more 
reversible in children 
 
• 
Bone Fractures 
• 
Slowed growth  
• 
Stomach ulcers 
• 
Stomach and intestinal 
tract bleeding from ulcers 
• 
Increased pressure in the 
brain which can lead to 
difficulty seeing, pressure 
in the eyes and 
headache 
• 
Damage to the joints 
which can result in pain 
and loss of motion 
usually involving the 
joints of the hip and knee 
 
 
Reproductive risks  
 
Because the drugs in this study may affect an unborn baby, you should not become pregnant or father a baby while 
on this study.  You should not breast-feed a baby while on this study.  It is a condition of this study that adequate 
birth control methods be used by all participants while enrolled in the study. Examples of these include total 
abstinence (no sex), oral contraceptives (“the pill”), an intrauterine device (IUD), Levonorgestrol implants (Norplant), 
or medroxyprogesterone acetate injections (Depo-provera shots).  If one of these methods of birth control cannot 
be used, contraceptive foam with a condom is recommended. Contraception methods is required during the entire 
study treatment including breaks in treatment, and a minimum of 6 months after the last dose of study drug.  Ask 
your doctor about counseling and more information about preventing pregnancy. 
 
Female patients who become pregnant or male patients whose partner becomes pregnant will be given 
instructions for discontinuation of study medication and will be removed from study. The study doctor will discuss 
the requirements for pregnancy outcome follow-up. 
 
Confidential Information  
 
There is the potential risk of accidental disclosure (release) of confidential information when you participate in 
research.  Please see the “Will my medical information be kept private?” section of this document for more details. 
 
Developing a Second Cancer 
 
It is possible that you may develop a second form of cancer as a result of this treatment.  Experience so far suggests 
that the chance of this happening is very small. Not enough information has been gathered in children to be able to 
give an accurate prediction, although it may be in the range of one in every 50 to 800 children treated.   
 
 
Are there benefits to subjects taking part in the study? 
 
Participation in this study may or may not benefit you. Participating in this study will not cure your relapsed leukemia 
or lymphoma.  Based on experience with the drugs used in the treatment plan, researchers believe this therapy 

 
 
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may cause your leukemia to stop growing or go into remission for a period of time.  Your cancer may not have any 
response to the therapy received while participating in this study.   
 
It is hoped that the information learned from this study may help future children or young adults with relapsed ALL 
and LLy. 
 
Your participation in this research study may contribute to the development of commercial products from which 
Takeda or others, may derive an economic benefit.  You will have no rights to any patents or discoveries arising 
from this research, and you will receive no economic benefit. 
 
What other choices do I have if I do not take part in this study? 
 
You do not have to participate in this study to receive treatment for recurrent leukemia. There is no “standard” 
therapy for recurrent leukemia. Most treatment plans have used drugs similar to those used in this protocol, although 
these drugs may be given in different combinations, and at different times.  You can receive other combinations of 
chemotherapy without participating in this study.   
 
As an alternative to this study, you may decide you don’t want additional treatment for your relapsed leukemia.  You 
will always receive medicines to help you feel more comfortable and deal with problems caused by your cancer or 
treatment whether you participate in this study or not. 
 
Talk to your doctor about your choices before you decide if you will take part in this study. 
 
 
Will my medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be kept private. However, 
we cannot guarantee total privacy. Your personal information may be given out if required by law. 
 
Members of the research team and, if appropriate, your primary care physicians and nurses will know that you are 
a research subject. All results will be kept confidential, but may be made available to you, and/or your physician if 
you wish.  Because this study involves the treatment of a medical condition, a copy of this consent form will be 
placed in your medical record. This will allow the doctors that are caring for you to obtain information about what 
medications or procedures you are receiving in the study and treat you appropriately. You may read your medical 
record. The records are available to those caring for you at this hospital. 
 
Organizations that may inspect/or copy your research records for quality assurance and data analysis may 
include but not limited to: 
• 
Therapeutic Advances in Childhood Leukemia Consortium (TACL) 
• 
The United States Food and Drug Administration (FDA) 
• 
Therapeutic Goods Administration, Australia 
• 
The Department of Health and Human Services (DHHS) 
• 
The Institutional Review Board (IRB) of CHLA  - Committee on Clinical Investigations 
 
As a result, these organizations may see your name; but they are bound by rules of confidentiality not to reveal your 
identity to others. These organizations, and Takeda, its collaborators or designees, will also have access to 
information about you and the study data in a form that does not mention your name but will instead be identified 
by a code number and your initials. Your study doctor is responsible for keeping a list of codes to make it possible 
to link your code to your name. This list will be kept in a safe place to make sure that in an emergency you can be 
identified and contacted. Reasonable steps will be taken to protect your right to privacy. No information about you, 

 
 
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or provided by you during the research, will be shared with others without your written permission, except as 
explained below: 
 
• 
If necessary to protect your rights or welfare (for example, if you are injured and need emergency care); 
or 
• 
If required by law (i.e., child abuse, reports of certain infectious diseases) 
 
The information collected will be used to meet the purpose of this clinical study. In addition, this information may be 
added to research databases and used in the future to 
• 
Study other therapies for patients, 
• 
Develop a better understanding of diseases included in the study, and 
• 
Improve the efficiency, design and methods of future studies. 
 
The coded information may be used by or sent to parties for clinical research, safety-reporting, other study-related 
uses described in this form and/or support applications to market the studied drug in the United States and in other 
countries. Some of these countries may not have data protection or privacy laws that offer the same level of 
protection as the data protection and privacy laws in your country. The study information may also be used in reports 
of the study or for scientific publications and presentations that will not identify study participants by name.   
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law.  This 
website will not include information that can identify you.  At most, the website will include a summary of the results.  
You can search this website at any time. 
 
 
What are the costs of taking part in this study? 
 
The health care costs during your participation in this study that are considered part of the standard treatment of 
your disease will be billed to your insurance or other third-party payer.  This includes blood tests, hospitalizations, 
procedures that will be done and medications.  
 
You will not have to pay for the following tests that will be done for research purposes only. 
• 
Test for how the Ixazomib are affecting your leukemia cells 
• 
The study drug Ixazomib will be supplied by Takeda Pharmaceuticals Company Limited 
 
Your family is responsible for other costs which may result from your participation in the study, such as, but not 
limited to, time off of work, car fare, baby sitter fees, and food purchased while at the hospital, etc.  You will not 
receive any type of payment for participating in this study.  Taking part in this study may lead to added costs to your 
insurance company. Please ask about any expected added costs or insurance problems. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer Institute’s Web 
site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage . You can print a copy of the “Clinical Trials 
and Insurance Coverage” information from this Web site. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send you a free 
copy. 
 
 
What happens if I am injured because I took part in this study? 
 
It is important that you tell your study doctor, __________________ [investigator’s name(s)], if you feel that you 

 
 
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have been injured because of taking part in this study.  You can tell the doctor in person or call him/her at 
__________________ [telephone number]. 
 
You will get medical treatment if you are injured as a result of taking part in this study.  You and/or your health plan 
will be charged for this treatment. The study, the institutions taking part in the study, and Takeda will not pay for 
such medical treatment and are not responsible for any underlying illnesses or the worsening of your disease.   
 
What are my rights if I take part in this study? 
 
Taking part in this study is voluntary. You may choose not to participate in this study. If you decide not to participate, 
you will not be penalized and you will still receive the standard treatment. 
 
If you choose to participate, you may discontinue your participation in the study at any time. If you discontinue 
participation in the study, physicians and hospital personnel will still take care of you. 
 
You also have the right to know about new information that may affect your health, welfare, or your willingness to 
participate in the study. You will be provided with this information as soon as it becomes available. 
 
Whether you participate or not, you will continue to get the best medical care this hospital can provide. 
 
Who can answer my questions about the study? 
 
You can talk to your study doctor about any questions or concerns you have about this study.  Contact your study 
doctor __________________ [name(s)] at __________________ [telephone number]. 
 
For questions about your rights while taking part in this study, call the ________________________ [name of center] 
Institutional Review Board (a group of people who review the research to protect your rights) at 
__________________ [telephone number].  [Note to Local Investigator: Contact information for patient 
representatives or other individuals in a local institution who are not on the IRB or research team but take calls 
regarding clinical trial questions can be listed here.]    
 
Where can I get more information? 
 
Call the National Cancer Institute’s Cancer Information Service: 
1-800-4-CANCER (1-800-422-6237) OR 1-800-332-8615 (for the hearing impaired) 
 
• 
You will be given a copy of this consent form. 
• 
You will be given a copy of this treatment plan upon request. 
• 
CancerNetTM: http:/cancernet.nci.nih.gov This site provides accurate cancer information including the 
Physicians Data Query (PDQ). The PDQ is the National Cancer Institute’s comprehensive cancer database. It 
contains peer-reviewed summaries on cancer treatment, screening, prevention, and supportive care; a registry 
of about 1,700 open and 10,300 closed cancer clinical trials from around the world; and directories of physicians, 
genetic counselors, and organizations that provide cancer care. 
• 
Visit the TACL Consortium Website at https://tacl.chla.usc.edu 
 
Product Complaints 
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction regarding the identity, 
strength, purity, quality, or stability of a drug product. In case patients or their legal guardians have questions 
about reporting product complaints you may contact the treating physician office to obtain more details. 

 
 
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CONSENT FOR OPTIONAL STUDIES FOR RESEARCH 
 
THESE TESTS ARE OPTIONAL. YOU MAY STILL PARTICIPATE IN THE STUDY EVEN IF YOU DO NOT 
AGREE TO THESE TESTS.   
 
Biology Studies using Bone Marrow Samples  
When bone marrow testing is being done as part of your standard evaluation(s) before you begin therapy and during 
the first 24 hours of receiving ixazomib, we would like to request extra samples (approximately ½ teaspoon bone 
marrow and 4 teaspoon of blood)  at different  time points to study  the effect of Ixazomib on your cancer cells in 
the bone marrow and blood.  
 
The tests may help us to better learn how this drug may work. Please indicate by initialing below whether you 
choose to participate in the biology studies. 
 
If you consent to this additional testing, your information resulting from the testing will be used as described 
above. 
 
Mark your choice and sign your name and the date 
 
YES, I agree to have bone marrow drawn on day 1 of block 1 for tests on cancer cells. 
 
_______ initials of subject (if subject is 14 years or older) 
 
_______ initials of parent/legal guardian (if subject is a minor) 
 
_______ initials of parent/legal guardian (if subject is a minor) 
 
NO, I do not agree to have bone marrow drawn on day 1 of block 1 tests on cancer cells. 
 
_______ initials of subject (if subject is 14 years or older) 
 
_______ initials of parent/legal guardian (if subject is a minor) 
 
                          _______ initials of parent/legal guardian (if subject is a minor) 
 
 
SIGNATURE OF RESEARCH SUBJECT 
Your signature below indicates:  
 
You have read this document and understand its meaning;  
 
You have had a chance to ask questions and have had these questions answered to your satisfaction;  
 
You agree to participate in this research study; and 
 
You will be given a copy of the signed permission form.  
 
______________________________________ 
Name of Subject 
 
 
 
 
  
 
______________________________________        
 ______________________ 
Signature of Subject 
 
 
 
 
  Date 
 

 
 
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SIGNATURE OF PARENT(S)/GUARDIAN (if the subject is a minor) 
Your signature below indicates that you have read this document; understand its meaning; have had a chance to 
ask questions; have had these questions answered to your satisfaction; and agree to your child’s participation in 
this research study. You have been given a signed copy of this assent/permission form. 
 
________________________________    
 
_______________________________  
Name(s) of Parent(s)/Guardian  
 
Name(s) of Parent(s)/Guardian 
 
 
________________________________                  
 ___________________________________ 
Signature of Parent (Guardian)        
 
 
  Date 
 
 
________________________________                  
 ___________________________________ 
Signature of Parent (Guardian)        
 
 
  Date 
 
 
SIGNATURE OF INVESTIGATOR 
I have explained the research to the subject and/or the subject’s parent(s)/guardian(s) and have answered all of 
their questions.  I believe that they understand the information described in this document and freely give 
consent/permission/assent to participate. 
 
________________________________________ 
Name of Investigator/Person obtaining consent 
 
 
_________________________________________ 
 
______________________________ 
Signature of Investigator/Person obtaining consent 
             Date 
 
SIGNATURE OF WITNESS (if applicable) 
My signature as witness certified that the subject and/or the subject’s parent(s)/guardian(s) signed this permission 
form in my presence as their voluntary act and deed. 
 
__________________________________ 
Name of Witness 
 
 
____________________________________ 
 
___________________________ 
Signature of Witness 
 
 
 
 
Date 

 
 
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APPENDIX I : PERFORMANCE STATUS SCALES/SCORES 
 
Performance Status Criteria 
Karnofsky and Lansky performance scores are intended to be multiples of 10 
ECOG (Zubrod) 
Karnofsky 
Lansky 
Scor
e 
Description 
Score 
Description 
Score 
Description 
0 
Fully active, able to carry 
on all pre-disease 
performance without 
restriction. 
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. 
1 
Restricted in physically 
strenuous activity but 
ambulatory and able to 
carry out work of a light 
or sedentary nature, e.g., 
light housework, office 
work. 
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. 
2 
Ambulatory and capable 
of all self-care but unable 
to carry out any work 
activities.  Up and about 
more than 50% of 
waking hours 
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. 
3 
Capable of only limited 
self-care, confined to 
bed or chair more than 
50% of waking hours.  
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. 
4 
Completely disabled.  
Cannot carry on any self-
care. Totally confined to 
bed or chair. 
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. 
 
 
 
 
 
 
 
 
 

 
 
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APPENDIX II: CYP3A4 STRONG INDUCERS  
 
The use of STRONG CYP3A4 INDUCERS should be discontinued prior to initiation of protocol therapy and 
should be avoided during protocol therapy if reasonable alternatives exist. This is NOT an all-inclusive list. 
Because the lists of these agents are constantly changing, it is important to regularly consult frequently updated 
medical references. 
 
 
• 
Barbiturates 
• 
Phenobarbital 
• 
Carbamazepine 
• 
Phenytoin 
• 
enzalutamide  
• 
Primidone 
• 
fosphenytoin 
• 
Rifampin 
• 
St. John’s wort 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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APPENDIX III:  PHARMACOKINETIC WORKSHEET – T2017-002 IXAZOMIB STUDY PHASE 1 
TACL Registration #: _______________ 
BSA (m2): _______________ 
 
Height (cm): _______________  
 
Assigned Dose (mg/m2): _______________ 
 
Weight (kg): _______________  
 
Actual dose (mg): _______________ 
 
CRC Name: ______________________ 
CRC Email Address: __________________________________ 
 
Block 1 Day1: Date:__________________ Time of Administration:__________________  
Patient <20 kg PK Schedule 
Sample 
# 
Day 
Date 
Hour 
Target 
Time 
Time 
obtained 
Comments 
1 
 
4 
 
72 Hours(to be collected 
before dose #2 on Day 4 of 
Block 1) 
 
 
 
 
 
Block 1 Day 11: Date:__________________ Time of Administration:__________________  
 
Sample 
# 
Day 
Date 
Hour 
Target 
Time 
Time 
obtained 
Comments 
2 
11 
 
Pre-dose  (- 2 hours) 
 
 
 
3 
11 
 
30 Min      (+/- 5 mins) 
 
 
 
4 
11 
 
4 Hours    (+/- 30 mins)  
 
 
5 
14 
 
72 Hours  (+/- 3 hours) 
 
 
 
 
Patient ≥20 kg PK Schedule Below: 
 
Block 1 Day 1: Date:__________________ Time of Administration:__________________  
 
Sample 
# 
Day 
Date 
Hour 
Target 
Time 
Time 
obtained 
Comments 
1 
1 
 
30 Min      (+/- 5 mins) 
 
 
 
2 
1 
 
1 Hour      (+/- 15 mins)  
 
 
3 
1 
 
2 Hours    (+/- 15 mins)  
 
 
4 
1 
 
4 Hours    (+/- 30 mins)  
 
 
5 
1 
 
8 Hours    (+/- 1 hour) 
 
 
 
6 
2 
 
24 Hours  (+/- 1 hour) 
 
 
 
7 
 
4 
 
72 Hours(to be collected 
before dose #2 on Day 4 of 
Block 1) 
 
 
 
 
Block 1 Day 11: Date:__________________ Time of Administration:_________________  
 
Sample 
# 
Day 
Date 
Hour 
Target 
Time 
Time 
obtained 
Comments 
8 
11 
 
Pre-dose  (- 2 hours) 
 
 
 
9 
11 
 
30 Min      (+/- 5 mins) 
 
 
 
10 
11 
 
1 Hour      (+/- 15 mins)  
 
 
11 
11 
 
2 Hours    (+/- 15 mins)  
 
 
12 
11 
 
4 Hours    (+/- 30 mins)  
 
 
13 
11 
 
8 Hours    (+/- 1 hour) 
 
 
 
14 
12 
 
24 Hours  (+/- 1 hour) 
 
 
 

 
 
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15 
14 
 
72 Hours  (+/- 3 hours) 
 
 
 
16 
22 
 
264 Hours (+/- 8 hours)  
 
 
 
 
PHARMACOKINETIC WORKSHEET – T2017-002 Ixazomib Study Phase 2 
 
TACL Registration #: _______________ 
BSA (m2): _______________ 
 
Height (cm): _______________  
 
Assigned Dose (mg/m2): _______________ 
 
Weight (kg): _______________  
 
Actual dose (mg): _______________ 
 
CRC Name: ______________________ 
CRC Email Address: __________________________________ 
 
Block 1 Day 1: Date:__________________ Time of Administration:__________________  
 
 Sample 
# 
Day 
Date 
Hour 
Target 
Time 
Time 
obtained 
Comments 
1 
 
4 
 
72 Hours (to be 
collected before dose 
#2 on Day 4 of Block 1) 
 
 
 
 
Block 1 Day 8: Date:__________________ Time of Administration:__________________  
 
Sample 
# 
Day 
Date 
Hour 
Target 
Time 
Time 
obtained 
Comments 
2 
8 
 
Pre-dose  (- 2 hours) 
 
 
 
 
Block 1 Day 11: Date:__________________ Time of Administration:__________________  
 
Patient <20 kg PK Schedule 
Sample 
# 
Day 
Date 
Hour 
Target 
Time 
Time 
obtained 
Comments 
3 
11 
 
Pre-dose  (- 2 hours) 
 
 
 
4 
14 
 
72 Hours  (+/- 3 hours) 
 
 
 
 
Patient ≥20 kg PK Schedule 
Sample 
# 
Day 
Date 
Hour 
Target 
Time 
Time 
obtained 
Comments 
3 
11 
 
Pre-dose  (- 2 hours) 
 
 
 
4 
11 
 
30 Min      (+/- 5 mins) 
 
 
 
5 
11 
 
2 Hours    (+/- 15 mins)  
 
 
6 
11 
 
4 Hours    (+/- 30 mins)  
 
 
7 
14 
 
72 Hours  (+/- 3 hours) 
 
 
 
 
 
 
Block 2 PK only for Patients ≥20 kg below: 
 
Block 2 Day 1: Date:__________________ Time of Administration:__________________ 
 
Sample 
# 
Day 
Date 
Hour 
Target 
Time 
Time 
obtained 
Comments 

 
 
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1 
1 
 
Pre-dose  (- 2 hours) 
 
 
 
 
Block 2 Day 15: Date:__________________ Time of Administration:__________________  
 
Sample 
# 
Day 
Date 
Hour 
Target 
Time 
Time 
obtained 
Comments 
2 
15 
 
Pre-dose  (- 2 hours) 
 
 
 
 
Block 2 Day 18: Date:__________________ Time of Administration:__________________  
 
Sample 
# 
Day 
Date 
Hour 
Target 
Time 
Time 
obtained 
Comments 
3 
18 
 
Pre-dose  (- 2 hours) 
 
 
 
 
Blood Collection procedure: 
2 ml PK samples should be collected into tubes provided in the ixazomib PK collection kit. This will be provided by 
Covance. 
 
Materials 
Blood samples for PK assessment must be collected in 2-mL vacutainer tubes containing K2EDTA as the 
anticoagulant.  Resulting blood and plasma PK samples must be stored in plastic storage tubes with caps.  No 
blood collection tubes with separation gel should be used. 
 
Plasma (0.5 mL) is stored in tubes containing 250 mg lyophilized citric acid.  
 
Preparation of Plasma Pharmacokinetic Samples 
 
1. Draw blood into labeled and chilled 2-mL lavender top K2EDTA vacutainer tube.  
 
2.  Mix the blood with the anticoagulant by gently inverting the tube 8-10 times and immediately place on wet 
ice.   
 
3. Centrifuge the blood samples for 10 minutes at 1000 x g at 4º C in a refrigerated centrifuge within 10 
minutes of sample collection.  
 
4.  Immediately following centrifugation, gently remove the plasma from the packed cells and aliquot into 
transfer vials filled with lyophilized citric acid. Each aliquot should contain exactly 0.5 mL of plasma. 
 
5. Vortex split tubes thoroughly. Any remaining plasma post-split 1/split 2 sample aliquots should be discarded 
following appropriate biohazard disposal procedures. 
 
NOTE: If < 0.5 mL plasma is obtained post centrifugation, do not process or store split 1 or split 2, record split 1: 
ISV (Insufficient Sample Volume), split 2: ISV. If < 1.0 mL plasma is obtained post centrifugation, process and 
store split 1 according to procedure; do not process or store split 2, record split 2: ISV. Discard remaining 
plasma using appropriate biohazard waste disposal procedures. 
 
6. Replace cap on tube and freeze the samples immediately at -70°C. 
 
Note:  No more than 60 minutes should elapse between blood collection and freezing the plasma samples. 
 
7. Keep samples frozen at -70°C or lower until shipment. 
 

 
 
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Note:  Wet ice is defined as a mixture of ice and water. 
 
 
Specimen Labeling: 
Each tube must be labeled with the study ID number, along with the date and time of the sample was obtained. 
No personal identifying patient information should be included in the specimen or transmittal form. 
 
Specimen Packaging and Shipping: 
Covance Clinical Laboratory Services 
8211 Scicor Drive, Indianapolis, IN 46214 USA 
 
 
 
 

 
 
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APPENDIX IV: GUIDANCE FOR DETERMINING PREVIOUS CUMULATIVE ANTHRACYCLINE 
DOSE 
 
Calculate cumulative anthracycline dose (all based on doxorubicin):  
Daunorubicin: x 0.5 
Doxorubicin: x 1 
Epirubicin: x 0.67 
Idarubicin: x 5 
Mitoxantrone: x 4 
Total Anthracycline Calculation Worksheet 
Instructions: 
In order to calculate the total anthracycline received by a patient, you will need to review the patient’s previous 
treatment.  You will need to document each dose of anthracycline chemotherapy prescribed and received by the 
patient. 
Step 1: Indicate which drug the patient received.  
Step 2: Enter the prescribed dose for that drug per the chemotherapy roadmap/orders. Be sure to list all doses. 
Step 3: Enter the corresponding conversion factor for the drug given. 
Step 4: Multiply the prescribed dose by the conversion factor and enter the result in the “Total Anthracycline” 
column. 
Step 5: After you have completed this worksheet for all doses, add all the total doses to obtain the Total Cumulative 
Dose. 
Drug 
Prescribed Dose 
The prescribed dose is the dose of 
chemotherapy written in the protocol.  It will 
be listed as mg/m2. (It is not the actual dose 
received by the patient) 
Conversion Factor 
Doxorubicin = 1 
Daunorubicin = 0.5 
      Epirubicin: = 0.67 
Idarubicin = 5 
Mitoxantrone = 4 
Total 
Anthracycline 
 Doxorubicin 
 Daunorubicin 
 Idarubicin 
 Mitoxantrone 
 Epirubicin 
EXAMPLE: 
 
10 mg/m2 
 
5  
 
50 mg/m2 
Doxorubicin 
 Daunorubicin 
 Idarubicin 
 Mitoxantrone 
 Epirubicin 
 
 
 
Doxorubicin 
 Daunorubicin 
 Idarubicin 
 Mitoxantrone 
 Epirubicin 
 
 
 
Doxorubicin 
 Daunorubicin 
 Idarubicin 
 Mitoxantrone 
 Epirubicin 
 
 
 
Total Cumulative Dose  

 
 
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 Protocol Amendment #2 Version Date:  
 Protocol Amendment #3 Version Date:  
 Protocol Amendment #4 Version Date:  
 Protocol Amendment #5 Version Date: 
 Protocol Amendment #6 Version Date 
 Protocol Amendment #7 Version Date: 
 
19December2019 
16September2020 
11May2021 
24January2022 
26October2022 
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07September2023 
Reference: http://survivorshipguidelines.org/ 
APPENDIX V: EVALUATING MECHANISMS OF IXAZOMIB RESPONSE AND RESISTANCE IN LEUKEMIA; 
IDENTIFYING BIOMARKERS AND MECHANISMS OF CHEMOTHERAPY RESISTANCE  
 
Eligible samples: 
 
All pre-treatment bone marrow samples are eligible. Peripheral blood samples should be sent to the Horton lab 
only if the patient samples meet the following criteria: 
 
Eligible patients must have an initial absolute blast count of at least 1000 blasts/µL. To calculate the absolute 
blast percentage, multiply the total WBC by the % peripheral blasts: 
 
(WBC)(% blast)(1000) = absolute blast count/µL 
 
As an example, if the patient has a WBC of 10 and 50% blasts, the absolute blast count is:  
 
(10)(.5)(1000) = 5000/µL 
 
If the initial % blasts is unknown, send peripheral blood samples only if the total WBC is more than 10 and notify 
the Horton lab of the % blast as soon as available (contact info provided below). 
 
Samples must be received by the Horton lab no later than 72h after collection. Bone marrow and peripheral 
blood samples can be batched if they will arrive within 72h. If samples will not arrive within 72h, please send the 
bone marrow separately from peripheral blood samples. Day 1 peripheral blood samples should be shipped 
together.  
 
Sample collection time points: 
 
 
Baseline 
Day 1 Hour 0 
(baseline) 
Day 1 Hour 6 
Day 1 Hour 24 
Bone marrow 
(induction only)1 
3mL green top2  
 
 
 
Peripheral blood 
(induction only)3 
5mL in heparin for 
proteasome assessment4 
3mL in Cellsave5 
2mL in heparin4 
3mL in Cellsave5 
2mL in heparin4 
(4-6h after start of 
systemic chemo) 
3mL in Cellsave5 
2mL in heparin4 
(24h after the start 
of systemic 
chemotherapy) 
 
** if ixazomib administration is delayed by >18h following start of systemic chemotherapy, collect pre-treatment 
sample only.  
 
*Sample Collection:  
 
1. Bone marrow: send in heparin or ACDA tube (ACDA preferred). Can also be sent diluted 1:1 in COG shipping 
media. Do not send bone marrow samples in Cell Save tubes.  
 
2. Peripheral blood: Collect 5 mL sample into the CellSave tubes (3 mL) and heparin tubes (2 mL). Either lithium 
heparin or sodium heparin is acceptable. Do not use PST (plasma separator tubes).  
 
Shipping Note: Samples collected on Saturday and Sunday can be shipped Monday for Tuesday arrival. See 
below for information on obtaining and shipping samples in ThermoSafe containers. 
 

 
 
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Specimen Requirements: Store samples in refrigerator until shipment.  CellSave tubes will be provided by the 
Horton lab to each institution upon IRB approval. Please check with your lead CRA to locate the tubes at your 
institution.  To obtain more CellSave tubes, please contact the Horton lab at the numbers provided below. If the 
CellSave tubes are not available, submit entire 5 mL sample in heparin tubes. Note that the sample integrity is 
greatly enhanced by the use of CellSave tubes.  
• 
Each sample should be clearly labeled to include the TACL registration number as well as the treatment 
accession number; study number, date and time sample was drawn.  
• 
On the Specimen Transmittal Form record the exact time and date that the sample is drawn along with 
the exact start time for administration of systemic chemotherapy. 
• 
Please note the WBC and % blasts on the specimen transmittal form. 
• 
The institutional immunophenotype report should be submitted with the Specimen transmittal form. At a 
minimum we need to know immunophenotype (B-cell or T-cell) status for each sample.  
 
Note: it is acceptable for blood to be collected from a central line. 
 
Shipping Requirements:  
 
Prior to sample collection, please contact Dr. Horton at (832) 824-4269 or Gaye Jenkins/Horton lab at (832) 824-
4676 for ThermoSafe shipping containers. ThemoSafe containers maintain biology samples at a constant 
temperature and are recommended, but not required, for biology sample shipment. Similar boxes are also 
available in your Pathology Department; boxes used for the shipment of antibodies or FISH probes are also 
acceptable and will be available more expeditiously than our shipping containers. Shipment of peripheral blood 
samples should not be delayed for receipt of shipping containers.   
 
If Thermo-Safe shipping container is not available: 
 
• 
Place collection tubes in a primary container. Wrap each collection tube separately to protect from 
breakage during shipment. Place the container in a Styrofoam box.  
• 
Please place an ice pack in the primary container. During the non-winter months (April-October) add 
additional ice packs to the Styrofoam box to assure the samples stays cold during shipment. Note that in 
the South and Southwest, at least 2 ice packs should be used year round.  
• 
Package sample as appropriate for biologic material. 
For all samples, including those in ThermoSafe containers: Include a small ice pack in the ThermoSafe container 
in the space provided. 
 
• 
Include a copy of the Specimen Transmittal Form with each shipment. 
• 
If possible, please include bone marrow immunophenotype report with the first peripheral blood sample. If 
this is not possible, please send the report that day via fax (832 825-1206) or email to Dr. Horton at 
tmhorton@txch.org and Gaye Jenkins at gnjenkin@txch.org (Please strip unnecessary identifiers) 
• 
Ship the sample by Federal Express Priority Overnight delivery to: 
 
Dr. Terzah Horton c/o Gaye Jenkins 
Feigin Center, Suite 760.01 
1102 Bates St. 
Baylor College of Medicine 
Houston, TX  77030 
832-824-4676 
 
• 
Notify Gaye Jenkins or Horton lab representative prior to shipment of the sample. Phone: (832) 824-4676 
or 832-824-4790. It is acceptable to leave a message if no one is available to answer the phone.  Please 
email the Fed-Ex tracking number to the email addresses above if prior notification is not possible. 

 
 
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• 
If possible, do not ship samples for delivery on a weekend or holiday. Please store samples over the 
weekend if samples are collected on a Friday. Mail on Monday for Tuesday delivery.  
 

 
 
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APPENDIX VI: PALATABILITY STUDY OF LIQUID ORAL IXAZOMIB (BLOCK 1 ONLY) 
 
TACL Registration #: _______________ 
Date:__________________ 
 
Dose Day: Day 1____   Day 4____  Day 8____  Day 11____  
Who Completed the form: Parent/Guardian ____  Child ____ 
 
1. 
What formulation of ixazomib is administered?  
Capsule ____ 
 
Liquid ____ 
2. 
Did you (or your child) swallow the dose?  
 
 Yes_____ 
 
No_____ 
3. 
What do you think of the taste?  
     1               2 
            3               4 
   5 
 
4. 
What do you think of the smell? 
              1                  2 
 3 
      4 
         5 
 
5. 
Any aftertaste?   
 
 
 
Yes____ 
 
No____ 
  
                     6.    How easy is it for you (your child) to take ixazomib? 
              1                  2 
 3 
      4 
         5 
 
                     7.    How easy is it to take other oral medications? 
Difficult 
Difficult 
Easy 
Easy 

 
 
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07September2023 
                    1                2              3 
     4 
        5 
 
 
 

 
 
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19December2019 
16September2020 
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07September2023 
APPENDIX VII: NEUROLOGICAL EXAM  
 
TACL Registration #: 
 
  TACL Protocol #: 
 
TACL Subject ID : 
 
   Enrollment Date: 
  
 
 
 
 
Assessment Date: 
 
 
 
 
 
If Pretreatment or Off 
Study Neurological 
Exam Section must be 
completed. 
 
Pretreatment 
 
Dose 3  
 
 
Dose 1 
 
Dose 4 
 
 
Dose 2 
 
Off Study 
Neurological Status : 
 
 
General: 
 
 
No neurological findings 
 
Stable 
 
 
 
Improved 
 
Worse 
 
Resolved 
 
 
 
Any Change from baseline: 
 
Yes 
 
No 
If Yes, go to Neuro  
exam; If no to both then 
assessment is complete. 
Any Change from previous assessment: 
 
Yes 
 
No 
 
 
 
Neurological Exam:  
 
Mark Normal or Abnormal with an X. 
If abnormal, record a brief description of the current abnormality. 
Record ND for any examination not done. 
 
 
 
Normal 
Abnormal 
Description of abnormality 
Muscle Tone & Strength: (weakness) 
 
 
 
 
 
 
 
Reflexes: (, biceps, knee,) 
 
 
 
 
 
 
 
Gait: 
 
 
 
 
 
 
 
Cranial Nerves: 
 
 
 
 
 
 
 
Sensory: (Pain, jaw pain, numbness, 
paresthesias, constipation,  
 
 
 
 
 
 
 
Stretch-extension of wrist: 
 
 
 
 
 
 
 
Stretch-dorsiflexion of foot: 
 
 
 
 
 
 
 
Comments: 
 
 
 
 
 
 
 
 
 
 

 
 
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 Protocol Amendment #4 Version Date:  
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19December2019 
16September2020 
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24January2022 
26October2022 
20July2023 
07September2023 
MD Signature 
 
 
 
 
Date