Phase I Study Of Vincristine, Doxorubicin, And Dexamethasone (VXD) Plus Ixazomib In Adults With Relapsed Or Refractory Acute Lymphoblastic Leukemia/Lymphoma, Lymphoblastic Lymphoma Or Mixed Phenotype Acute Leukemia
Phase: PHASE1
Conditions: Relapsed or Refractory Acute Lymphoblastic Leukemia, Relapsed or Refractory Lymphoblastic Lymphoma, Mixed Phenotype Acute Leukemia
Sponsor: Ehab L Atallah

  
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CLINICAL STUDY PROTOCOL  
(IISR-2012-M100016) 
X16016 
Phase I Study Of Vincristine, Doxorubicin, And Dexamethasone (VXD) Plus 
Ixazomib In Adults With Relapsed Or Refractory Acute Lymphoblastic 
Leukemia/Lymphoma, Lymphoblastic Lymphoma Or Mixed Phenotype Acute 
Leukemia 
 
Indication: 
 
 
Relapsed or refractory acute lymphoblastic 
leukemia/lymphoma, Lymphoblastic Lymphoma Or 
Mixed Phenotype Acute Leukemia 
 
 
Phase: 
Phase I 
 
 
 
Protocol History 
Original 
Amendment 1 
Amendment 2 
Amendment 3 
                        
 
8th, August, 2013 
4th, June 2014 
31st, July 2014 
2nd, June 2015 
 
 
Investigator and Study Center: 
Ehab Atallah 
Medical College of Wisconsin and Froedtert Hospital 
9200 Wisconsin Avenue, Milwaukee, WI 53226 
414.805.4662 
e-mail address:eatallah@mcw.edu 
 

  
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Co-I : Mary Horowitz, MD 
Professor of Medicine  
Division of Hematology and Oncology 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414.805.4600 
 
Co-I : Christopher Chitambar, MD 
Professor of Medicine  
Division of Hematology and Oncology 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414.805.4600 
 
Co-I:   Parameswaran Hari, MD, MRCP, MS 
Associate Professor of Medicine 
Division of Hematology and Oncology 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414.805.4600 
 
Co-I:   Timothy Fenske, MD 
Associate Professor of Medicine  
Division of Hematology and Oncology 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414.805.4600 
 
 
 
 

  
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Co-I:   Laura Michaelis, MD 
 
      Associate Professor 
Division of Hematology and Oncology 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414.805.4600 
 
Co-I:   Mehdi Hamadani, MD 
 
      Associate Professor 
Division of Hematology and Oncology 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414.805.4600 
 
Co-I:   Karen Carlson, MD 
 
      Assistant Professor 
Division of Hematology and Oncology 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414.805.4600 
 
Co-I:   Anita D’Souza, MD 
 
      Assistant Professor 
Division of Hematology and Oncology 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414.805.4600 
 
 
 
 

  
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Co-I:   Carlos Arce-Lara, MD 
 
      Associate Professor 
Division of Hematology and Oncology 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414.805.4600 
 
Co-I:   Alexandra Harrington, MD  
Assistant Professor of Medicine 
Department of Hematopathology 
Medical College of Wisconsin  
9200 W. Wisconsin Avenue 
Milwaukee, WI  53226 
 
Statistician:   Brent Logan, PhD 
Medical College of Wisconsin  
9200 W. Wisconsin Avenue 
Milwaukee, WI  53226 
 
 
 
 
Investigational pharmacy: 
Angela Urmanski, Pharm D 
Froedtert Hospital 
9200 W. Wisconsin Avenue 
Milwaukee, WI  53226 
 
Research Coordinator: 
Arielle Baim 
Medical College of Wisconsin  

  
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9200 W. Wisconsin Avenue 
Milwaukee, WI  53226 
 
Jessica Guhl 
Medical College of Wisconsin  
9200 W. Wisconsin Avenue 
Milwaukee, WI  53226 
 

  
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PROTOCOL SUMMARY  
Study Title:  Phase I Study Of Vincristine, Doxorubicin, And Dexamethasone 
(Vxd) Plus Ixazomib In Adults With Relapsed Or Refractory Acute Lymphoblastic 
Leukemia/Lymphoma, Lymphoblastic Lymphoma Or Mixed Phenotype Acute 
Leukemia 
Phase:  I 
Number of Patients:  9-18 
Study Objectives  
 
Primary Objectives 
• The primary objective is to determine the maximum tolerated dose of VXD 
+ixazomib and to assess the tolerability of  VXD + ixazomib in adult 
patients with relapsed or refractory acute lymphoblastic 
leukemia/lymphoma, lymphoblastic lymphoma or mixed phenotype acute 
Leukemia 
Secondary Objectives 
To estimate the overall response rate (ORR) including both complete 
remission (CR) and complete remission with incomplete count recovery (CRi) 
with VXD +ixazomib 

  
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Overview of rationale and Study Design:   
In this phase I study, escalating doses of ixazomib will be combined with the VXD 
regimen.  
The MTD of single agent ixazomib was 1.76 to 2.0mg/m2 when given on a twice a 
week schedule and > 2.34 mg/m2 to 2.97 mg/m2 on a weekly schedule in 
previous studies1-4. The only reported combination study involved the 
combination of ixazomib with lenalidomide and dexamethasone5.  In that study, 
escalating doses of IXAZOMIB from 1.68 to 3.95 mg/m2 were given orally on days 
1, 8, and 15 in combination with dexamethasone 40 mg on days 1, 8, 15, and 22 
and lenalidomide 25 mg/day on days 1–21 every 28 Days. The MTD of ixazomib 
was 2.97 mg/m2 and the recommended phase II dose (RP2D) was 2.23 mg/m2. 
The dose limiting toxicities were skin rash, nausea and vomiting. The clinical 
development of ixazomib included a population PK analysis evaluating the 
feasibility of switching from BSA-based dosing to fixed dosing.6  The results of 
this analysis support the transition to fixed dosing. In this trial our aim will be to 
escalate the dose to ixazomib orally to a dose of 4.0 mg (RP2D of 2.23 mg/m2 ×  
the mean patient BSA of 1.86 m2). 
 
Three patients will be treated per dose level unless dose limiting toxicity (DLT) is 
observed.  The starting dose of ixazomib will be 2.3 mg orally on days 1, 8 and 
15. If no DLT is seen in the first 3 patients, the dose will be increased to 3 mg and 
then to 4 mg orally on days 1, 8 and 15 in a classic 3 +3 phase I design. We will 
not attempt to increase the dose beyond 4 mg orally which, if achieved with 
acceptable toxicity, would be accepted as the recommended phase 2 dose 
(RP2D). 0 of 3 DLTs would allow escalation to the next dose level. 1 of 3 DLTs 
will require expanding to six patients; 1 of 6 DLTs will allow escalation again. 2 
DLTs will require dose de-escalation.  The maximum tolerated dose (MTD) will be 
the highest dose administered at which no more than 1 DLT was observed. All 
patients will be evaluated for hematopoetic stem cell transplantation (HSCT). If 
patients achieve CR and are eligible for HSCT, they will proceed to HSCT. If they 

  
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are not eligible, no donor is identified or if HSCT will be delayed, and the patient 
has achieved benefit, then treatment may be repeated for another cycle as 
clinically indicated. 
Study Population:   
Inclusion criteria 
 
• Male or female patients 18 years or older  
• Have relapsed B or T-precursor acute lymphocytic leukemia/lymphoma, 
lymphoblastic lymphoma or mixed phenotype acute leukemia with 
increased bone marrow or peripheral blood blasts by morphology with or 
without CNS involvement  
• Prior therapy: At least two prior treatment attempts to induce remission 
with no limit on the number of prior treatment regimens.  
• Patients may have received an allogeneic stem cell transplantation  
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2  
• Patients must meet the following clinical laboratory criteria: 
• Direct bilirubin ≤ 1.5 × the upper limit of the normal range (ULN). 
• Alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST) ≤ 3 × ULN. 
• Calculated creatinine clearance ≥ 30 mL/min  
• Absolute neutrophil count (ANC) > 1,000/cmm and platelets > 
75,000/cmm unless the cytopenias are secondary to disease 
• Life expectancy adequate for evaluating the treatment effect per treatment 
physician discretion 
• Patients must be at least 2 weeks from major surgery, radiation therapy, 
participation in other investigational trials and have recovered from 
clinically significant toxicities of these prior treatments  
• Female patients who: 
• Are postmenopausal for at least 1 year before the screening visit, 
OR 
• Are surgically sterile, OR 

  
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• If they are of childbearing potential, agree to practice 2 effective 
methods of contraception, at the same time, from the time of signing 
the informed consent form through 90 days after the last dose of 
study drug, OR 
• Agree to practice true abstinence when this is in line with the 
preferred and usual lifestyle of the subject.  (Periodic abstinence [eg, 
calendar, ovulation, symptothermal, postovulation methods] and 
withdrawal are not acceptable methods of contraception.) 
• Male patients, even if surgically sterilized (ie, status post-vasectomy), must 
agree to one of the following: 
• Agree to practice effective barrier contraception during the entire 
study treatment period and through 90 days after the last dose of 
study drug, OR 
• Agree to practice true abstinence when this is in line with the 
preferred and usual lifestyle of the subject.  (Periodic abstinence (eg, 
calendar, ovulation, symptothermal, post-ovulation methods] and 
withdrawal are not acceptable methods of contraception.) 
Exclusion criteria 
• Patients who are Ph+ ALL who are naive to therapy with an approved 
tyrosine kinase inhibitor. 
• Prior exposure to ≥350 mg/m2 of anthracycline (in doxorubicin equivalent 
dosing), or left ventricular fractional shortening less than 50%.  
• Failure to have fully recovered (ie, ≤ Grade 2 toxicity) from the effects of 
prior chemotherapy regardless of the interval since last treatment. 
• Major surgery within 14 days before enrollment. 
• Chemotherapy in the last 14 days. (Steroids or Intrathecal chemotherapy 
will be allowed).  

  
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• Systemic treatment, within 7 days before study enrollment, with strong 
inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong 
inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, 
voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A 
inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, 
phenobarbital), or use of Ginkgo biloba or St. John’s wort. 
• Uncontrolled intercurrent illness including, but not limited to ongoing or 
active infection, symptomatic congestive heart failure, or psychiatric 
illness/social situations that would limit compliance with study 
requirements. Patients receiving intravenous antibiotics for infections that 
are under control may be included in this study.  
• Known allergy to any of the study medications, their analogues, or 
excipients in the various formulations of any agent.  
• Inability to swallow oral medication, inability or unwillingness to comply 
with the drug administration requirements, or GI procedure that could 
interfere with the oral absorption or tolerance of treatment. 
• Diagnosed or treated for another malignancy within 2 years before study 
enrollment or previously diagnosed with another malignancy and have any 
evidence of residual disease.  Patients with nonmelanoma skin cancer or 
carcinoma in situ of any type are not excluded if they have undergone 
complete resection. 
• Patient has ≥ Grade 2 peripheral neuropathy. 
• Participation in clinical trials with other investigational agents not included 
in this trial, within 14 days of the start of this trial and throughout the 
duration of this trial.  

  
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• Female patients who are breastfeeding or have a positive serum 
pregnancy test during the screening period or a positive urine pregnancy 
test on Day 1 before first dose of study drug. 
Duration of Study:  A minimum of 2 years 
SCHEDULE OF EVENTS    
Day 
Scree
ninga 
Cycle 1 
and 2 
Week 1 
We
ekly 
Q 2 
we
eks 
Q 4 
we
eks 
End of 
Studyb 
Follow-up 
Informed 
consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Inclusion/exclu
sion criteria 
X 
 
 
 
 
 
 
Medical History X 
X 
 
 
 
 
 
Medication 
history 
X 
 
 
 
 
 
 
Concomitant 
medications 
X 
X 
 
X 
 
X 
 
Physical 
examination 
X 
X 
 
X 
 
X 
 
ECOG 
performance 
status 
X 
X 
 
X 
 
 
 
Vitals 
X 
X 
 
X 
 
X 
 
Height and 
weightc 
X 
Xd 
 
 
 
X 
 
CBC with 
differential 
X 
X 
X 
 
 
X 
 
Serum 
Chemistry 
X 
X 
X 
 
 
X 
 

  
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panele 
Direct Bilirubin 
X 
 
X 
 
 
 
 
Fibrinogen 
X 
X 
X 
 
 
 
 
Serum or urine 
pregnancy test 
X 
X f 
 
 
 
 
 
Cardiac 
Ejection 
Fraction 
(MUGA/Echoc
ardiogram) 
X 
xi 
 
 
 
 
 
Bone marrow 
biopsy/aspirate
g 
X 
 
 
 
X 
X 
 
Adverse Event 
Reporting 
Recorded from the first dose of study drug through 30 days after last 
dose of study drug 
Survival h 
 
 
 
 
 
 
X 
 
a Screening procedures to occur up to 14 days before Cycle 1 Week 1 Visit, except 
for pregnancy test (within 7 days prior to Week 1 Visit).  
b Perform end-of-study procedures 4 weeks after study completion or at time of 
early withdrawal. If study procedure cannot be performed on the scheduled day, the 
procedure must be performed within 48 hours. 
c Height will be measured at Screening only. 
d Weight will be checked on day 1 of every cycle 
e Including albumin, total protein, total bilirubin, ALT, AST, LDH, alkaline 
phosphatase, bicarbonate, sodium, potassium, chloride, creatinine, BUN, and 
glucose. 
f Serum βHCG pregnancy test in female patients of childbearing potential does not 
need to be repeated for Cycle 1 Week 1 Visit if the screening test was completed 
within 72 hours of Cycle 1 Week 1. 
g Bone marrow aspirate and/or biopsy and cytogenetics must be performed within 4 
weeks prior to Week 1 Visit. Bone marrow biopsies at week 4 ±3 days 
h Patients will be followed monthly until progression and then annually for survival. 
i For cycle 2 only 
 

  
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TABLE OF CONTENTS 
PROTOCOL SUMMARY ......................................................................................................6 
SCHEDULE OF EVENTS ...................................................................................................11 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS .........................................15 
1. BACKGROUND AND STUDY RATIONALE................................................................19 
1.1 Background .................................................................................................................19 
1.2 Ixazomib .......................................................................................................................26 
1.3 Preclinical Experience ..................................................................................................26 
1.4 Clinical Experience .......................................................................................................27 
1.5 Pharmacokinetics and Drug Metabolism ......................................................................29 
1.6 Clinical Trial Experience Using the Oral Formulation of ixazomib .....................30 
1.7 Relapsed and/or Refractory Multiple Myeloma ...........................................................36 
1.8 Newly Diagnosed Multiple Myeloma (NDMM) ..........................................................37 
1.9 Clinical Trial Experience Using the Intravenous Formulation of ixazomib ................37 
1.10 Potential Risks and Benefits .......................................................................................37 
2. STUDY OBJECTIVES .....................................................................................................38 
2.1 Primary Objectives .....................................................................................................38 
2.2 Secondary Objectives ...............................................................................................38 
3. STUDY DESIGN ..............................................................................................................38 
4. STUDY POPULATION ....................................................................................................39 
4.1 Inclusion Criteria ........................................................................................................39 
4.2 Exclusion Criteria .......................................................................................................41 
5. TREATMENT PLAN ........................................................................................................42 
6. DRUG INFORMATION ...................................................................................................44 
6.1 Description of Investigational Agents (ixazomib) ..................................................44 
6.2 Study Drug Administration ..........................................................................................45 
6.3 Doxorubicin .................................................................................................................46 
6.4 Vincristine ....................................................................................................................49 
6.5 Dexamethasone .........................................................................................................52 
7. DOSE-MODIFICATION GUIDELINES .........................................................................55 
7.1 Recommended ixazomib Criteria for Beginning or Delaying a Subsequent 
Treatment Cycle & Dose Modifications for Treatment Associated 
Toxicity .................................................................................................................55 
7.2 Dexamethasone .........................................................................................................57 
7.3 Vincristine ....................................................................................................................58 
7.4 Criteria for Beginning a Subsequent Treatment Cycle for IT ..............................59 
7.5 Criteria for Toxicity Recovery for a New Cycle of Therapy to Begin: ................60 
8. EXCLUDED CONCOMITANT MEDICATIONS AND PROCEDURES ....................60 
8.1 Permitted Concomitant Medications and Procedures ..........................................61 
9. PRECAUTIONS AND RESTRICTIONS .......................................................................62 
10. PREGNANCY .................................................................................................................62 
11. PACKAGING AND LABELING OF IXAZOMIB .........................................................63 
11.1 Storage, Handling, and Accountability for ixazomib ...........................................64 
12. STUDY COMPLIANCE .................................................................................................65 
13. TERMINATION OF TREATMENT AND/OR STUDY PARTICIPATION ...............65 

  
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14. STATISTICAL AND QUANTITATIVE ANALYSES ...................................................66 
14.1 Statistical Methods ...................................................................................................66 
15. ADVERSE EVENTS ......................................................................................................66 
15.1 Definitions .................................................................................................................66 
15.1.1 Pretreatment Event Definition .........................................................................66 
15.1.2 Adverse Event Definition .................................................................................66 
15.1.3 Serious Adverse Event Definition ...................................................................67 
15.2 Procedures for Reporting Serious Adverse Events ............................................68 
15.3 Procedures for Reporting Drug Exposure During Pregnancy and Birth 
Events ..................................................................................................................71 
16. ADMINISTRATIVE REQUIREMENTS .......................................................................72 
16.1 Data and Safety Monitoring ....................................................................................72 
16.2 Product Complaints .................................................................................................72 
17. REFERENCES ...............................................................................................................74 
18. APPENDICES ................................................................................................................78 
18.1 Eastern Cooperative Oncology Group (ECOG) Scale for Performance 
Status ...................................................................................................................78 
18.2 Response Criteria ....................................................................................................79 
 

  
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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
Abbreviation 
Term 
AE 
adverse event 
ALL 
acute lymphoblastic leukemia 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myelogenous leukemia 
ANC 
absolute neutrophil count 
apt 
activated partial thromboplastin time 
Ara-C 
Cytarabine 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
βhCG 
beta-human chorionic gonadotropin 
BID 
bis in die; twice a day 
BM 
bone marrow 
BSA 
body surface area 
BTZ 
bortezomib 
BUN 
blood urea nitrogen 
BZD 
Benzodiazepines 
CBC 
complete blood count 
CNS 
central nervous system 
CO2 
carbon dioxide 
CR 
complete remission  

  
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Abbreviation 
Term 
CT 
computed tomography 
CYP 
cytochrome P450 
DDIs 
DLT 
Drug-Drug Interactions 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ELISA 
enzyme-linked immunosorbent assay 
EOS 
End of Study (visit) 
EOT 
End of Treatment (visit) 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony stimulating factor 
GGT 
gamma glutamyl transferase 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practices 
GM-CSF 
granulocyte macrophage-colony stimulating factor 
GMP 
Good Manufacturing Practice 
Hb 
Hemoglobin 
Hct 
Hematocrit 
HIV 
human immunodeficiency virus 

  
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Abbreviation 
Term 
HSCT 
Hematopoetic stem cell transplantation 
IB 
Investigator’s Brochure 
IC50 
concentration producing 50% inhibition 
ICF 
informed consent form 
IEC 
independent ethics committee 
IRB 
institutional review board 
IV 
intravenous; intravenously 
LDH 
lactate dehydrogenase 
LFT 
liver function test(s) 
Millennium 
Millennium Pharmaceuticals, Inc., and its affiliates 
MTD 
maximum tolerated dose 
MUGA 
multiple gated acquisition (scan) 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NPO 
nothing by mouth 
NYHA 
New York Heart Association 
PBMC 
peripheral blood mononuclear cell 
PD 
progressive disease (disease progression) 
PK 
pharmacokinetic(s) 
PO 
per os; by mouth (orally) 
PR 
partial remission  

  
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Abbreviation 
Term 
QD 
quaque die; each day; once daily 
QID 
quater in die; 4 times a day 
QOD 
quaque altera die; every other day 
QOL 
quality of life 
QTc 
rate-corrected QT interval (millisec) of electrocardiograph 
RBC 
red blood cell 
SAE 
serious adverse event 
SC 
Subcutaneous 
SD 
TEAEs 
stable disease 
treatment emergent adverse events (TEAEs) 
ULN 
upper limit of the normal range 
US 
United States 
WBC 
white blood cell 
WHO 
World Health Organization 
 
 
 
 
 
 
 
 

  
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1.    
BACKGROUND AND STUDY RATIONALE 
1.1 Background 
An estimated 6070 patients will be diagnosed with ALL in 2013, and 1 in 798 men 
and women will be diagnosed with ALL in their lifetime7. The median age for 
diagnosis of ALL is 14 years, and approximately 40% are >20 years old8. Despite 
the marked improvement in overall survival in children with ALL, treatment of ALL in 
adults remains challenging with 50-60% of patients dying of their disease.  
 
Treatment of patients with newly diagnosed ALL: 
Several regimens are currently utilized for the therapy of patients with newly 
diagnosed ALL with remarkably similar outcome. The two most commonly used 
regimens in the United States are the HyperCVAD regimen and the CALGB 
regimen. The HyperCVAD regimen is a multiagent intensive chemotherapy regimen 
composed of alternating cycles of cytoxan/doxorubicin/ vincristine/ dexamthasone 
alternating with high dose cytarabine and methotreaxte. All patients receive 4 to 16 
intrathecal chemotherapy injections depending on risk stratification. Cranial 
irradiation was only given to patients with cranial nerve root involvement. In the 
phase II study of the HyperCVAD regimen, 288 patients were enrolled. Despite 92% 
percent of patients achieving CR, the 5 year survival was 38%. The other intensive 
multiagent chemotherapy regimen developed by the CALGB group utilizes several 
treatment blocks and included cytoxan, doxorubicin, vincristine, asparaginase and 
prednisone. All patients receive cranial irradiation and intrathecal chemotherapy for 
CNS prophylaxis. In the phase II study, 197 patients were enrolled. Again most 
patients achieved CR, but the 3 year estimated overall survival was 50%i 
 
Treatment of relapsed ALL: 
Several large retrospective studies have evaluated the outcome of adult patients 
with relapsed ALL. The PETHEMA (Programa Español de Tratamiento en 
Hematologia) group, analyzed the outcome of patients in first relapse. Of the 263 
patients, 45% of patients achieved remission with a median overall survival of 4.5 

  
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months and 5 year survival of 10%. Age of patient and relapse > 2 years were the 2 
major predictors of outcome9. In the MRC UKALL12/ECOG 2993 study, of the 1372 
patients who entered remission, 609 (44%) relapsed. With a median follow up of 54 
months, only 42 of the 609 patients were alive10.  In another study by the German 
Multicenter Study Group for Adult Acute Lymphoblastic Leukemia, data of 547 
patients with relapsed ALL were analyzed. The median survival was 8.4 months for 
all patients with a 3 year survival of 24%. The CR rate after first and second salvage 
was 42% and 33% respectively11. This CR rate in patients receiving second salvage 
therapy was very similar to the study by O’Brien et al. Of the 288 patients analyzed, 
only 18% achieved CR. The median duration of remission was 7 months with a 
median overall survival of 3 months12. In order to better define the outcome of 
pediatric patients with relapsed ALL, the Therapeutic Advances in Childhood 
Leukemia (TACL) consortium reported on patients with relapsed and refractory ALL 
previously treated at TACL institutions between the years of 1995 and 2004. The 
CR rate for patients in early first relapse, late first relapse, second and third relapse 
was 83%, 93%, 44%  and 27% respectively. Five-year DFS rates in CR2 and CR3 
were 27% ± 4% and 15% ± 7% respectively13. 
 
Several regimens are utilized in the treatment of patients with relapsed ALL. In a 
phase II study, 88 patients received the augmented HyperCVAD (augHyperCVAD) 
regimen. The augHyperCVAD is similar to the HyperCVAD regimen with the 
addition of asparaginase, and intensification of both dexamethasone and vincristine. 
The CR rate was 46% with a median survival of 6.3 months for the entire cohort. 
Eight (9%), of the patients died within the first 30 days. Seven of those deaths were 
secondary to infectious complications14. Another recently approved drug for the 
therapy of relapsed ALL in pediatric patients is clofarabine. In a phase II study, 61 
pediatric patients with refractory or relapsed ALL received clofarabine 52 mg/m2 
intravenously over 2 hours daily for 5 days, every 2 to 6 weeks. The median age 
was 12 years (range, 1 to 20 years), and the median number of prior regimens was 
three (range, two to six regimens). Of those, 30% achieved CR/CRp. In another 
study by Miano et al, clofarabine (40 mg/m(2)/day), etoposide (100 mg/m(2)/day) 

  
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and cyclophosphamide (440 mg/m(2)/day) administered as one or two induction 
cycles over 5 days, was administered to patients with relapsed acute leukemia. Of 
the 40 children enrolled, 16 had AML and 24 had ALL. Of the 24 patients with ALL, 
10 (42%) achieved CR. However, results of clofarabine combinations have been 
disappointing in adult patients with relapsed ALL. In a phase II study, 37 patients 
with relapsed refractory ALL were enrolled. Of those, only 17% patients achieved 
CR/CRp, and the median survival was 3 months15. Another recently approved drug 
for the therapy of relapsed T-cell ALL is nelarabine. Nelarabine is purine analogue 
with specific activity against T-cells. In a phase II study, 126 patients with relapsed 
or refractory T-cell acute lymphoblastic leukemia/lymphoma (ALL/LBL) were 
enrolled. Of those, 45 (36%) achieved CR. The overall survival was 24% at 1 year 
(11% at 6 years). The overall survival was 31% for patients who proceeded to 
HCT16. Nelarabine in combination with etoposide and cyclophosphamide has also 
been evaluated in a small number of patients and appeared to be safe17.  
 
The VXLD regimen (vincristine, doxorubicin, PEG asparaginase and 
dexamethasone) was evaluated in the pediatric group. In that study, 124 pediatric 
patients with ALL in first relapse were enrolled. Of those, 69 had early relapse (ER; 
< 36 months from initial diagnosis) and 55 with late relapse. The CR rate was 68% 
+/- 6% for patients with early relapse and 96% +/- 3% for patients with late relapse. 
No unexpected toxicities occurred. Hematological toxicity was the most common 
toxicity with neutropenia and thrombocytopenia occurring in 97.6 and 79.8% of 
patient respectively. Grade 3 or 4 toxicities which occurred with a higher than 10% 
incidence are detailed in Table (1). Overall 5 patients died on therapy and all were 
secondary to infections. Based on these results, the VXLD was chosen as the 
backbone for the therapy of patients with relapsed ALL to which various drugs 
would be added for evaluation18. Details of the VXLD regimen are shown in Table 
(2). 
 
 
 

  
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Table (1) 
Toxicity 
VXLD (n = 124) 
No. 
% 
Febrile neutropenia 
50 
40.3 
Fibrinogen 
40 
32.3 
Hemoglobin 
78 
62.9 
Hyperglycemia 
15 
12.1 
Neutrophils/granulocytes (ANC/AGC) 121 
97.6 
Platelets 
99 
79.8 
ALT 
18 
14.5 
Transfusion 
 
 
Platelets     
93 
75.0 
pRBCs     
95 
76.6 
 
Based on the poor results previously discussed for adult patients with relapsed ALL, 
several new treatment approaches are currently being evaluated. These include 
monoclonal antibodies19, bispecific antibodies20 and proteosome inhibitors21.  
 
 
 
Several preclinical studies have shown that ALL cells are sensitive to proteosome 
inhibition and that there is a synergistic effect when the proteosome inhibitor (PI) 
bortezomib (BTZ) is combined with chemotherapy 22-24.  
 
Proteosomes are expressed at abnormally high levels in human leukemic cell lines 
25 leading to a study by Naujokat et al that evaluated the effect of proteosome 
inhibitors on human immature leukemic cell lines. Three proteosome inhibitors, 
lactacystin, benzyloxycarbonyl(Z)-leucyl-leucyl-leucinal (ZLLLal; MG-132) and 4-
hydroxy-5-iodo-3-nitrophenylacetyl-leucyl-leucyl-leucine vinyl sulfone (NLVS), 

  
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induced apoptosis in leukemic cell lines CCRF-CEM, U937 and K562 as well as in 
myelogenic and lymphatic leukemia cells obtained from adults with relapsed acute 
leukemias. However, the proteosome inhibitors did not induce significant apoptosis 
in granulocytes and lymphocytes from the peripheral blood, suggesting a 
preferential effect on rapidly proliferating cells 26. BTZ is a proteosome inhibitor with 
activity against multiple hematologic malignancies. It is currently FDA approved for 
the therapy of multiple myeloma and mantle cell lymphoma. BTZ was evaluated in a 
pediatric pre-clinical testing program and was found to have in vitro and in vivo 
activity 23. For in vitro testing, BTZ was incubated with rhabdomyosarcoma, 
rhabdoid, Ewing sarcoma, glioblastoma, neuroblastoma, ALL, acute myelogenous 
leukemia (AML) and non Hodgkin lymphoma (NHL) cell lines. The median IC50 for 
ALL cell lines was significantly lower than the median IC50 for solid tumor lines (12 
nM vs. 30 nM, P < 0.0094). For in vivo testing, BTZ was administered to mice 
intraperitoneally at 1 mg/kg twice weekly for 6 weeks and evaluated in 41 xenograft 
tumor models. There were no responses in the solid tumor xenograft models, while 
four of seven ALL xenografts demonstrated objective responses (two partial and 
two complete responses). Based on these findings, BTZ was evaluated as a single 
agent in a phase I study in patients with relapsed refractory acute leukemia. As a 
single agent, BTZ had minimal activity. Five of 15 patients had hematological 
improvement.  Patients received a median of 5 doses with disease progression 
being the most common cause for discontinuation of drug27.  
 
In another preclinical study, BTZ potentiated the effect of chemotherapy 22. BTZ 
was synergistic with dexamethasone and additive with vincristine, asparaginase, 
cytarabine, and doxorubicin. Based on the finding of synergism with corticosteroids, 
Messinger et al combined vincristine, pegasparaginase, dexamethasone and 
doxorubicin (VXLD) with escalating doses of BTZ in a phase I study.  The standard 
dose of the VXLD regimen was used with no dose escalation of the 
chemotherapeutic agents. BTZ was escalated from 1 mg/m2 to 1.3 mg/m2 on D1, 
D4, D8 and D11. The investigators did not attempt to increase BTZ beyond 1.3 
mg/m2 which is the dose currently used in multiple myeloma.  Ten patients with 

  
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relapsed refractory ALL were enrolled. One patient experienced significant toxicity 
in the form of hypotension, fever, rhabdomyolysis, hypophosphatemia and change 
in mental status 70 minutes after the BTZ infusion at the 1.3 mg/m2 dose level. The 
drug was discontinued and the patient recovered from the toxicity. That cohort was 
then expanded at the same dose level of 1.3 mg/m2 and no other patient 
experienced a similar toxicity. The phase II portion was recently reported at ASH 
2011. Of the 22 patients enrolled on the study, 20 had B cell and 2 had T cell ALL. 
The overall response rate was 73% (14 CR and 2 CRp). The 2 patients with T cell 
ALL did not respond. Two patients developed grade 3 or higher peripheral 
neuropathy. Three patients died on study from infectious complications 24,28. Based 
on the very high response rate in the phase II study, the Children’s Oncology Group 
(COG) has adopted this regimen as the current clinical trial for patients with 
relapsed ALL. However, the combination has not been evaluated in adults with 
relapsed refractory ALL. Given the high efficacy seen in children, it seems logical to 
evaluate VXLD + BTZ in adults. One concern in the VXLD+ BTZ regimen is the 
potential for peripheral neuropathy, as both vincristine and BTZ have a high 
incidence of peripheral neuropathy.  
 
Similar synergism between chemotherapy and other second generation proteosome 
inhibitors such as carfilzomib and ixazomib is observed in vitro in multiple myeloma 
29,30 and lymphoma cells 31.  
 
Ixazomib has a shorter proteosome dissociation half-life and improved antitumor 
activity when compared to BTZ 32. Additionally, there were no grade 3 peripheral 
neuropathy events reported in the phase I or II trials 1,3,5. The previous protocol 
version proposed combining a modified VXLD regimen with oral ixazomib for the 
treatment of adults with relapsed/refractory ALL. The modification was a reduction 
in pegaspargase administration frequency from weekly to every other week. The 
reason for this is twofold: 1) Adequate asparagine depletion can be achieved by a 
every 2 week schedule with pegaspargase 33; and, 2) adults have poorer tolerance 
to asparaginase compounds in general34.  

  
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Of the three patients enrolled on the VXLD + ixazomib protocol (previous version of 
this protocol), one patient had a grade 5 hyperbilirubinemia, one had a grade 4 
hyperbilirubinemia and the third patient had grade 3 hyperbilirubinemia. 
Hyperbilirubinemia was attributed to pegaspargase. One patient achieved complete 
remission. All three patients were at the 2.3 mg level. Based on that, this revised 
protocol was developed eliminating pegaspargase from the regimen due to poor 
tolerance. PEG aspargase is known to have a grade 3-4 liver toxicity in 30- 50% of 
patients35,36. The toxicity is much more common in adults than in children. In one 
study35, Grade 3/4 hyperbilirubinemia occurred in 31% of patients . Patients with 
grade 3/4 hyperbilirubinemia were older than those without hepatotoxicity (median 
age 39 vs 31 years).  Grade 3/4 hepatotoxicity was long, with a median duration of 
34 days to return to grade 1 for bilirubin and 38 days to return to grade 2 for 
transaminitis. Based on this the toxicities were expected.  
In contrast hepatic failure or hyperbilirubinemia is an extremely rare event reported 
in patients receiving oral MLN9708 (please see IB attached) 
 In addition, more data has emerged suggesting that proteasome inhibition reverses 
glucocorticoid resistance. Therefore, the study postulates that by eliminating 
pegaspargase in this regimen we would maintain efficacy with reduced toxicity8,37. 
The VXD regimen (or VAD regimen) was evaluated in several trials both in the 
upfront and relapsed setting albeit older studies38,39. In the relapsed setting, 5 of 10 
patients with relapsed ALL had a complete remission. In newly diagnosed patients, 
the complete remission rate was higher in patients < 60 years old compared to 
those older than 60 (60% vs. 90%) demonstrating that the combination of 
vincristine, anthracyclin and steroids is an effective regimen for patients with ALL.  
 
 
Lymphoblastic lymphoma (LBL) and mixed phenotype acute leukemia 
(MPAL): 
Lymphoblastic lymphoma is categorized in the same disease entity as ALL by the 
WHO40. Patients with LBL are treated with the same regimens utilized to treat 
ALL41. Therefore patients with the diagnosis of relapsed LBL will be included in the 

  
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study. MPAL is a rare type of leukemia where the blast cells express both myeloid 
and lymphoid markers40. Outcome of therapy is dismal in patients with MPAL. The 
CR rates range from 30-80% with a median disease free survival of 5-12 months 
and a median overall survival of 6.5-30 months42. Several retrospective studies 
have demonstrated that patients with MPAL have a better prognosis when treated 
with an ALL like regimen42-45. Based on that, patients with relapsed MPAL will be 
included on this study.  
Table (2) 
 
VXLD 
Modified VXLD 
VXD 
Drug 
Day 
Day 
Day 
Doxorubicin 60 mg/m2 
1 
1 
1 
Vincristine 1.5 mg/ m2a 
1, 8, 15, 22 
1, 8, 15, 22 
1, 8, 15, 22 
Pegaspargase 2500 IU/m2bc 
2, 8, 15, 22 
2, 15 
 
Dexamethasone 10 mg/m2 
1-14 
1-14 
1-14 
IT cytarabine 100 mg 
1 
1 
1 
IT methotrexate 12 mg 
8  (CNS−) 
8  (CNS−) 
8  (CNS−) 
Triple IT:  
-Methotrexate: 15 mg 
-Hydrocortisone: 15 mg 
-Cytarabine: 30 mg 
8, 15, 22,  
(CNS+) 
8, 15, 22,  
(CNS+) 
8, 15, 22,  
(CNS+) 
aCap at 2 mg, b Cap at 3750 IU per dose, c PEG asparaginase 1000 IU/m2 for 
patients > 55 years old 
IT: Intrathecal. CNS +: Central nervous system involvement, CNS-: No CNS 
involvement 
 
1.2 Ixazomib  
1.3    Preclinical Experience 
Please refer to the current ixazomib Investigator’s Brochure (IB) and Safety 
Management Attachment (SMA). 

  
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1.4    Clinical Experience 
Ixazomib has been evaluated as an oral single agent in phase 1 studies that have 
included patients with advanced solid tumors, lymphoma, relapse/refractory MM 
(RRMM), and relapsed or refractory light-chain (AL) amyloidosis and demonstrated 
early signs of activity. Ongoing studies continue to investigate both single-agent 
ixazomib and ixazomib in combination with standard treatments. Based on 
encouraging preliminary data observed in patients with MM requiring systemic 
treatment, 2 phase 3 trials in newly diagnosed MM (NDMM) (C16014) and RRMM 
(C16010) patient populations are currently evaluating ixazomib in combination with 
Revlimid and Dexamethasone (RevDex) versus placebo/RevDex. Both trials are 
combining ixazomib at a weekly dose of 4.0 mg on Days 1, 8, and 15 in a 28-day 
cycle to a standard dose of lenalidomide with a weekly dexamethasone dose of 40 
mg. In addition, ongoing clinical pharmacology studies include evaluation of drug-
drug interactions with ketoconazole and rifampin, effect of food, and oral 
bioavailability. Studies evaluating the safety and pharmacokinetic (PK) of ixazomib 
alone (in Japanese patients) and in combination with lenalidomide and 
dexamethasone in Asian adult patients (including Japanese patients) with a 
diagnosis of NDMM are ongoing. 
 
As of 27 March 2013, preliminary clinical data is available for a total of 653 patients 
across 13 studies. The emerging safety profile indicates that ixazomib is generally 
well tolerated. The adverse events (AEs) are consistent with the class-based effects 
of proteasome inhibition and are similar to what has been previously reported with 
VELCADE though the severity of some, for example peripheral neuropathy, is less. 
While some of these potential toxicities may be severe, they can be managed by 
clinical monitoring and standard medical intervention, or, as needed, dose 
modification or discontinuation. 
 
Fatigue was the most common AE reported among 384 patients treated in the oral 
(PO) studies (47%). Other common AEs reported in the pooled intravenous (IV) and 
PO safety populations include nausea, thrombocytopenia, diarrhea, and vomiting. 

  
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Rash is also a commonly reported treatment-emergent event; however, there is 
some variety in its characterization and causality resulting in different preferred 
terms to describe it. A high-level term outline of rash events includes rashes, 
eruptions and exanthems NEC; pruritus NEC; erythemas; papulosquamous 
conditions; and exfoliative conditions. The dose escalation phases of most trials 
reported in the IB have now completed enrollment, and gastrointestinal (GI) 
symptoms were the common dose-limiting toxicities (DLTs) when the use of 
prophylactic anti-emetics was not permitted per protocol. In the expansion cohorts 
or phase 2 cohorts (as per each study), the incidence and severity of GI symptoms 
was mitigated by the use of the lower maximum tolerated dose 
(MTD)/recommended phase 2 dose (RP2D) (as per each study) and standard 
clinical usage of anti-emetics and/or antidiarrheal medications as deemed 
appropriate. Prophylactic use of anti-emetics has not been required as with other 
agents but (as outlined in Section 6.7) has been used according to standard 
practice and are effective. 
 
The most frequent (at least 20%) treatment-emergent adverse events (TEAEs) 
reported with the PO formulation pooled from single-agent studies (n = 201) 
irrespective of causality to ixazomib, include nausea (53%), fatigue (51%), diarrhea 
(44%), thrombocytopenia (34%), vomiting (38%), decreased appetite (32%), fever 
(21%), and anemia (21%). The most frequent (at least 20%) TEAEs reported with 
the PO formulation pooled from combination trials (irrespective of the combination) 
(n = 173), irrespective of causality to ixazomib, include diarrhea (47%), fatigue 
(44%), nausea (38%), peripheral edema (35%), constipation (33%), insomnia 
(29%), thrombocytopenia (28%), anemia (26%), vomiting (26%), neutropenia (25%), 
back pain (24%), pyrexia (23%), peripheral edema (21%, each), fever (20%), cough 
(20%), hypokalemia (20%), neutropenia (20%), and upper respiratory tract infection 
(20%). Overall rash of all grades is reported in approximately 50% of patients and is 
more common when ixazomib is given in combination with lenalidomide where rash 
is an overlapping toxicity. 
 

  
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Additional detailed information regarding the clinical experience of ixazomib may be 
found in the IB, including information on the IV formulation.  
  
1.5   Pharmacokinetics and Drug Metabolism 
 
Clinical IV and PO PK data show that ixazomib citrate (measured as the biologically 
active boronic acid form of ixazomib [MLN2238]) has multi-exponential disposition 
with a rapid initial phase that is largely over by 4 hours.  Oral ixazomib citrate is 
rapidly absorbed with a median single-dose first time of occurance of maximum 
(peak) concentration (Tmax) of approximately 0.5 to 2.0 hours and a terminal 
disposition half-life (t1/2) after multiple dosing of approximately 5 to 7 days.46  Results 
of a population PK analysis (n = 137) show that there is no relationship between 
body surface area (BSA) or body weight and clearance (CL).  Also, based on 
stochastic simulations for fixed dose, exposures are independent of the individual 
patient’s BSA.6  Based on these data, a recommendation was made for fixed dosing 
in clinical trials.  An absolute bioavailability of 67% was determined for ixazomib 
using the population PK analysis.  See the IB.  Please refer to the current ixazomib 
IB and Safety Management Attachment (SMA) for information on the PK for IV 
doses of ixazomib. 
Metabolism appears to be the major route of elimination for ixazomib,  and urinary 
excretion of the parent drug is negligible (< 5% of dose).  In vitro studies indicate 
that ixazomib is metabolized by multiple cytochrome enzymes P450 (CYPs) and 
non-CYP enzymes/proteins.  The rank order of relative biotransformation activity of 
the 5 major human CYP isozymes was 3A4 (34.2%) > 1A2 (30.7%) > 2D6 (14.7%) 
> 2C9 (12.1%) > 2C19 (< 1%).  Ixazomib is not an inhibitor of CYPs 1A2, 2C9, 
2C19, 2D6, or 3A4, nor a time-dependent inhibitor of CYP3A4/5.  The potential for 
ixazomib treatment to produce drug-drug interactions (DDIs) via CYP inhibition is 
inferred to be low.  However, there may be a potential for DDIs with a concomitant 
strong CYP3A4 or CYP1A2 inhibitor or inducer because of the potential for first-
pass metabolism when ixazomib is administered via the PO route and because of 

  
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the moderate contribution of CYP3A4- and CYP1A2-mediated metabolism of 
ixazomib in human liver microsomes.   Ixazomib may be a weak substrate of 
P-glycoprotein (Pgp), breast cancer resistance protein (BCRP), and multidrug 
resistance associated protein (MRP2) efflux pump transporters.   Ixazomib is not an 
inhibitor of Pgp, BCRP, and MRP2.  The potential for DDIs with substrates or 
inhibitors of Pgp, BCRP, and MRP2 is, therefore, inferred to be low. Clinical Study 
C16009 (Arm 1) with ketoconazole, a strong CYP3A4 inhibitor, showed a 2-fold 
increase in area under the plasma concentration versus time curve (AUC) in the 
presence of ketoconazole. This resulted in the continued exclusion of strong 
CYP3A4 inhibitors in ongoing/planned clinical studies. 
Further details on these studies are provided in the IB. 
 
 
1.6    Clinical Trial Experience Using the Oral Formulation of ixazomib  
As of 27 March 2013, a total of 507 patients with differing malignancies (multiple 
myeloma,  AL amyloidosis, nonhematologic cancers, and lymphoma) have been 
treated in studies evaluating the oral ixazomib formulation.  These patients have 
been treated with different doses of IXAZOMIB either as a single-agent treatment 
(in 201 patients) or in combination with currently clinically available treatments (in 
306 patients).  Information regarding the ongoing studies, patient populations, and 
doses investigated is included in Table 1-1. 
 

  
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Table 1-1   
Clinical Studies of Oral ixazomib 
Trial/ 
Population 
Description 
Doses Investigated 
C16003 
RRMM 
N = 60 
PO,TW, single 
agent 
0.24-2.23 mg/m2, TW 
MTD:  2.0 mg/m2 
DLT:  rash, thrombocytopenia 
Closed to enrollment 
C16004 
RRMM 
N = 60 
PO, W, single 
agent 
0.24-3.95 mg/m2, W 
MTD:  2.97 mg/m2 
DLT:  rash, nausea, vomiting, diarrhea 
Closed to enrollment 
C16005 
NDMM 
N = 65 
PO, W, 
combination with 
LenDex 
28 day cycle 
1.68-3.95 mg/m2, W 
MTD:  2.97 mg/m2 
DLT:  nausea, vomiting, diarrhea, 
syncope 
RP2Da:  4.0 mg fixed (switched to 
fixed dosing in phase 2, equivalent to 
2.23 mg/m2) 
Closed to enrollment 
C16006 
NDMM 
N = 20 
PO, TW (Arm A- 
42 day cycle) 
and W (Arm B- 
28 day cycle), 
combination with 
Melphalan and 
Prednisone 
Arm Aa:  3-3.7mg, fixed dose, TW 
DLT: rash, thrombocytopenia, subileus 
Arm Ba: 3-5.5 mg, fixed dose, W 
DLT: Esophageal ulcer, nausea, 
vomiting, hematemesis, 
thrombocytopenia, ileus, neurogenic 
bladder 
MTD = 3.0 mg 
C16007 
RRAL 
N = 27 
PO, W, single 
agent 
4-5.5 mg, fixed dosea, W 
MTD: 4 mg 
DLT: thrombocytopenia, diarrhea, 
dyspnea, acute rise in creatinine, 
cardiac arrest 
MTD: 4.0 mg W 
C16008 
NDMM 
N=64 
PO, TW, 
combination with 
LenDex 21 day 
cycle 
3.0-3.7 mg fixed dosea W 
MTD: 3.0 mg 
Closed to enrollment 
C16009 
Solid 
tumors, 
Lymphomas 
N = 54 
PO, W, single 
agent 
5.5 mg fixed dosea W 
C16010 
RRMM 
N = 1 
PO, W, 
combination with 
LenDex 
4.0 mg W 

  
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Table 1-1   
Clinical Studies of Oral ixazomib 
C16011 
RRAL 
N = 4 
PO, W, with Dex 
versus 
physician’s 
choice of a Dex-
based regimen 
4.0 mg W 
C16013 
RRMM 
N = 9 
PO, W, with LenDex 
4.0 mg W 
C16014 
Symptomati
c MM 
N=701 
PO, combination with LenDex 
ixazomib 4.0 mg or matching placebo on 
Days 1, 8, and 15, plus Len 25 mg on Days 
1-21 (10 mg if low creatinine clearance, with 
escalation to 15 mg if tolerated) and Dex 
40 mg (or 20 mg if >75 years old) on Days 1, 
8, 15, and 22 
C16015 
Symptomati
c MM with 
normal renal 
function or 
severe renal 
impairment 
N=28 
PO, combination with Dex 
Part A: ixazomib  3.0 mg on Day 1 
Part B: ixazomib  4.0 mg on Days 1, 8, and 
15, plus Dex 40 mg (or 20 mg if >75 years 
old) on Days 1, 8, 15 and 22 of a 28-day 
cycle 
 
C16017 
RR follicular 
lymphoma 
N=58 
PO, W 
4.0, 5.3, and 7.0 mg, W 
Treatment at RP2D once determined. 
 
C16018 
Advanced solid 
tumors or 
hematologic 
malignancies 
with varying 
degrees of liver 
dysfunction 
N=45 
Part A: PO, Day 1 of 15-day 
cycle 
Part B: PO, W 
1.5 mg (severe hepatic impairment), 2.3 mg 
(moderate hepatic impairment), or 4.0 mg 
(normal hepatic function) 
 
TB-
MC010034 
RRMM 
N = 10 
PO, W 
4.0 mg, W 
Single agent: 4.0 mg 
Combination with Rd 
 
Abbreviations:  RRAL = Relapsed and/or refractory Primary systemic light chain (AL) amyloidosis; BSA = body 
surface area; Dex=dexamethasone; DLT = dose-limiting toxicity; IV = intravenously; LenDex = lenalidomide 
plus dexamethasone; MTD = maximum tolerated dose; NDMM = newly diagnosed multiple myeloma; PO = 
orally; RR= relapsed and/or refractory; RRAL= relapsed and/or refractory systemic light chain amyloidosis 
RRMM = relapsed and/or refractory multiple myeloma; TBD = to be determined; TW = twice weekly; W = 
weekly; RP2D= recommended phase 2 dose. 
Note that blinded data from pivotal Studies C16010 and C16011 are not included.   
a Approximate BSA and fixed dosing equivalence:  3 mg~ equivalent to 1.68 mg/m2 BSA dosing; 4.0 mg ~ 
equivalent to 2.23 mg/m2 BSA dosing; and 5.5 mg~ equivalent to 2.97 mg/m2 BSA dosing. 

  
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Overview of the Oral Formulation of ixazomib 
The emerging safety profile indicates that oral IXAZOMIB is generally well tolerated. 
The adverse events (AEs) are consistent with the class-based effects of 
proteasome inhibition and are similar to what has been previously reported with 
VELCADE though the severity of some, for example peripheral neuropathy, is less.  
While some of these potential toxicities may be severe, they can be managed by 
clinical monitoring and standard medical intervention, or, as needed, dose 
modification or discontinuation.   
In the 4 ongoing studies (C16003, C16004, C16007, and C16009) investigating 
single-agent oral IXAZOMIB in patients with differing malignancies (multiple 
myeloma, AL amyloidosis, nonhematologic cancers, and lymphoma), a total of 201 
patients have been treated as of 27 March 2013. These patients have been treated 
with different doses of ixazomib as they are all phase 1 trials. An overview of the 
most frequent (at least 10%) AEs occurring in the pooled safety population from 
single-agent oral ixazomib Studies (C16003, C16004, C16007, and C16009) is 
shown in Table 1-2. 
Table 1-2 
Summary of Most Common (At Least 10% of Total) Treatment-
Emergent Adverse Events in Oral Single-Agent Studies 
 
Primary System Organ Class  
Preferred Term 
Oral Single Agent Total  
N=201 
Subjects with at Least One 
Adverse Event 
197 (98) 
Gastrointestinal disorders 
160 (80) 
Nausea 
106 (53) 
Diarrhoea 
88 (44) 
Vomiting 
77 (38) 
Constipation 
46 (23) 
Abdominal pain 
33 (16) 
General disorders and 
administration site conditions 
151 (75) 
Fatigue 
103 (51) 
Pyrexia 
51 (25) 
Oedema peripheral 
27 (13) 
Asthenia 
31 (15) 
Nervous system disorders 
92 (46) 
Headache 
29 (14) 
Dizziness 
26 (13) 

  
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Neuropathy peripheral 
21 (10) 
Metabolism and nutrition 
disorders 
107 (53) 
Decreased appetite 
64 (32) 
Dehydration 
37 (18) 
Blood and lymphatic system 
disorders 
98 (49) 
Thrombocytopenia 
68 (34) 
Anaemia 
42 (21) 
Neutropenia 
29 (14) 
Lymphopenia 
20 (10) 
Skin and subcutaneous tissue 
disorders 
90 (45) 
Rash maculara 
23 (11) 
Musculoskeletal and connective 
tissue disorders 
93 (46) 
Back pain 
24 (12) 
Arthralgia 
28 (14) 
Respiratory, thoracic and 
mediastinal disorders 
78 (39) 
Cough 
28 (14) 
Dyspnoea 
30 (15) 
Infections and infestations 
89 (44) 
Upper respiratory tract 
infection 
31 (15) 
Source:  ixazomib Investigator’s Brochure Edition 7 
Abbreviations:  MedDRA = Medical Dictionary for Regulatory Activities, version 15.0. 
Subject Incidence:  A subject counts once for each preferred term.  Percentages use the 
number of treated subjects as the denominator. 
a Note that rash maculopapular and rash macular represent the 2 most common terms used 
to describe rash. 
 
As of 27 March 2013, there are 5 studies actively enrolling patients with multiple 
myeloma to investigate oral ixazomib in combination with standard combination 
regimens.   
The most frequent (at least 10%) AEs occurring in the pooled safety population from 
Studies C16005, C16006, C16008, and C16013 are shown for all grades (Table 1-
3).  Note that in combination trials, related is defined as related to any study drug in 
the combination regimen. 
 
 

  
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Table 1-3 
Most Common (At Least 10% of Total) Treatment- Emergent 
Adverse Events in Oral Ixazomib Combination Studies 
 
Primary System Organ Class 
      Preferred Term 
Total Oral Combo Agent 
(5/6/8/13) 
n = 173 
n (%) 
Subjects with at Least One Adverse Event 
163 (94) 
Gastrointestinal disorders 
139 (80) 
 Nausea 
65 (38) 
 Diarrhoea 
81 (47) 
 Vomiting 
51 (29) 
 Constipation 
57 (33) 
General disorders and administration site 
conditions 
132 (76) 
 Fatigue 
76 (44) 
 Pyrexia 
39 (23) 
 Oedema peripheral 
61 (35) 
 Asthenia 
20 (12) 
Nervous system disorders 
115 (66) 
 Headache 
28 (16) 
 Dizziness 
34 (20) 
 Neuropathy peripheral 
45 (26) 
Metabolism and nutrition disorders 
91 (53) 
 Decreased appetite 
25 (14) 
 Hypokalaemia 
34 (20) 
Blood and lymphatic system disorders 
88 (51) 
 Thrombocytopenia 
49 (28) 
 Anaemia 
45 (26) 
 Neutropenia 
43 (25) 
 Lymphopenia 
20 (12) 
Skin and subcutaneous tissue disorders 
102 (59) 
 Rash maculopapulara 
29 (17) 
 Rash maculara 
22 (13) 
Musculoskeletal and connective tissue 
disorders 
99 (57) 
 Back pain 
42 (24) 
 Pain in extremity 
31 (18) 
 Arthralgia 
22 (13) 
Respiratory, thoracic and mediastinal 
disorders 
80 (46) 
 Cough 
36 (21) 

  
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 Dyspnoea 
26 (15) 
Infections and infestations 
92 (53) 
 Upper respiratory tract infection 
35 (20) 
Psychiatric disorders 
73 (42) 
 Insomnia 
50 (29) 
Source:  ixazomib Investigator’s Brochure Edition 7 
Abbreviations:  MedDRA = Medical Dictionary for Regulatory Activities, version 15.0. 
Subject Incidence:  A subject counts once for each preferred term.  Percentages use the 
number of treated subjects as the denominator.  
Data from ongoing blinded pivotal trials (C16010) are not included. 
a Note that rash maculopapular and rash macular represent the 2 most common terms used 
to describe rash.   
 
The clinical experience with ixazomib also shows early signs of antitumor activity as 
evidenced by at least a 50% reduction in disease burden in some patients and 
prolonged disease stabilization in others across all ongoing trials. The antitumor 
activity has been seen with single-agent ixazomib, when combined with established 
therapies, and across the malignancies studied (advanced solid tumors [3], non-
Hodgkin’s disease, Hodgkin’s disease [4], relapsed and/or refractory multiple 
myeloma [RRMM; 5; 6], relapsed or refractory systemic light chain amyloidosis 
[RRAL; 7], and newly diagnosed multiple myeloma [NDMM; 8; 9; 10]) to date. 
 
Though additional data are needed to characterize the clinical benefit of this drug, 
the emerging data supports the ongoing development of ixazomib. 
 
1.7    Relapsed and/or Refractory Multiple Myeloma 
The early development of ixazomib in patients with RRMM involves 2 studies 
(C16003 and C16004) with similar objectives, but each investigated 1 of the 2 
dosing schedules commonly used with the first-in-class proteasome inhibitor, 
VELCADE. 
Study C16003 is an open-label, dose escalation, phase 1 study of ixazomib dosing 
on a twice-weekly schedule on Days 1, 4, 8, and 11 of a 21-day cycle in adult 
patients with RRMM.(11, 12)  Study C16004 is an open-label, dose escalation, 
phase 1 study of ixazomib dosing on a weekly schedule on Days 1, 8, and 15 of a 
28-day cycle in adults patients with RRMM.(13, 14, 15)  Both studies have now 
completed enrollment.  The DLTs in Study C16003 were rash macular and 
thrombocytopenia and the DLTs in C16004 were nausea, diarrhea, vomiting, and 
erythema multiforme. 

  
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In the dose escalation component of both studies, patients had multiple myeloma 
that had relapsed following at least 2 lines of therapy that must have included 
bortezomib, thalidomide (or lenalidomide), and corticosteroids.  In both studies, 
when the MTD was established, cohorts of patients representing the heterogeneous 
patient population currently seen in clinical practice were to be enrolled into 1 of 4 
expansion cohorts, including a relapsed and refractory cohort, a carfilzomib cohort, 
a proteasome inhibitor-naïve cohort, and a VELCADE-relapsed cohort. 
Final study results are currently being analyzed, but preliminary data suggest that 
ixazomib has anti-tumor activity in heavily pretreated MM patients, with durable 
responses/disease control, and is generally well tolerated. Please refer to the 
ixazomib IB and SMA for further information.  
1.8     
Newly Diagnosed Multiple Myeloma (NDMM) 
Multiple research paths are being explored in patients with NDMM with a focus on 
evaluating ixazomib in combination with agents commonly used across treatment 
settings.  The development of ixazomib in combination with lenalidomide with 
dexamethasone (LenDex) in patients with NDMM who are transplant eligible or 
ineligible involves 2 studies (C16005 and C16008) with similar study designs except 
for a few key differences, namely the schedules of ixazomib and dexamethasone.   
ixazomib is also being evaluated in combination with melphalan and prednisone 
(MP) for patients who are not transplant eligible due to age or coexisting morbidity 
(in Study C16006).  
All 3 studies are phase 1/2, with phase 1 focusing on safety and phase 2 on efficacy 
(and further characterization of safety).  Please refer to the ixazomib IB and SMA for 
further information.  
1.9     
Clinical Trial Experience Using the Intravenous Formulation of ixazomib 
See the IB for descriptions of the 2 ongoing studies that investigated IV ixazomib in 
advanced solid tumors and advanced lymphoma (Studies C16001 and C16002, 
respectively).   
1.10 Potential Risks and Benefits 
Please refer to the current ixazomib IB and SMA. 

  
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The clinical benefit of ixazomib continues to be studied in a comprehensive and 
global development plan that involves studies sponsored by Millennium.  Ixazomib 
appears to show early signs of anti-tumor activity as evidenced by at least 50% 
reduction in disease burden in some patients, including patients that have been 
heavily pretreated as well as those with newly diagnosed MM, and prolongs 
stabilization of the underlying disease in other patients across all ongoing trials.  
The preliminary findings are favorable when considering historical and currently 
available therapies for the patient populations evaluated.  Though additional data 
are needed to characterize the clinical benefit of this drug, the emerging data 
supports expanded development of ixazomib for the treatment of patients with 
advanced malignancy. 
This study will be conducted in compliance with the protocol, good clinical practice 
(GCP), applicable regulatory requirements, and International Conference on 
Harmonisation (ICH) guidelines. 
2.    
STUDY OBJECTIVES 
2.1     
Primary Objectives 
The primary objective is to determine the maximum tolerated dose of IXAZOMIB 
with VXD and to assess the tolerability of VXD + ixazomib in adult patients with 
relapsed refractory acute lymphocytic leukemia/lymphoma, lymphoblastic 
lymphoma or mixed phenotype acute leukemia 
2.2     
Secondary Objectives 
• To estimate the overall response rate (ORR) including both complete 
remission (CR) and complete remission with incomplete count 
recovery (CRi) with VXD + ixazomib 
3. STUDY DESIGN  
In this phase I study, escalating doses of ixazomib will be combined with a fixed 
dose VXD regimen. Ixazomib will be administered on day 1, 8, and 15. If the patient 
experiences a DLT the dose of MLN maybe reduced to the next dose level on day 8 
or day 15 in that patient. DLT would be any grade 3 or more toxicity which is 

  
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thought to be probably or definitely related to ixazomib. Three patients will be 
treated per dose level unless dose limiting toxicity (DLT) is observed.  The starting 
dose of ixazomib will be 2.3 mg orally on days 1, 8 and 15. If toxicity is seen at this 
level then dose may be reduced to 1.5 mg (dose level -1).  If no DLT is seen in the 
first 3 patients, the dose will be increased to 3 mg and then to 4 mg orally on days 
1, 8 and 15 in a classic 3 +3 phase I design. The study will not attempt to increase 
the dose beyond 4 mg orally which, if achieved with acceptable toxicity, would be 
accepted as the recommended phase 2 dose (RP2D). 0 of 3 DLTs would allow 
escalation to the next dose level. 1 of 3 DLTs will require expanding to six patients; 
1 of 6 DLTs will allow escalation again. Two DLTs will require dose de-escalation.  
Given that the liver toxicity with the VXLD + ixazomib was attributed to 
pegaspargase and it is eliminated from this protocol, we will start at dose level 1 of 
2.3 mg. The maximum tolerated dose (MTD) will be the highest dose administered 
at which no more than 1 DLT was observed. All patients will be evaluated for 
hematopoetic stem cell transplantation. If patients achieve CR and are eligible for 
HSCT, they will proceed to HSCT. If they are not eligible, no donor is identified or if 
HSCT will be delayed, and the patient has achieved benefit, then treatment may be 
repeated at the discretion of the investigator. A total of 9-18 patients will be enrolled 
on the study. The study duration will be about 2 years. The DLT observation period will 
be from first dose of MLN9708 to 28 days after the first dose. Dose escalation to a higher 
dose level will require the last patient on the previous dose level to be out of the DLT 
observation period. 
 
Patients will be offered an opportunity to provide samples to the institutional bank 
for use in future research.  
 
4.    
STUDY POPULATION 
4.1     
Inclusion Criteria  
Each patient must meet all of the following inclusion criteria to be enrolled in the 
study: 

  
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• Male or female patients 18 years or older  
• Have relapsed B or T-precursor acute lymphocytic leukemia/lymphoma, 
lymphoblastic lymphoma or  mixed phenotype acute leukemia with increased 
bone marrow or peripheral blood blasts by morphology with or without CNS 
involvement  
• Prior therapy: At least two prior treatment attempts to induce remission with 
no limit on the number of prior treatment regimens.  
• Patients are eligible after allogeneic stem cell transplantation  
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2  
• Patients must meet the following clinical laboratory criteria: 
o Total bilirubin ≤ 1.5 × the upper limit of the normal range (ULN). 
o Alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST) ≤ 3 × ULN. 
o Calculated creatinine clearance ≥ 30 mL/min  
o Absolute neutrophil count (ANC) > 1,000/cmm and platelets > 
75,000/cmm unless the cytopenias are secondary to disease 
• Life expectancy reasonably adequate for evaluating the treatment effect 
• Patients must be at least 2 weeks from major surgery, radiation therapy, 
participation in other investigational trials and have recovered from clinically 
significant toxicities of these prior treatments 
• Female patients who: 
o Are postmenopausal for at least 1 year before the screening visit, OR 
o Are surgically sterile, OR 
o If they are of childbearing potential, agree to practice 2 effective 
methods of contraception, at the same time, from the time of signing 
the informed consent form through 90 days after the last dose of study 
drug, OR 
o Agree to practice true abstinence when this is in line with the preferred 
and usual lifestyle of the subject.  (Periodic abstinence [eg, calendar, 
ovulation, symptothermal, post-ovulation methods] and withdrawal are 
not acceptable methods of contraception.) 

  
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• Male patients, even if surgically sterilized (ie, status post-vasectomy), must 
agree to one of the following: 
o Agree to practice effective barrier contraception during the entire study 
treatment period and through 90 days after the last dose of study 
drug, OR 
o Agree to practice true abstinence when this is in line with the preferred 
and usual lifestyle of the subject.  (Periodic abstinence (eg, calendar, 
ovulation, symptothermal, post-ovulation methods] and withdrawal are 
not acceptable methods of contraception.). 
 
4.2     
Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the 
study: 
• Patients who are Ph+ ALL who are naive to therapy with an approved 
tyrosine kinase inhibitor. 
• Prior exposure to ≥350 mg/m2 of anthracycline (in doxorubicin equivalent 
dosing), or left ventricular fractional shortening less than 50%.  
• Failure to have fully recovered (ie, ≤ Grade 2 toxicity) from the effects of 
prior chemotherapy regardless of the interval since last treatment. 
• Major surgery within 14 days before enrollment. 
• Chemotherapy in the last 14 days. (Steroids or Intrathecal chemotherapy 
will be allowed).  
• Systemic treatment, within 7 days before study enrollment, with strong 
inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong 
inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, 
voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A 

  
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inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, 
phenobarbital), or use of Ginkgo biloba or St. John’s wort. 
• Uncontrolled intercurrent illness including, but not limited to ongoing or 
active infection, symptomatic congestive heart failure, or psychiatric 
illness/social situations that would limit compliance with study 
requirements. Patients receiving intravenous antibiotics for infections that 
are under control may be included in this study.  
• Known allergy to any of the study medications, their analogues, or 
excipients in the various formulations of any agent.  
• Inability to swallow oral medication, inability or unwillingness to comply 
with the drug administration requirements, or GI procedure that could 
interfere with the oral absorption or tolerance of treatment. 
• Diagnosed or treated for another malignancy within 2 years before study 
enrollment or previously diagnosed with another malignancy and have 
any evidence of residual disease.  Patients with nonmelanoma skin 
cancer or carcinoma in situ of any type are not excluded if they have 
undergone complete resection. 
• Patient has ≥ Grade 2 peripheral neuropathy. 
• Participation in clinical trials with other investigational agents not included 
in this trial, within 14 days of the start of this trial and throughout the 
duration of this trial.  
• Female patients who are breastfeeding or have a positive serum 
pregnancy test during the screening period or a positive urine pregnancy 
test on Day 1 before first dose of study drug. 
5.    
TREATMENT PLAN 
All patients will start therapy within 4 weeks from the bone marrow biopsy.  

  
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Lumbar puncture with intrathecal chemotherapy will be performed on all patients on 
day 1 (+/-1 day) to evaluate for disease.  
 
BM or peripheral blood blast will be collected for correlative studies (optional) prior 
to starting therapy. Details of therapy are as follows: 
 
Vincristine 1.5 mg/m2 to a maximum dose of 2 mg IV on days 1, 8, 15 and 22 
Dexamethasone 10 mg/m2 orally or intravenously on days 1-14 
Doxorubicin 60 mg/m2 on day 1 by IV bolus.  
 
For patients without CNS involvement:  
-Cytarabine 100 mg will be administered intrathecally on day 1 (+/-1 day) 
(cytarabine dose should be reduced to 50 mg if given through a central ommaya 
reservoir) 
-Methotrexate 12 mg will be administered intrathecally on day 8  (+/-1 day) 
 
For patients with CNS involvement: 
-Cytarabine 100 mg will be administered intrathecally on day 1 (+/-1 day) 
(cytarabine dose should be reduced to 50 mg if given through a central ommaya 
reservoir) 
-Triple intrathecal chemotherapy with cytarabine 30 mg, methotrexate 15 mg and 
hydrocortisone 15 mg on (Day  8, 15 and 22   (+/-1 day)). 
 
A bone marrow biopsy/aspirate will be performed at D28 +\- 3 days. For patients in 
remission, and have an available donor for HCT should proceed to HCT and be 
removed from the protocol treatment. Patients will still be followed for survival and 
progression free survival. A second cycle of treatment may be administered at the 
investigators discretion.  
 
Ixazomib will be administered orally once weekly on day 1, 8 and 15. The first 3 
patients will receive 2.3 mg orally (dose level 1). Dose escalation or de-escalation 

  
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will then proceed as previously detailed. There will be no intrapatient dose 
escalation. 
 
Table (7) Ixazomib dosing 
 
Day 
Oral Dosing (mg) 
Dose level -1 1, 8, 15 
1.5 
Dose level 1 
1, 8, 15 
2.3 
Dose level 2 
1, 8, 15 
3 
Dose level 3 
1, 8, 15 
4 
 
Supportive care: 
All patients will receive antibacterial, antiviral, antifungal and pnuemocystis carinii 
pneumonia (PCP) prophylaxis. Prophylaxis regimen may follow institutional 
guidelines. The following prophylaxis maybe used as guidelines: 
Quinolones for antibacterial prophylaxis e.g., levofloxacin 500 mg orally daily 
Antiviral prophylaxis: acyclovir 800 mg orally twice daily 
Antifungal prophylaxis: Fluconazole 400 mg orally daily, or Liposomal Amphotericin 
B 9 mg/kg IV once per week or Caspofungin 50 mg IV /daily 
PCP prophylaxis with SS bactrim daily, pentamidine inhalation 300 mg monthly, 
dapsone 100 mg daily or mepron  
 
6.  DRUG INFORMATION 
6.1 Description of Investigational Agents (ixazomib) 
Ixazomib Capsules 
The ixazomib drug product is provided in strengths of 4.0-, 3.0-, and 2.3-mg and 
2.0-, 0.5-, and 0.2 mg capsules as the active boronic acid. The different dose 

  
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strengths are differentiated by both capsule size and color as described below: 
 
 
 
Dose 
Strength 
Capsule Size 
Capsule 
Color 
4.0 mg 
Size 4 
Ivory 
3.0 mg 
Size 3 
Light gray 
2.3 mg 
Size 2 
Light pink 
2.0 mg 
Size 2 
Swedish 
orange 
0.5 mg 
Size 3 
Dark green 
0.2 mg 
Size 4 
White opaque 
 
 
 
For additional details, please see the ixazomib IB. 
 
All protocol-specific criteria for administration of study drug must be met and 
documented before drug administration.  Study drug will be administered only to 
eligible patients under the supervision of the investigator or identified sub-
investigator(s).  Patients should be monitored for toxicity, as necessary, and doses 
of ixazomib should be modified as needed to accommodate patient tolerance to 
treatment; this may include symptomatic treatment, dose interruptions, and 
adjustments of ixazomib dose. 
6.2 Study Drug Administration 
Ixazomib Administration 
All protocol-specific criteria for administration of study drug must be met and 
documented before drug administration.  Study drug will be administered or 
dispensed only to eligible patients under the supervision of the investigator or 
identified subinvestigator(s).  Patients should be monitored for toxicity, as 
necessary, and doses of ixazomib should be modified as needed to accommodate 
patient tolerance to treatment; this may include symptomatic treatment, dose 
interruptions, and adjustments of ixazomib dose (see Section 6.3). 
Patients should be instructed to swallow ixazomib capsules whole, with water, and 
not to break, chew, or open the capsules.  Study drug should be taken on an empty 

  
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stomach (no food or drink, except water) at least 1 hour before or 2 hours after a 
meal.  Each capsule should be swallowed separately with a sip of water.  Followed 
by 8 ounces (240 mL) of water.   
Missed doses can be taken, as soon as the patient remembers, if 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. 
Ixazomib Destruction 
Investigational ixazomib (expired or end of study) should be destroyed according to 
the institution’s standard operating procedure.  Be sure to document removal and 
destruction on drug accountability logs. 
Please refer to the Pharmacy Manual for additional instructions. 
6.3 Doxorubicin 
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 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 
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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. 
Formulation and Stability: 
Doxorubicin is available as red-orange lyophilized powder for injection in 10 mg¹, 20 
mg¹, 50 mg¹, 150 mg² vials and a preservative-free 2 mg/mL solution in 10 mg¹, 20 
mg¹, 50 mg¹, 75 mg¹, 200 mg² vials. 
¹ Contains lactose monohydrate, 0.9 NS, HCl to adjust pH to 3. The Adriamycin 
RDF (rapid dissolution formula) also contains methylparaben 1 mg per each 10 
mg of doxorubicin to enhance dissolution.² Multiple dose vial contains lactose, 0.9% 
NS, HCl to adjust pH to 3. 
Aqueous Solution: 
Store refrigerated 2°-8°C (36°-46°F). Protect from light. Retain in carton until 
contents are used. 
Powder for Injection: 
Store unreconstituted vial at room temperature 15°-30°C (59°-86°F). Retain in 
carton until contents are used. Reconstitute with preservative-free normal saline to 

  
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a final concentration of 2 mg/mL. After adding the diluent, the vial should be shaken 
and the contents allowed to dissolve. The reconstituted solution is stable for 7 days 
at room temperature under normal room light (100 footcandles) and 15 days under 
refrigeration 2°-8°C (36°-46°F). Protect from exposure to sunlight. Doxorubicin may 
be further diluted in 0.9%NaCl or dextrose containing solutions and administered by 
infusion. 
Guidelines for Administration: See Treatment and Dose Modification sections of 
the protocol.  Administer IV through the tubing of rapidly infusing solution of D5W or 
0.9% NaCl preferably into a large vein. Protect the diluted solution from sunlight. To 
avoid extravasation, the use of a central line is suggested. 
Supplier: Commercially available from various manufacturers. See package insert 
for further information. 
Adverse effects 
Cardiovascular: 
Acute cardiotoxicity: Atrioventricular block, bradycardia, bundle branch block, ECG 
abnormalities, extrasystoles (atrial or ventricular), sinus tachycardia, ST-T wave 
changes, supraventricular tachycardia, tachyarrhythmia, ventricular tachycardia 
Delayed cardiotoxicity: LVEF decreased, CHF (manifestations include ascites, 
cardiomegaly, dyspnea, edema, gallop rhythm, hepatomegaly, oliguria, pleural 
effusion, pulmonary edema, tachycardia); myocarditis, pericarditis 
Central nervous system: Malaise 
Dermatologic: Alopecia, itching, photosensitivity, radiation recall, rash; discoloration 
of saliva, sweat, or tears 
Endocrine & metabolic: Amenorrhea, dehydration, infertility (may be temporary), 
hyperuricemia 

  
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Gastrointestinal: Abdominal pain, anorexia, colon necrosis, diarrhea, GI ulceration, 
mucositis, nausea, vomiting 
Genitourinary: Discoloration of urine 
Hematologic: Leukopenia/neutropenia (75%; nadir: 10-14 days; recovery: by day 
21); thrombocytopenia and anemia 
Local: Skin “flare” at injection site, urticaria 
Neuromuscular & skeletal: Weakness 
Postmarketing and/or case reports: Anaphylaxis, azoospermia, bilirubin increased, 
coma (when in combination with cisplatin or vincristine), conjunctivitis, fever, 
gonadal impairment (children), growth failure (prepubertal), hepatitis, 
hyperpigmentation (nail, skin & oral mucosa), infection, keratitis, lacrimation, 
myelodysplastic syndrome, neutropenic fever, neutropenic typhlitis, oligospermia, 
peripheral neurotoxicity (with intra-arterial doxorubicin), phlebosclerosis, radiation 
recall pneumonitis (children), secondary acute myelogenous leukemia, seizure 
(when in combination with cisplatin or vincristine), sepsis, shock, Stevens-Johnson 
syndrome, systemic hypersensitivity (including urticaria, pruritus, angioedema, 
dysphagia, and dyspnea), toxic epidermal necrolysis, transaminases increased, 
urticarial  
Supportive Care: 
Cardio Protective: Dexaroxane may be used and dosed per institutional standards 
6.4 Vincristine 
Source and Pharmacology: Vincristine is an alkaloid isolated from Vinca rosea 
Linn (periwinkle). It binds to tubulin, disrupting microtubules and inducing 
metaphase arrest. Its serum decay pattern is triphasic. The 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 

  
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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. 
Formulation and Stability: 
Vincristine is supplied in a vial each mL of which contains vincristine sulfate, 1 mg 
(1.08 μmol); mannitol, 100 mg; Sterile Water for Injection; acetic acid and sodium 
acetate are added for pH control.  The pH of Vincristine Sulfate Injection, USP 
ranges from 3.5 to 5.5. This product is a sterile 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. 
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.  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. 
When dispensed the container or syringe containing vincristine must be 
enclosed in an overwrap bearing the statement “DO NOT REMOVE COVERING 
UNTIL MOMENT OF INJECTION. FATAL IF GIVEN INTRATHECALLY. FOR 
INTRAVENOUS USE ONLY.” 

  
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Supplier: 
Commercially available from various manufacturers. See package insert for more 
detailed information. 
Adverse Effects: 
Cardiovascular: Edema, hyper-/hypotension, MI, myocardial ischemia 
Central nervous system: Ataxia, coma, cranial nerve dysfunction (auditory damage, 
extraocular muscle impairment, laryngeal muscle impairment, paralysis, paresis, 
vestibular damage, vocal cord paralysis), dizziness, fever, headache, neurotoxicity 
(dose-related), neuropathic pain (common), seizure, vertigo 
Dermatologic toxicity: Alopecia (common), rash 
Endocrine & metabolic: Hyperuricemia, parotid pain, SIADH (rare) 
Gastrointestinal: Abdominal cramps, abdominal pain, anorexia, constipation 
(common), diarrhea, intestinal necrosis, intestinal perforation, nausea, oral ulcers, 
paralytic ileus, vomiting, weight loss 
Genitourinary: Bladder atony, dysuria, polyuria, urinary retention 
Hematologic: Anemia (mild), leukopenia (mild), thrombocytopenia (mild), thrombotic 
thrombocytopenic purpura 
Hepatic: Hepatic sinusoidal obstruction syndrome (SOS; veno-occlusive liver 
disease) 
Local: Phlebitis, tissue irritation/necrosis (if infiltrated) 
Neuromuscular & skeletal: Back pain, bone pain, deep tendon reflex loss, difficulty 
walking, foot drop, gait changes, jaw pain, limb pain, motor difficulties, muscle 
wasting, myalgia, paralysis, paresthesia, peripheral neuropathy (common), 
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Ocular: Cortical blindness (transient), nystagmus, optic atrophy with blindness 
Otic: Deafness 
Renal: Acute uric acid nephropathy, hemolytic uremic syndrome 
Respiratory: Bronchospasm, dyspnea, pharyngeal pain 
Miscellaneous: Allergic reactions (rare), anaphylaxis (rare), hypersensitivity (rare 
6.5 Dexamethasone 
Source and Pharmacology: Dexamethasone is a synthetic fluorinated 
glucocorticoid devoid of mineralocorticoid effects. Dexamethasone, 0.75 mg, has 
potent anti-inflammatory activity equivalent to approximately 5 mg of prednisone. 
Glucocorticoids produce widespread and diverse physiologic effects on 
carbohydrate, protein, and lipid metabolism, electrolyte and water balance, 
functions of the cardiovascular system, kidney, skeletal muscle, and the nervous 
systems. Glucocorticoids reduce the concentration of thymus-dependent 
lymphocytes (T-lymphocytes), monocytes, and eosinophils.  Glucocorticoids 
selectively bind to the cortisol receptors on human lymphoid cells which are found in 
larger numbers on leukemic lymphoblasts. They also decrease binding of 
immunoglobulin to cell surface receptors and inhibit the synthesis and/or release of 
interleukins, thereby decreasing T-lymphocyte blastogenesis and reducing 
expansion of the primary immune response. The specific cellular mechanisms that 
act to halt DNA synthesis are thought to be related to inhibition of glucose transport 
or phosphorylation, retardation of mitosis, and inhibition of protein synthesis. 
Elimination half-lives for the following age groups have been reported to be: infants 
and children under 2 years of age: 2.3 to 9.5 hours, 8 to 16 years: 2.82 to 7.5 hours, 
and adults (age not specified): 3 to 6 hours. The biologic half-life is 36- 72 hours. It 
is primarily metabolized in the liver and excreted by the kidneys. 
Formulation and Stability:  

  
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Available in 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 4 mg, and 6 mg tablets; 
liquid formulations are available in 0.5 mg/5 mL and 0.5 mg/0.5 mL 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. Four milligrams of dexamethasone sodium phosphate is equivalent to 
3.33 mg of dexamethasone.  Vial sizes include 1 mL, 5 mL, 10 mL, 25 mL, and 30 
mL and are available in multi-dose vials as well as unit of use vials and syringes. 
Inactive ingredients vary depending on manufacturer but include creatinine, sodium 
and propyl paraben, benzyl alcohol, and EDTA. 
Guidelines for Administration:  
See Treatment and Dose Modifications section of the protocol. 
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 preservatives should be used within 24 hours, but maintain 
stability for at least 14 days in PVC bags at room temperature protected from light. 
Supplier:  
Commercially available from various manufacturers. See package insert for further 
information 
Adverse effects: 
Cardiovascular: Arrhythmia, bradycardia, cardiac arrest, cardiomyopathy, CHF, 
circulatory collapse, edema, hypertension, myocardial rupture (post-MI), syncope, 
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Central nervous system: Depression, emotional instability, euphoria, headache, 
intracranial pressure increased, insomnia, malaise, mood swings, neuritis, 
personality changes, pseudotumor cerebri (usually following discontinuation), 
psychic disorders, seizure, vertigo 
Dermatologic: Acne, allergic dermatitis, alopecia, angioedema, bruising, dry skin, 
erythema, fragile skin, hirsutism, hyper-/hypopigmentation, hypertrichosis, perianal 
pruritus (following I.V. injection), petechiae, rash, skin atrophy, skin test reaction 
impaired, striae, urticaria, wound healing impaired 
Endocrine & metabolic: Adrenal suppression, carbohydrate tolerance decreased, 
Cushing's syndrome, diabetes mellitus, glucose intolerance decreased, growth 
suppression (children), hyperglycemia, hypokalemic alkalosis, menstrual 
irregularities, negative nitrogen balance, pituitary-adrenal axis suppression, protein 
catabolism, sodium retention 
Gastrointestinal: Abdominal distention, appetite increased, gastrointestinal 
hemorrhage, gastrointestinal perforation, nausea, pancreatitis, peptic ulcer, 
ulcerative esophagitis, weight gain 
Genitourinary: Altered (increased or decreased) spermatogenesis 
Hepatic: Hepatomegaly, transaminases increased 
Local: Postinjection flare (intra-articular use), thrombophlebitis 
Neuromuscular & skeletal: Arthropathy, aseptic necrosis (femoral and humoral 
heads), fractures, muscle mass loss, myopathy (particularly in conjunction with 
neuromuscular disease or neuromuscular-blocking agents), neuropathy, 
osteoporosis, parasthesia, tendon rupture, vertebral compression fractures, 
weakness 
Ocular: Cataracts, exophthalmos, glaucoma, intraocular pressure increased 
Renal: Glucosuria 

  
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Respiratory: Pulmonary edema 
Miscellaneous: Abnormal fat deposition, anaphylactoid reaction, anaphylaxis, 
avascular necrosis, diaphoresis, hiccups, hypersensitivity, impaired wound healing, 
infections, Kaposi's sarcoma, moon face, secondary malignancy 
7.    
DOSE-MODIFICATION GUIDELINES  
7.1  
Recommended ixazomib Criteria for Beginning or Delaying a 
Subsequent Treatment Cycle & Dose Modifications for Treatment 
Associated Toxicity 
• Treatment with ixazomib will use a cycle length of 28 days.  
 
All non-hematological toxicity considered to be related to treatment with ixazomib 
must have resolved to ≤ Grade 1, to the patient’s baseline values, or to a level 
considered acceptable by the physician (eg, hypokalemia that can be managed by 
replacements) before the next dose of ixazomib could be given. There will be no 
dose modifications or delays for hematological toxicity as all patients will experience 
neutropenia and/or thrombocytopenia with the VXD regimen. In the pediatric study, 
Grade 3 or 4 neutropenia and thrombocytopenia occurred in 97.6 and 79.8% of 
patients treated with VXLD respectively.  
 
 
 
 
Treatment modifications due to ixazomib-related AEs are outlined in Table (8 
and 9). 

  
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Table (8) Ixazomib Treatment Modification (Delays, Reductions, and 
discontinuations) Due to Adverse Events (Non-Hematologic Toxicities) 
Adverse Event (Severity) 
Action on Study Drug 
Further Considerations 
Grade 1 peripheral 
neuropathy 
• No action 
Grade 1 signs and symptoms:  
asymptomatic; without pain or 
loss of function; clinical or 
diagnostic observations only47 
New or worsening Grade 
1 peripheral neuropathy 
with pain or Grade 2 
• Hold study drug until 
resolution to Grade ≤ 1 
or baseline 
Grade 2 signs and symptoms:  
Moderate symptoms; limiting 
instrumental activities of daily 
living (ADL)47 
New or worsening Grade 
2 peripheral neuropathy 
with pain or Grade 3 
• Hold study drug until 
resolution to Grade ≤ 1 
or baseline 
Reduce study drug to 
next lower dose upon 
recovery 
Grade 3 signs and symptoms:  
severe symptoms; limiting self-
care ADL; assistive device 
indicated47 
New or worsening Grade 
4 peripheral neuropathy 
• Discontinue study drug 
 
 
Once ixazomib is reduced for any toxicity, the dose may not be re-escalated. 
 
 
Table (9)  Ixazomib Treatment Modification (Delays, Reductions, and 
Discontinuations) Due to Adverse Events (Non-Hematologic Toxicities other 
than peripheral neuropathy) 

  
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Grade 3 nonhematologic 
toxicity judged to be 
related to ixazomib 
 
• Hold study drug until 
resolution to Grade < 1 
or baseline 
 
Symptomatic recommendations 
noted in Section  3.4 
If not recovered to 
< Grade 1 or baseline in 
one week 
 
• Reduce study drug to 
next lower dose upon 
return to < Grade 1 or 
baseline 
 
Grade 4 nonhematologic 
toxicities judged to be 
related to study drug 
• Consider permanently 
discontinuing study 
drug 
Exceptions are cases in which 
the investigator determines the 
patient is obtaining a clinical 
benefit  
7.2 Dexamethasone 
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. 
Hyperglycemia: Dose should not be reduced for hyperglycemia. Rather, insulin 
therapy should be employed to control the blood glucose level. 
Pancreatitis: Do not modify dose for asymptomatic elevations of amylase and/or 
lipase. Discontinue steroids, except for stress doses, in the presence of 
hemorrhagic pancreatitis or severe pancreatitis (abdominal pain > 72 hours and > 
Grade 3 amylase elevation (> 2.0x ULN). 
Muscle Weakness:  Dose may be reduced for grade 2 or 3 muscle weakness. 
Osteonecrosis (ON, also referred to as avascular necrosis): Do not modify 
corticosteroid therapy for osteonecrosis during Induction or Delayed Intensification.  
Varicella: Steroids should be held during active infection except during Induction. 
Do not hold during incubation period following exposure. 

  
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Inability to use oral doses: 
For dexamethasone, substitute the IV preparation mg for mg.  
Severe infection: Do not hold or discontinue steroids during Induction without 
serious consideration, as this is a critical period in the treatment of ALL.  
Severe psychosis: Steroid dose may be decreased by 50% for severe psychosis. 
7.3   Vincristine 
Severe neuropathic pain (Grade 3 or greater): Hold dose(s). When symptoms 
subside, resume at 50% previous calculated 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, since 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. Drugs such 
as gabapentin may be of value. 
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.  
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. 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. 
Jaw pain: Treat with analgesics; do not modify vincristine dose. 
Hyperbilirubinemia: 
Direct bilirubin Dose reduction 

  
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< 3.1 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 mg/dL Withhold dose and administer next scheduled dose if toxicity has 
resolved. 
Do not make up missed doses. 
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. 
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. Suggestions below may be helpful but none are 
considered definitive: 
1. Stop infusion, aspirate drug and blood if possible, remove needle. 
2. Apply warm compress immediately for 1 hour then rotate on/off every 15 minutes 
for 24 hours. 
3. Hyaluronidase 150 units/mL reconstituted with NS-inject 1 mL for each 1 mL of 
drug 
extravasated. 
7.4   Criteria for Beginning a Subsequent Treatment Cycle for IT 
• Platelets >30 cmm 
• Fibrinogen >100 mg/dL 

  
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7.5  Criteria for Toxicity Recovery for a New Cycle of Therapy to Begin: 
• Absolute neutrophil count (ANC) > 1,000/cmm and platelets > 75,000/cmm 
unless the cytopenias are secondary to disease 
• All other nonhematologic toxicity (except for alopecia) must have resolved to 
≤Grade 1 or to the patient’s baseline condition. 
If the patient fails to meet the above criteria for retreatment, hold treatment.  The 
patient should be re-evaluated weekly or more frequently to determine whether the 
criteria for retreatment have been met and a new cycle can begin.  If the criteria for 
retreatment have been met refer to the appropriate drug modification guidelines to 
resume therapy.   
8.    
EXCLUDED CONCOMITANT MEDICATIONS AND PROCEDURES 
The following medications and procedures are prohibited during the study: 
Systemic treatment with any of the following metabolizing enzyme inhibitors is not 
permitted during this study.  (A drug-drug interaction [DDI] with a strong inhibitor 
would increase ixazomib exposure and could lead to a higher probability of an AE.): 
• Strong inhibitors of CYP1A2:  fluvoxamine, enoxacin, ciprofloxacin 
• Strong inhibitors of CYP3A:  clarithromycin, telithromycin, itraconazole, 
voriconazole, ketoconazole, nefazodone, and posaconazole 
Systemic treatment with any of the following metabolizing enzyme inducers should 
be avoided unless there is no appropriate alternative medication for the patient’s 
use (Rationale:  Unlike with inhibitors, if there were to be a DDI with an inducer,  
ixazomib exposure would be less; therefore, there would be a reduced chance of an 
AE.  However, there may be less chance for an antitumor effect, but that is not an 
absolute reason to be taken off ixazomib): 

  
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• Strong CYP3A inducers:  rifampin, rifapentine, rifabutin, carbamazepine, 
phenytoin, and phenobarbital 
• Excluded foods and dietary supplements include St John’s wort and Ginkgo 
biloba are not permitted. 
The following procedures are prohibited during the study: 
• Any antineoplastic treatment with activity against ALL other than study drugs 
in this treatment regimen. 
• Radiation therapy (note that in general, the requirement for local radiation 
therapy generally indicates disease progression). 
• Platelet transfusions to help patients meet eligibility criteria are not allowed 
within 3 days prior to study drug dosing for any dosing day. 
• Adjuvant hormone therapy for breast or prostate cancer 
8.1     
Permitted Concomitant Medications and Procedures 
The following medications and procedures are permitted during the study: 
• Antiemetics, including 5-HT3 serotonin receptor antagonists, may be used at 
the discretion of the investigator. 
• Loperamide or other antidiarrheal should be used for symptomatic diarrhea 
at discretion of the investigator. The dose and regimen will be according to 
institutional guidelines. IVF should be given to prevent volume depletion. 
• Growth factors (eg, granulocyte colony stimulating factor [G-CSF], 
granulocyte macrophage-colony stimulating factor [GM-CSF], recombinant 
erythropoetin) are permitted.  Their use should follow published guidelines 
and/or institutional practice; however, alternative usage may be reviewed 
with the Millennium Clinical or Medical Representative. Erythropoietin will be 

  
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allowed in this study. Their use should follow published guidelines and/or 
institutional practice. 
• Patients should be transfused with red cells and platelets as clinically 
indicated and according to institutional guidelines. 
• Antiviral therapy such as acyclovir may be administered if medically 
appropriate. 
• Concomitant treatment with bisphosphonates will be permitted, as 
appropriate. 
• Patients who experience worsening neuropathy from baseline may be 
observed for recovery and have dose reductions/delays as indicated in the 
protocol, and any supportive therapy or intervention may be initiated as 
appropriate at the discretion of the investigator. 
• Supportive measures consistent with optimal patient care may be given 
throughout the study. 
9.    PRECAUTIONS AND RESTRICTIONS  
Fluid deficit should be corrected before initiation of treatment and during treatment. 
Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided with impaired 
renal function given reported NSAID-induced renal failure in patients with decreased 
renal function.  
10.  PREGNANCY 
It is not known what effects ixazomib has on human pregnancy or development of 
the embryo or fetus.  Therefore, female patients participating in this study should 
avoid becoming pregnant, and male patients should avoid impregnating a female 
partner.  Non-sterilized female patients of reproductive age group and male patients 
should use effective methods of contraception through defined periods during and 
after study treatment as specified below. 

  
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Female patients must meet 1 of the following:  
• Postmenopausal for at least 1 year before the screening visit, or 
• Surgically sterile, or 
• If they are of childbearing potential, agree to practice 2 effective methods of 
contraception from the time of signing of the informed consent form through 3 
months after the last dose of study drug, or 
• Agree to practice true abstinence when this is in line with the preferred and 
usual lifestyle of the subject.  (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, postovulation methods] and withdrawal are not acceptable 
methods of contraception.) 
Male patients, even if surgically sterilized (ie, status post-vasectomy) must agree to 
1 of the following: 
• Practice effective barrier contraception during the entire study treatment 
period and through 90 days after the last dose of study drug, or  
• Agree to practice true abstinence when this is in line with the preferred and 
usual lifestyle of the subject.  (Periodic abstinence (eg, calendar, ovulation, 
symptothermal, postovulation methods for the female partner] and withdrawal 
are not acceptable methods of contraception.)  
  
 
11.  
PACKAGING AND LABELING OF IXAZOMIB 
The study drug ixazomib capsules will be provided by Millennium.  The study drug 
will be labeled and handled as open-label material, and packaging labels will fulfill 
all requirements specified by governing regulations.  
The capsules are individually packaged using cold-form foil-foil blisters that are in a 
child-resistant carton.  There are 3 capsules in each wallet/carton 

  
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11.1 Storage, Handling, and Accountability for ixazomib 
Upon receipt at the investigative site,  ixazomib should remain in the blister and 
carton provided until use or until drug is dispensed. The container should be stored 
at the investigative site refrigerated (36°F to 46°F, 2°C to 8°C). 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 countries where local regulations permit,  ixazomib capsules dispensed to the 
patient for take-home dosing should remain in the blister packaging and refrigerated 
as noted above until the point of use. The investigative site is responsible for 
providing the medication to the patient in the correct daily dose configurations. 
Comprehensive instructions should be provided to the patient in order to ensure 
compliance with dosing procedures. Patients who are receiving take-home 
medication should be given only 1 cycle of medication at a time. Patients should be 
instructed to store the medication refrigerated (36°F to 46°F, 2°C to 8°C) for the 
duration of each cycle. Patients should be instructed to return their empty blister 
packs to the investigative site, rather than discarding them. Reconciliation will occur 
accordingly when the patient returns for their next cycle of take-home medication. 
Any extreme in temperature should be reported as an excursion and should be 
dealt with on a case-by-case basis. 
Because ixazomib is an investigational agent, it should be handled with due care. 
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 cleanup and 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. 

  
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In case of contact with the powder (eg, from a broken capsule), 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. 
Patients are to be instructed on proper storage, accountability, and administration of 
ixazomib, including that ixazomib is to be taken as intact capsules. 
For additional details, please see the ixazomib IB and Pharmacy Manual. 
12. STUDY COMPLIANCE 
Study drug will be administered or dispensed only to eligible patients under the 
supervision of the investigator or identified sub-investigator(s).  The appropriate 
study personnel will maintain records of study drug receipt and dispensing. 
13. TERMINATION OF TREATMENT AND/OR STUDY PARTICIPATION 
Patients will be informed that they have the right to withdraw from the study at any 
time for any reason, without prejudice to their medical care.  The investigator also 
has the right to withdraw patients from the study for any of the following reasons: 
• Adverse event 
• Protocol violation 
• Lost to follow-up 
• Progressive disease 
• Study terminated  
• Other 
At the time of withdrawal, all study procedures outlined for the End of Study visit 
should be completed. The primary reason for patient’s withdrawal from the study 
should be recorded in the source documents and CRF. 

  
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14.    STATISTICAL AND QUANTITATIVE ANALYSES 
14.1     Statistical Methods 
This phase I trial will use a standard dose-escalation scheme involving cohorts of 
three patients without intra-patient dose escalation.  A total of 9-18 patients will be 
enrolled to determine the safety of ixazomib with fixed VXD.  Adverse events will be 
summarized with descriptive statistics at each dose level of ixazomib.  Objective 
response will be summarized by dose level and overall with descriptive statistics 
such as the objective response rate with a 95% confidence interval. 
 
15.    ADVERSE EVENTS   
15.1     Definitions 
15.1.1   Pretreatment Event Definition 
A pretreatment event is any untoward medical occurrence in a patient or subject 
who has signed informed consent to participate in a study but before administration 
of any study medication; it does not necessarily have to have a causal relationship 
with study participation. 
15.1.2   Adverse Event Definition 
Adverse event (AE) means any untoward medical occurrence in a patient or subject 
administered a pharmaceutical product; the untoward medical occurrence does not 
necessarily have a causal relationship with this treatment.  An AE can therefore be 
any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal 
(investigational) product whether or not it is related to the medicinal product.  This 
includes any newly occurring event, or a previous condition that has increased in 
severity or frequency since the administration of study drug. 

  
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An abnormal laboratory value will not be assessed as an AE unless that value leads 
to discontinuation or delay in treatment, dose modification, therapeutic intervention, 
or is considered by the investigator to be a clinically significant change from 
baseline.   
15.1.3   Serious Adverse Event Definition 
Serious AE (SAE) means any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life-threatening (refers to an AE in which the patient was at risk of death 
at the time of the event.  It does not refer to an event which hypothetically 
might have caused death if it were more severe). 
• Requires inpatient hospitalization or prolongation of an existing 
hospitalization (see clarification in the paragraph below on planned 
hospitalizations). 
• Results in persistent or significant disability or incapacity. (Disability is 
defined as a substantial disruption of a person’s ability to conduct normal life 
functions). 
• Is a congenital anomaly/birth defect. 
• Is a medically important event.  This refers to an AE that may not result in 
death, be immediately life threatening, or require hospitalization, but may be 
considered serious when, based on appropriate medical judgment, may 
jeopardize the patient, require medical or surgical intervention to prevent 1 of 
the outcomes listed above, or involves suspected transmission via a 
medicinal product of an infectious agent.   Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug 

  
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abuse; any organism, virus, or infectious particle (eg, prion protein 
transmitting Transmissible Spongiform Encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent.   
Clarification should be made between a serious AE (SAE) and an AE that is 
considered severe in intensity (Grade 3 or 4), because the terms serious and 
severe are NOT synonymous.  The general term severe is often used to describe 
the intensity (severity) of a specific event; the event itself, however, may be of 
relatively minor medical significance (such as a Grade 3 headache).  This is NOT 
the same as serious, which is based on patient/event outcome or action criteria 
described above, and is usually associated with events that pose a threat to a 
patient’s life or ability to function.  A severe AE (Grade 3 or 4) does not necessarily 
need to be considered serious.  For example, a white blood cell count of 1000/mm3 
to less than 2000 is considered Grade 3 (severe) but may not be considered 
serious.  Seriousness (not intensity) serves as a guide for defining regulatory 
reporting obligations. 
15.2   Procedures for Reporting Serious Adverse Events 
AEs may be spontaneously reported by the patient and/or in response to an open 
question from study personnel or revealed by observation, physical examination, or 
other diagnostic procedures.  Any clinically relevant deterioration in laboratory 
assessments or other clinical finding is considered an AE.  When possible, signs 
and symptoms indicating a common underlying pathology should be noted as one 
comprehensive event.  For serious AEs, the investigator must determine both the 
intensity of the event and the relationship of the event to study drug administration. 
For serious pretreatment events, the investigator must determine both the intensity 
of the event and the relationship of the event to study procedures.  
AEs which are serious must be reported to Millennium Pharmacovigilance (or 
designee) from the first dose of study drug through 30 days after administration of 
the last dose of IXAZOMIB. Any SAE that occurs at any time after completion of 
IXAZOMIB treatment or after the designated follow-up period that the sponsor-

  
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investigator and/or sub-investigator considers to be related to any study drug must 
be reported to Millennium Pharmacovigilance (or designee).  In addition, new 
primary malignancies that occur during the follow-up periods must be reported, 
regardless of causality to study regimen, for a minimum of three years after the last 
dose of the investigational product, starting from the first dose of study drug. All new 
cases of primary malignancy must be reported to Millennium Pharmacovigilance (or 
designee).  Planned hospital admissions or surgical procedures for an illness or 
disease that existed before the patient was enrolled in the trial are not to be 
considered AEs unless the condition deteriorated in an unexpected manner during 
the trial (e.g., surgery was performed earlier or later than planned).  All SAEs should 
be monitored until they are resolved or are clearly determined to be due to a 
patient’s stable or chronic condition or intercurrent illness(es). 
Since this is an investigator-initiated study, the principal investigator Ehab Atallah, 
MD also referred to as the sponsor-investigator, is responsible for reporting serious 
adverse events (SAEs) to any regulatory agency and to the sponsor- investigator’s 
EC or IRB.   Regardless of expectedness or causality, all SAEs (including serious 
pretreatment events) must also be reported in English to Millennium 
Pharmacovigilance (or designee): 
Fatal and Life Threatening SAEs within 24 hours but no later than 4 calendar days 
of the sponsor-investigator’s observation or awareness of the event 
 
All other serious (non-fatal/non-life threatening) events within 4 calendar days 
of the sponsor-investigator’s observation or awareness of the event 
See below for contact information for the reporting of SAEs to Millennium 
Pharmacovigilance.   
The sponsor-investigator must fax or email the SAE Form per the timelines above.  
A sample of an SAE Form will be provided.   
The SAE report must include at minimum: 
• Event term(s),  
• Serious criteria,  

  
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• Intensity of the events (s): Sponsor-investigator’s or sub-investigator’s 
determination of Intensity for each SAE, including any lab abnormalities, will 
be determined by using the NCI CTCAE version specified in the protocol, as 
a guideline, whenever possible.  The criteria are available online at 
http://ctep.cancer.gov/reporting/ctc.html. 
• Causality of the events(s): Sponsor-investigator’s or sub-investigator’s 
determination of the relationship of the event(s) to study drug administration. 
Follow-up information on the SAE may be requested by Millennium.  
Intensity for each SAE, including any lab abnormalities, will be determined by using 
the NCI CTCAE version used at your institution, as a guideline, whenever possible.  
The criteria are available online at http://ctep.cancer.gov/reporting/ctc.html 
In the event that this is a multisite study, the sponsor-investigator is responsible to 
ensure that the SAE reports are sent to Millennium Pharmacovigilance (or 
designee) from all sites participating in the study.  Sub-investigators must report all 
SAEs to the sponsor-investigator so that the sponsor-investigator can meet his/her 
foregoing reporting obligations to the required regulatory agencies and to 
Millennium Pharmacovigilance, unless otherwise agreed between the sponsor-
investigator and sub-investigator(s).   
Relationship to all study drugs for each SAE will be determined by the investigator 
or sub-investigator by responding yes or no to the question: Is there a reasonable 
possibility that the AE is associated with the study drug(s)? 
Sponsor-investigator must also provide Millennium Pharmacovigilance with a copy 
of all communications with applicable regulatory authorities related to the study 
products(s), including, but not limited to, telephone conversation logs, as soon as 
possible but no later than 5 calendar days of such communication. 
 
 

  
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SAE and Pregnancy Reporting Contact Information 
Fax Number: 1-800-963-6290 
Email: TakedaOncoCases@cognizant.com 
Suggested Reporting Form:   
• 
SAE Report Form (a sample is provided by Millennium) 
• 
US FDA MedWatch 3500A:  
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
• 
Any other form deemed appropriate by the sponsor-investigator 
15.3  
Procedures for Reporting Drug Exposure During Pregnancy and Birth 
Events 
If a woman becomes pregnant or suspects that she is pregnant while participating in 
this study, she must inform the investigator immediately and permanently 
discontinue study drug.  The sponsor-investigator must fax a completed Pregnancy 
Form to the Millennium Department of Pharmacovigilance or designee (see Section 
8.2).  The pregnancy must be followed for the final pregnancy outcome. 
If a female partner of a male patient becomes pregnant during the male patient’s 
participation in this study, the sponsor-investigator must also immediately fax a 
completed Pregnancy Form to the Millennium Department of Pharmacovigilance or 
designee (see Section 8.2).  Every effort should be made to follow the pregnancy 
for the final pregnancy outcome. 
Suggested Pregnancy Reporting Form: 
• Pregnancy Report Form (a sample is provided by Millennium)   
 

  
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16.    ADMINISTRATIVE REQUIREMENTS 
16.1  Data and Safety Monitoring 
The Medical College of Wisconsin Cancer Center Data Safety Monitoring 
Committee (DSMC) is responsible for monitoring data quality and subject safety for 
all cancer center investigator initiated clinical trials. A six to 8 member Data and 
Safety Monitoring Committee will complete a review of protocol-specific data safety 
monitoring reports, to provide recommendations on trial continuation, suspension or 
termination. The DSMC will review these reports no less than bi-annually. A 
summary of the DSMC activities are as follows  
• Review the clinical trials for data integrity and safety  
• Review all adverse events requiring expedited reporting as defined per 
protocol  
• Review all DSM reports  
• Submit a summary of any recommendations related to study conduct  
• Terminate the study if deemed unsafe for patients  
DSMC will review each new patient entry following induction. The study should not 
enroll any additional patients until the DSMC reviews the current patient report, and 
after the patient has completed the DLT observation period. The DLT observation 
period will be from first dose of MLN9708 to 28 days after the last dose. Dose 
escalation to a higher dose level will require the last patient on the previous dose 
level to be out of the DLT observation period. 
 
16.2  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.  Individuals who identify a potential product complaint situation should 
immediately contact MedComm Solutions (see below) and report the event.  

  
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Whenever possible, the associated product should be maintained in accordance 
with the label instructions pending further guidance from a Millennium Quality 
representative. 
 
 
For Product Complaints, 
call MedComm Solutions at 
877-674-3784 (877 MPI DRUG)  
(US and International) 
 
Product complaints in and of themselves are not AEs.  If a product complaint results 
in an SAE, an SAE form should be completed and sent to Millennium 
Pharmacovigilance(refer to Section 8.2). 

  
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17.    REFERENCES    
1. 
Assouline S, Chang J, Rifkin R, et al. MLN9708, a Novel, Investigational 
Proteasome Inhibitor, in Patients with Relapsed/Refractory Lymphoma: Results of a Phase 1 
Dose-Escalation Study. ASH Annual Meeting Abstracts;118:2672. 
2. 
Kumar S, Bensinger W, Reeder CB, et al. Weekly dosing of the investigational oral 
proteasome inhibitor MLN9708 in patients (pts) with relapsed/refractory multiple myeloma 
(MM): A phase I study. ASCO Meeting Abstracts;30:8034. 
3. 
Richardson PG, Baz R, Wang L, et al. Investigational Agent MLN9708, An Oral 
Proteasome Inhibitor, in Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma 
(MM): Results From the Expansion Cohorts of a Phase 1 Dose-Escalation Study. ASH 
Annual Meeting Abstracts;118:301. 
4. 
Rodler ET, Infante JR, Siu LL, et al. First-in-human, phase I dose-escalation study of 

  
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investigational drug MLN9708, a second-generation proteasome inhibitor, in advanced 
nonhematologic malignancies. ASCO Meeting Abstracts;28:3071. 
5. 
Berdeja JG, Richardson PG, Lonial S, et al. Phase 1/2 Study of Oral MLN9708, A 
Novel, Investigational Proteasome Inhibitor, in Combination with Lenalidomide and 
Dexamethasone in Patients with Previously Untreated Multiple Myeloma (MM). ASH 
Annual Meeting Abstracts;118:479. 
6. 
Gupta N, Saleh M, Venkatakrishnan K. Flat-Dosing Versus BSA-Based Dosing for 
MLN9708, An Investigational Proteasome Inhibitor: Population Pharmacokinetic (PK) 
Analysis of Pooled Data From 4 Phase-1 Studies 53rd ASH Annual Meeting and Exposition; 
2011 10-13 Dec; San Diego, CA. p. abstr 1433. 
7. 
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA: A Cancer Journal for 
Clinicians;63:11-30. 
8. 
Jing D, Bhadri VA, Beck D, et al. Opposing regulation of BIM and BCL2 controls 
glucocorticoid-induced apoptosis of pediatric acute lymphoblastic leukemia cells2015. 
9. 
Oriol A, Vives S, Hernandez-Rivas JM, et al. Outcome after relapse of acute 
lymphoblastic leukemia in adult patients included in four consecutive risk-adapted trials by 
the PETHEMA Study Group. Haematologica;95:589-96. 
10. 
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18.    APPENDICES 
18.1     Eastern Cooperative Oncology Group (ECOG) Scale for Performance 
Status 
Grade 
Description 
0 
Normal activity.  Fully active, able to carry on all predisease 
performance without restriction 
1 
Symptoms but ambulatory.  Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of a light or sedentary 
nature (eg, light housework, office work) 
2 
In bed < 50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% 
of waking hours. 
3 
In bed > 50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-
care.  Totally confined to bed or chair 
5 
Dead 
Source:  Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET 
et al. Toxicity and response criteria of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol 1982; 5 (6):649-55.48 
 
 
 
 
 
 
 
   
 

  
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18.2     Response Criteria 
 
CR—M1 (<5% blasts) bone marrow with no evidence of circulating blasts or 
extramedullary disease and with recovery of peripheral counts (absolute neutrophil 
count (ANC) >750/µl and platelet count >75,000/µl).  
 
CR without platelet recovery (CRp), M1 bone marrow with no circulating blasts or 
extramedullary disease and recovery of ANC >750/µl, but insufficient recovery of 
platelets (<75,000/µl);  
 
Partial remission (PR), complete disappearance of circulating blasts and 
achievement of M2 (5–25% blasts) marrow status, without new sites of 
extramedullary disease, and with recovery of absolute neutrophil counts (ANC 
>750/µl) 
 
Stable disease (SD), does not satisfy the criterion for PD, or has recovery of ANC 
>750/µl but fails to qualify for CR, CRp, or PR;  
 
Progressive disease (PD), an increase of at least 25% in the absolute number of 
circulating leukemic cells, development of new sites of extramedullary disease, or 
other laboratory or clinical evidence of PD, with or without recovery of ANC or 
platelets.  
 
 
 
 
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