Clinical trial NCT01887587
Conditions: Relapsed or Refractory Acute Lymphoblastic Leukemia Relapsed or Refractory Lymphoblastic Lymphoma Mixed Phenotype Acute Leukemia
Sponsor: Ehab L Atallah
Start date: 2013-06-01; Completion date: 2016-02-29
Enrollment: 5 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a phase I study of vincristine, doxorubicin and dexamethasone (modified VXD) plus MLN9708 in adults with relapsed or refractory acute lymphoblastic leukemia/lymphoma, lymphoblastic lymphoma or mixed phenotype acute leukemia.

Detailed description:
In this phase I study, escalating doses of MLN9708 will be combined with a fixed dose modified VXD regimen. The study drug, MLN9708, will be administered on day 1, 8, and 15. If the patient experiences a dose limiting toxicity (DLT) the dose of MLN9708 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 thought to be probably or definitely related to MLN9708. Three patients will be treated per dose level unless DLT is observed. The starting dose of MLN9708 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. 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. If patients achieve complete response (CR) and are eligible for hematopoietic stem cell transplantation (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 maybe repeated at the discretion of the investigator. A total of 9-18 patients will be enrolled on the study. The study duration would be about 2 years.

Arms: arm 1: Vincristine-1.5 mg/m2 to a max dose of 2 mg IV on days 1, 8, 15 and 22

Dexamethasone- 10 mg/m2 orally or IV on days 1-14

Doxorubicin- 60 mg/m2 on day 1 by IV bolus.

MLN9708 (Ixazomib)- 2.3 mg orally on days 1, 8 and 15. Escalations will be to 3mg or 4 mg, respectively, on days 1, 8 and 15 based on the dosing schema.

For patients without central nervous system (CNS) involvement:

* Cytarabine 100 mg administered intrathecally on day 1 (cytarabine dose should be reduced to 50 mg if given through a central ommaya reservoir)
* Methotrexate 12 mg administered intrathecally on day 8

For patients with CNS involvement:

-Cytarabine 100 mg 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 1, 8, 15 and 22 (+/-1 day)).
Interventions: intervention 1: MLN9708 intervention 2: Vincristine intervention 3: Doxorubicin intervention 4: Dexamethasone
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol documents:
Prot_SAP_000.pdf: 
  
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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 
associated with apoptosis or programmed cell death. Doxorubicin induced 


  
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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), 
sensorimotor dysfunction, sensory loss 


  
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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, 
thromboembolism, vasculitis 


  
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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. 
Fielding AK, Richards SM, Chopra R, et al. Outcome of 609 adults after relapse of 
acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood 
2007;109:944-50. 
11. 
Gokbuget N, Stanze D, Beck J, et al. Outcome of relapsed adult lymphoblastic 
leukemia depends on response to salvage chemotherapy, prognostic factors, and 
performance of stem cell transplantation. Blood;120:2032-41. 
12. 
O'Brien S, Thomas D, Ravandi F, et al. Outcome of adults with acute lymphocytic 
leukemia after second salvage therapy. Cancer 2008;113:3186-91. 
13. 
Ko RH, Ji L, Barnette P, et al. Outcome of Patients Treated for Relapsed or 
Refractory Acute Lymphoblastic Leukemia: A Therapeutic Advances in Childhood 
Leukemia Consortium Study. Journal of Clinical Oncology;28:648-54. 
14. 
Faderl S, Thomas DA, O'Brien S, et al. Augmented hyper-CVAD based on dose-
intensified vincristine, dexamethasone, and asparaginase in adult acute lymphoblastic 
leukemia salvage therapy. Clin Lymphoma Myeloma Leuk;11:54-9. 
15. 
Advani AS, Gundacker HM, Sala-Torra O, et al. Southwest Oncology Group Study 
S0530: a phase 2 trial of clofarabine and cytarabine for relapsed or refractory acute 
lymphocytic leukaemia. Br J Haematol;151:430-4. 
16. 
GÃ¶kbuget N, Basara N, Baurmann H, et al. High single-drug activity of nelarabine 
in relapsed T-lymphoblastic leukemia/lymphoma offers curative option with subsequent 
stem cell transplantation. Blood;118:3504-11. 
17. 
Commander LA, Seif AE, Insogna IG, Rheingold SR. Salvage therapy with 
nelarabine, etoposide, and cyclophosphamide in relapsed/refractory paediatric T-cell 
lymphoblastic leukaemia and lymphoma. British Journal of Haematology;150:345-51. 
18. 
Raetz EA, Borowitz MJ, Devidas M, et al. Reinduction platform for children with 
first marrow relapse of acute lymphoblastic Leukemia: A Children's Oncology Group 
Study[corrected]. J Clin Oncol 2008;26:3971-8. 
19. 
Kantarjian H, Thomas D, Jorgensen J, et al. Inotuzumab ozogamicin, an anti-
CD22â€“calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: 
a phase 2 study. The Lancet Oncology;13:403-11. 


  
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20. 
Topp MS, Goekbuget N, Zugmaier G, et al. Anti-CD19 BiTE Blinatumomab Induces 
High Complete Remission Rate In Adult Patients with Relapsed B-Precursor ALL: Updated 
Results of An Ongoing Phase II Trial. ASH Annual Meeting Abstracts;118:252-. 
21. 
Messinger YH, Gaynon PS, Sposto R, et al. Bortezomib with chemotherapy is highly 
active in advanced B-precursor acute lymphoblastic leukemia: Therapeutic Advances in 
Childhood Leukemia & Lymphoma (TACL) Study. Blood;120:285-90. 
22. 
Horton TM, Gannavarapu A, Blaney SM, D'Argenio DZ, Plon SE, Berg SL. 
Bortezomib interactions with chemotherapy agents in acute leukemia in vitro. Cancer 
Chemother Pharmacol 2006;58:13-23. 
23. 
Houghton PJ, Morton CL, Kolb EA, et al. Initial testing (stage 1) of the proteasome 
inhibitor bortezomib by the pediatric preclinical testing program. Pediatric Blood & Cancer 
2008;50:37-45. 
24. 
Messinger Y, Gaynon P, Raetz E, et al. Phase I study of bortezomib combined with 
chemotherapy in children with relapsed childhood acute lymphoblastic leukemia (ALL): A 
report from the therapeutic advances in childhood leukemia (TACL) consortium. Pediatric 
Blood & Cancer;55:254-9. 
25. 
Kumatori A, Tanaka K, Inamura N, et al. Abnormally high expression of 
proteasomes in human leukemic cells. Proc Natl Acad Sci U S A 1990;87:7071-5. 
26. 
Naujokat C, Sezer O, Zinke H, Leclere A, Hauptmann S, Possinger K. Proteasome 
inhibitors induce caspase-dependent apoptosis and accumulationof p21WAF1/Cip1 in 
human immatureleukemic cells. European Journal of Haematology 2000;65:221-36. 
27. 
Cortes J, Thomas D, Koller C, et al. Phase I Study of Bortezomib in Refractory or 
Relapsed Acute Leukemias. Clinical Cancer Research 2004;10:3371-6. 
28. 
Messinger YH, Gaynon P, Sposto R, et al. Bortezomib Combined with VXLD 
Chemotherapy Is Highly Effective In Advanced B-Lineage Acute Lymphoblastic Leukemia 
Allowing Early Study Termination Due to Efficacy. A Therapeutic Advances in Childhood 
Leukemia (TACL) Consortium Phase II Study. ASH Annual Meeting Abstracts;118:251-. 
29. 
Bianchi G, Ramakrishnan VG, Kimlinger T, Haug J, Rajkumar SV, Kumar S. 
Investigational Agent MLN2238/MLN9708, a Specific, Orally Available, Small Molecule 
Proteasome Inhibitor, Shows Promising In Vitro Activity Against Multiple Myeloma Cell 
Lines. ASH Annual Meeting Abstracts;116:3014. 
30. 
Chauhan D, Tian Z, Zhou B, et al. In Vitro and In Vivo Selective Antitumor Activity 
of a Novel Orally Bioavailable Proteasome Inhibitor MLN9708 against Multiple Myeloma 
Cells. Clinical Cancer Research;17:5311-21. 
31. 
Gu J, Czuczman NM, Kaufman GP, Mavis C, Hernandez-Ilizaliturri FJ, Czuczman 
MS. The Novel Proteasome Inhibitor Carfilzomib (CFZ) Potentiates the Anti-Tumor 
Activity of Chemotherapeutic Agents in Rituximab-Chemotherapy Resistant Lymphoma 
Through Inducing G2/M Cell Cycle Arrest and Cell Death. ASH Annual Meeting 
Abstracts;118:4970-. 
32. 
Kupperman E, Lee EC, Cao Y, et al. Evaluation of the Proteasome Inhibitor 
MLN9708 in Preclinical Models of Human Cancer. Cancer Research;70:1970-80. 
33. 
Wetzler M, Sanford BL, Kurtzberg J, et al. Effective asparagine depletion with 
pegylated asparaginase results in improved outcomes in adult acute lymphoblastic leukemia: 
Cancer and Leukemia Group B Study 9511. Blood 2007;109:4164-7. 
34. 
Stock W, Douer D, DeAngelo DJ, et al. Prevention and management of 
asparaginase/pegasparaginase-associated toxicities in adults and older adolescents: 


  
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recommendations of an expert panel. Leukemia & Lymphoma;52:2237-53. 
35. 
Aldoss I, Lunning MA, Avramis VI, et al. High-Grade Pegylated Asparaginase-
Related Hepatotoxicity Occurrence In a Pediatric-Inspired Adult Acute Lymphoblastic 
Leukemia Regimen Does Not Necessarily Predict Recurrent Hepatotoxicity In Subsequent 
Cycles2013. 
36. 
Larson RA, Dodge RK, Burns CP, et al. A five-drug remission induction regimen 
with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and 
leukemia group B study 8811. Blood 1995;85:2025-37. 
37. 
Horton T. Yin and yang of glucocorticoid receptors in apoptosis2015. 
38. 
Elias L, Shaw MT, Raab SO. Reinduction therapy for adult acute leukemia with 
adriamycin, vincristine, and prednisone: a Southwest Oncology Group study. Cancer 
treatment reports 1979;63:1413-5. 
39. 
Kantarjian HM, O'Brien S, Smith T, et al. Acute lymphocytic leukaemia in the 
elderly: characteristics and outcome with the vincristine-adriamycin-dexamethasone (VAD) 
regimen. Br J Haematol 1994;88:94-100. 
40. 
Swerdlow S, Campo E, Harris N, et al. WHO classification of tumours of 
haematopoietic and lymphoid tissues. IARC, Lyon. 2008. 
41. 
Thomas DA, O'Brien S, Cortes J, et al. Outcome with the hyper-CVAD regimens in 
lymphoblastic lymphoma2004. 
42. 
Wolach O, Stone RM. How I treat mixed phenotype acute leukemia2015. 
43. 
Aribi A, Bueso-Ramos C, Estey E, et al. Biphenotypic acute leukaemia: a case 
series. British Journal of Haematology 2007;138:213-6. 
44. 
Matutes E, Pickl WF, Van't Veer M, et al. Mixed-phenotype acute leukemia: clinical 
and laboratory features and outcome in 100 patients defined according to the WHO 2008 
classification. Blood 2011;117:3163-71. 
45. 
Zhang Y, Wu D, Sun A, et al. Clinical characteristics, biological profile, and 
outcome of biphenotypic acute leukemia: a case series. Acta haematologica 2011;125:210-8. 
46. 
Gupta N, Liu G, Berg D, Kalebic T, Gomez-Navarro J. Clinical Pharmacokinetics of 
Intravenous and Oral MLN9708, An Investigational Proteasome Inhibitor: An Analysis of 
Data From Four Phase 1 Monotherapy Studies. Blood (ASH Annual Meeting Abstracts) 
2010;116:abstr 1813. 
47. 
Common Terminology Criteria for Adverse Events (CTCAE). 2010. 
48. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the 
Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-55. 
 


  
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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.  
 
 
 
 
i  
                                                 

ICF_001.pdf: 
Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A - Version: October 1, 2012 
 
IRB Protocol Number: PRO00020384  
IRB Approval Period: 8/11/2015 – 12/9/2015  
Page 1 of 20 
MCW Version: 08-13-15 
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8/14/2015 
 
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Medical College of Wisconsin and Froedtert Hospital 
CONSENT TO PARTICIPATE IN RESEARCH 
 
Name of Study Subject: ____________________________ 
 
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 
 
Ehab Atallah, MD 
Froedtert & Medical College of Wisconsin 
Division of Hematology and Oncology 
9200 W. Wisconsin Avenue 
Milwaukee, WI 53226-0509 
414-805-6800 
 
You are invited to take part in this research study. This form tells you why this research 
study is being done, what will happen in the research study, possible risks and benefits 
to you, your choices, and other important information. If there is anything that you do not 
understand, please ask questions. Then you can decide if you want to join this study or 
not.   
 
A1. INTRODUCTION – WHY ARE WE ASKING YOU ABOUT THIS STUDY? 
 
You are being invited to participate in this research study because you have relapsed or 
refractory acute lymphoblastic leukemia/lymphoma or mixed phenotype acute leukemia.  
 
A total of about 18 people are expected to participate in this study at the Medical 
College of Wisconsin/Froedtert Hospital. 
 
The Director of the study is Ehab Atallah, MD in the Department of Medicine. A study 
team works with Dr. Atallah. You can ask who these people are.  
 
Millennium Pharmaceuticals, Inc. provides financial support to the Medical College of 
Wisconsin, including Dr. Atallah and other key members of his/her study staff, for work 
on this study as well as others being conducted at the Medical College of Wisconsin. 
Previously a sub-investigator for this study reviewed safety data for another Millennium 
study.  This sub-investigator received compensation for the work he did reviewing the 
safety data. Dr. Atallah is the sponsor of the study. 
 
A2. DO I HAVE TO BE IN THIS STUDY? 
 
You can decide whether to take part in this study or not. You are free to say yes or no. If 
you say no, your regular medical care will not change. Even if you join this study, you do 
not have to stay in it. You may stop at any time.  


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A - Version: October 1, 2012 
 
IRB Protocol Number: PRO00020384  
IRB Approval Period: 8/11/2015 – 12/9/2015  
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A research study is different from routine medical care in three ways: 1) there are extra 
risks that we will tell you about in this form; 2) you may have some extra medical tests 
and visits; 3) the study procedures, tests and visits follow a set plan that must be kept. 
 
A3. WHY IS THIS RESEARCH STUDY BEING DONE? 
 
Ixazomib  is a new drug which so far has been mostly used in studies for multiple 
myeloma patients either alone or with other combination of drugs.  To date 
approximately 300 patients have been treated with oral Ixazomib either alone or with 
other combinations of drugs. 
  
In this study we want to find out more about the side effects (problems and symptoms) 
and what doses are safe using a new drug Ixazomib in combination with modified VXD 
(vincristine, doxorubicin, and dexamethasone) for relapsed or refractory acute 
lymphoblastic leukemia/lymphoma. Everyone in this study will receive Ixazomib which is 
still experimental and is not approved by the U.S. Food and Drug Administration.   
 
B1. WHAT WILL HAPPEN IF I TAKE PART IN THE STUDY?   
 
STUDY DRUGS 
 
The duration of your treatment will depend upon how you are feeling, how well you 
tolerate the study drug and how your disease responds to the study drug.  If you are 
responding to therapy you could continue to receive the study treatment for up to two 
cycles (1 cycle = 28 days). 
 
You will receive the following drugs while you are on the study: 
 
Vincristine: You will be given 1.5 mg/m2 to a maximum dose of 2 mg through a vein 
(IV) on days 1, 8, 15 and 22. 
 
 
Dexamethasone:  You will be given 10 mg/m2 of Dexamethasone by mouth (orally) or 
through a vein (IV) on days 1-14. 
 
Doxorubicin:  You will be given 60 mg/m2 of Doxorubicin on day 1 through a vein (IV).  
 
Cytarabine and Methotrexate:  A lumbar puncture (also known as a "spinal tap") to 
diagnose and treat any ALL cells that have infiltrated into the central nervous system 
(CNS) will be done.  At that time you will be given: 
 
 
 
For patients without CNS involvement:  


Medical College of Wisconsin & Froedtert Hospital  
 
 
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Cytarabine: You will be given 100 mg by an injection into the spinal fluid 
(intrathecally) on day 1  (+/-1 day) (cytarabine dose should be reduced to 50 mg 
if given through a central ommaya reservoir). 
Methotreaxte:  You will be given 12 mg by an injection into the spinal fluid 
(intrathecally) on day 8  (+/-1 day). 
 
For patients with CNS involvement: 
Cytarabine: You will be given 100 mg by an injection into the spinal fluid 
(intrathecally) on day 1 (+/-1 day) (cytarabine dose should be reduced to 50 mg if 
given through a central ommaya reservoir). 
Cytarabine: You will be given 30 mg an injection into the spinal fluid 
(intrathecally) on (Days,8, 15 and 22  (+/-1 day)). 
Methotrexate: 15 mg an injection into the spinal fluid (intrathecally) on (Days,8, 
15 and 22  (+/-1 day)) 
Hydrocortisone: 15 mg an injection into the spinal fluid (intrathecally) on 
(Days,8, 15 and 22  (+/-1 day)). 
 
Ixazomib:  You will be given Ixazomib by mouth (orally) on weekly on days 1, 8 and 15. 
There are 3 groups.  Up to 6 patients will be enrolled in each group.   
 
Group 1:  Will receive 2.3 mg orally (dose level 1) 
Group 2:  Will receive 3.0 mg orally (dose level 2) 
Group 3:  Will receive 4.0 mg orally (dose level 3) 
 
Your study doctor may decide to adjust your dose of any of the medications 
above if he/she feels this is necessary. 
 
STUDY PROCEDURES 
 
Before any tests or procedures are done, you will be asked to sign this consent form. 
The study doctor will discuss the study with you and answer your questions.   
If you decide to join the study, some screening tests will be done first to see if you are 
eligible.  
 
Some of these tests and procedures are considered ‘standard of care’ which means that 
they would be done even if you were not participating in this research study and some 
are considered for research purpose which means they are being done only because 
you have agreed to be in this research study. 
 
At every visit, you will be asked what medications you are taking or have taken since 
your last visit. You will also be asked how you are feeling and if you are having or have 
had any symptoms or side effects from your last visit.   
 
Below is a list of the tests and procedures which will be done during the study.   
 


Medical College of Wisconsin & Froedtert Hospital  
 
 
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IRB Protocol Number: PRO00020384  
IRB Approval Period: 8/11/2015 – 12/9/2015  
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• 
Complete Medical history & Demographics:  A complete medical history will 
be taken including any medications you have used or are currently using, and 
any therapies you have had.   
• Physical exam: A physical exam will be done including your height and weight.  
Your height will only be measured during the screening period.  This will also 
include an exam of your nervous system.  
• Vital signs:  This will include your heart rate, blood pressure and temperature.  
• Eastern Cooperative Oncology Group (ECOG) Performance Status: This is a 
scale which will be used by your study doctor to assess how the disease affects 
your daily living abilities.   
• Blood samples (disease assessments, hematology, chemistry, 
coagulation): Blood samples will be taken to determine the state of your disease 
and later to determine how well you are responding to the study treatment.   
o Hematology and Chemistry: These blood samples (about 2 ½ 
tablespoons) will be used to evaluate your blood counts and blood 
chemistry (this includes tests of liver and kidney function, blood sugar, 
minerals and proteins).  These results will be used to see if you are well 
enough to receive the study drugs.   
o Direct Bilirubin:  This blood sample will be used to see how your liver is 
functioning. 
o Fibrinogen: This blood sample (about ½ teaspoon) will test to see how 
well your blood clots.   
o Serum or Urine Pregnancy test:  If you are a woman that is child 
bearing, a blood sample or urine sample will be taken to make sure you 
are not pregnant; you cannot be in this study if you are pregnant, or if you 
are planning to become pregnant.   
• Echocardiogram (ECHO) or MUGA:  These tests are to measure your heart’s 
rhythm and the strength of your heart’s contractions.   
•    Bone marrow biopsy or aspirate: These samples will be tested to look at your 
disease at the beginning of the study and measure the amount of disease you 
have and how your disease responds to treatment. For this procedure, a 
numbing drug is injected into the skin over one of your hipbones.  A needle is 
then inserted into the hipbones and a small piece of bone and/or fluid is 
removed.  
 
Optional Correlative Study Sample 
 
Dr. Atallah would also like to keep a portion of your bone marrow or blood sample for 
future research studies in the institutional bank.  These optional samples will be taken 
either from your bone marrow or blood at the same time that you get your other 
standard of care tests completed.  You will be asked to sign a separate consent that 
will detail how the samples are stored and when the samples are taken if you are 


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A - Version: October 1, 2012 
 
IRB Protocol Number: PRO00020384  
IRB Approval Period: 8/11/2015 – 12/9/2015  
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8/14/2015 
 
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interested in participating in these optional samples.  Talk to a member of the 
study team if you are interested in hearing more about this option. 
 
STUDY PERIODS 
 
This study is split up into 4 different periods: Screening, Treatment, End of Treatment, 
Follow-up.   
 
Screening:  
 
After you have agreed to participate in the study and have signed this form, you will 
enter screening which can last up to 14 days before you receive the first dose of study 
drug. You will have tests and evaluations as listed below, to determine if you are eligible 
to participate in the study.  If you have had some of the tests or procedures described 
below recently they may not need to be repeated. 
 
• Medical History & Demographics 
• Complete physical exam 
• Vital signs 
• Height and Weight 
• ECOG Performance Status 
• Blood samples (hematology, chemistry, direct bilirubin, fibrinogen) 
• Pregnancy test (if female and child bearing) 
• ECHO or MUGA 
• Bone Marrow biopsy/aspirate within 4 weeks of week 1 
 
If the screening information shows that you meet the requirements, then you will be able 
to start the study. If the screening information shows that you are not eligible for the 
study, the study doctors will discuss other options with you and/or refer you back to your 
regular doctor.  
 
Treatment:  
Once it has been determined that you are eligible to participate in this study, you will be 
enrolled and you will begin taking the study drug combination (Ixazomib with modified 
VXD).   
The following are the procedures that will occur during the treatment period of the study.  
These may change slightly if your doctor feels it is in your best interest. 
Cycles 1 and 2 Week 1 
 
• Medical History  
• Complete physical exam 
• Vital signs 


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A - Version: October 1, 2012 
 
IRB Protocol Number: PRO00020384  
IRB Approval Period: 8/11/2015 – 12/9/2015  
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• Weight 
• ECOG Performance Status 
• Blood samples (hematology, chemistry, fibrinogen) 
Weekly 
 
• Blood samples (hematology, chemistry, direct bilirubin, fibrinogen) 
 
Every 2 Weeks 
 
• Complete physical exam 
• ECOG Performance Status 
• Vitals 
 
Every 4 Weeks 
 
• Bone Marrow biopsy/aspirate 
 
End of Treatment or Early Termination 
 
End of Study 
 
The following will be performed when your participation in the study ends early or 
you complete the treatment phase of the study: 
 
• Complete physical exam 
• Vital signs 
• Weight 
• Blood samples (hematology, chemistry) 
• Bone Marrow biopsy/aspirate 
 
Follow-Up 
 
Progression Free Survival (PFS) Follow-up 
 
After the end of treatment, if you were removed from the study for any reason other 
than your disease getting worse, you will be asked to return to the clinic monthly to 
monitor your disease status.  This will continue until your disease worsens.    
 
Overall Survival (OS) Follow-up 
 
If your study treatment was stopped because your disease got worse, then you will 
be contacted by the clinic yearly to monitor how you are doing.   
 
B2. HOW LONG WILL I BE IN THE STUDY? 


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A - Version: October 1, 2012 
 
IRB Protocol Number: PRO00020384  
IRB Approval Period: 8/11/2015 – 12/9/2015  
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You will take the study medication for up to two cycles (1 cycle =28 days). When study 
treatment ends, you will be followed until the study completed. 
 
B3. CAN I STOP BEING IN THE STUDY?   
 
You are free to withdraw from the study at any time. If you leave, your regular medical 
care will not change. If you are thinking about leaving, please tell the study doctor.  
 The doctor can tell you about the effects of stopping, and you and the doctor can talk 
about what follow-up care would help you the most. 
 You might be asked to come back for one more visit to check your health. 
 
The study doctor may take you out of this study at any time. This would happen if: 
• 
They think it is in your best interest. 
• 
You do not follow the study rules. 
• 
The whole study is stopped. 
If this happens, the study doctor will tell you. 
 
B4. ARE THERE ANY SPECIAL INSTRUCTIONS WHILE I AM IN THE STUDY?  
 
• Your Ixazomib should be taken on an empty stomach (no food or drink) at least 1 
hour before or 2 hours after a meal. 
• Missed doses of Ixazomib can be taken as soon as you remember as long as the 
next scheduled dose is 72 hours or more away.  If you vomit after ingestion, you 
should not take an additional dose, but should resume dosing at the time of the 
next scheduled dose. 
 
C1. WHAT HEALTH RISKS OR PROBLEMS CAN I EXPECT FROM THE STUDY? 
 
There are risks to taking part in any research study. There is a risk that you may get a 
drug, drug combination or dose of a drug that does not help your condition or may make 
it worse.  There also may be problems (side effects) we do not know about yet, from 
drug itself, or how it combines with other drugs you are taking. If we learn about new 
important side effects, we will tell you.  
 
We watch everyone in the study for problems (side effects). You need to tell the study 
doctor or a member of the study team immediately if you experience any 
problems, side effects, or changes in your health.  If you have problems, call Dr. 
Atallah immediately at 414-805-6800. In an emergency, call 911. 
 
C2. RISKS OF TREATMENT 
 
The research drug itself may cause problems (side effects).  Side effects may be mild or 
very serious.  Some can last a long time or never go away.  Many go away soon after 
you stop taking the drug. Drugs can affect individuals in different ways. . Complications 


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of some of the side effects below may lead to life-threatening events such and possibly 
death. 
 
 
The side effects that other people have experienced so far with the drugs are:  
 
Ixazomib 
 
Based on studies of Ixazomib that are using both an intravenous (IV) liquid and an oral 
(pill), it is possible to predict some of the discomforts and risks.  However, it is possible 
that Ixazomib may cause risks that have not yet been observed in patients.  The 
following risks might be seen: 
 
o Low platelet count which may increase the chance of bleeding 
o Skin rash which may range from some red areas, small flat spots, or small 
raised bumps that may or may not be itchy in a few areas or all over the 
body  
o Feeling tired or weak  
o Nausea  
o Vomiting  
o Diarrhea  
o Numbness or tingling or pain feelings in hands and feet  
o Fever  
o Constipation  
o Lowered red cells or anemia which may make you feel tired;  
o Lowered white blood cells called neturophils that may increase your risk of 
infection  and may be associated with fever  
o Distortion of the sense of taste i.e. an abnormal or impaired sense of 
taste.  
o Trouble falling asleep, staying asleep or both  
• Other discomforts and  risks reported in studies with Ixazomib, which may have 
been due to the patient’s disease, Ixazomib, other medications, or some 
combination of these include: 
o Not feeling like eating  
o Electrolyte imbalance (blood chemical imbalance)  
o Loss of water from the body (dehydration) because of vomiting and/or 
loose stools  
o High blood creatinine and renal failure, which means your kidneys are 
having trouble working well; Patients who had lost body water 
(dehydration) because of vomiting and/or loose stools have had high 
levels of creatinine indicating that the kidneys were failing to function 
adequately. In some severe situations, less kidney function may require 
temporary treatment with a machine that supports the function of the 
kidney (dialysis)  
o Headache  


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o Flu-like symptoms and other upper respiratory tract infections  
o Feeling short of breath  
o Lung infections including pneumonia or pneumonitis  
o Cough  
o Chills  
o Pain in the abdomen  or back  
o Swelling or fluid buildup in the arms or legs  
o General aches or pains in muscles, joints, bones, or arms and legs  
o Feeling dizzy  
o Lowered blood pressure  that can commonly cause you to feel light 
headed, faint or pass out when you stand up  
o Lowered white blood cells called lymphocytes  
o Pain (muscular) in extremities  
 
Some discomforts and risks that occur with lesser frequency (<1%) than those 
mentioned above, should be noted because they are severe, life-threatening or 
fatal.  With limited experience, we do not know if Ixazomib causes such 
problems.  Stevens Johnson’s Syndrome, a severe, life-threatening or deadly condition 
that may involve rash, skin peeling and mouth sores has been reported in ongoing 
Ixazomib studies.  Stevens Johnson Syndrome is a disorder of the immune system, 
which differs from a regular skin rash.  
 
In addition posterior reversible encephalopathy syndrome has also been reported with 
Ixazomib with lesser frequency (<1%). This condition affects the brain and may cause 
headaches, changes in your vision, changes in your mental status, or seizures (fits), but 
is usually reversible.   
 
 Additionally, it is worth noting that: 
 
• Ixazomib is similar to the drug known as VELCADE ® (bortezomib) for Injections, 
which is approved for the treatment of multiple myeloma (a cancer of the plasma 
cell), as well as mantle cell lymphoma (a cancer of the lymph nodes) in patients 
who have received at least one prior therapy. 
• Ixazomib, like Velcade, should not be taken if you have ever had an allergic 
reaction to boron or boron containing products. 
 
•  The following side effects have been reported with VELCADE use and therefore 
may also be a risk with Ixazomib: 
 
o Reactivation of the herpes virus infection such as herpes zoster (shingles) 
that can sometimes cause local pain that may last after recovery from the 
skin rash and does not go away for some time;  and 
o Rapid death of cancer cells that may let large amounts of the cells into the 
blood that injure organs, such as kidneys (this is referred to as tumor lysis 


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syndrome).  Your study doctor can talk with you about other common side 
effects with VELCADE use.  
 
• The more severe but rare side effects seen with VELCADE, include but are not 
limited to,  worsening of your heart function (congestive heart failure), disorders 
that could affect the function of your lung that could be serious enough to result 
in death, and liver failure. Your doctor can talk to you further about the risks of 
VELCADE. 
 
• Other drugs and supplements may affect the way Ixazomib works.  Tell your 
doctor about all drugs and supplements you are taking while you are in this 
study. 
 
Vincristine Side Effects: 
 
• Hair loss that is often reversible 
• Lowered white blood cells, that may increase the risk of infection 
• Lowered platelets;  that may increase the chance of bleeding  
• Lowered red cells or anemia which may make you feel tired 
• Damage to nerves that may result in numbness, tingling sensation, nerve pain, 
difficulty walking which may continue through the duration of treatment, and perhaps 
longer after treatment has stopped. These events may be worse if you have a pre-
existing condition that affects the muscles or the nerves of the muscles 
• Loss of muscle coordination, tremors, muscle weakness or muscle wasting, muscle 
aches 
• Back pain, jaw pain, throat pain, bone pain, limb pain 
• Weakness and loss of muscle tone 
• Constipation, impaction of the colon bloating, bowel blockage, damage to the 
intestine, holes in the intestine or death of intestinal tissue 
• Abdominal cramps, weight loss and loss of appetite 
• Nausea, vomiting 
• Ulcers or sores in the mouth and throat 
• Diarrhea 
• Increased or decrease in urination, difficulty urinating, burning upon urination or 
worsening of kidney function 
• High blood pressure, or low blood pressure, development of heart disease if you 
have previously been treated with radiation therapy to the chest 
• Shortness of breath, trouble breathing, which can start suddenly and be severe and 
require treatment 
• Rash 
• Severe headache 
• Fast death of cancer cells that may let toxins into the blood and injure organs, such 
as the kidneys 


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Vincristine Rare Side Effects: 
 
• Allergic reactions which include sudden serious reactions, rash, swelling, which can 
be life- threatening 
• If vincristine leaks out of the vein into the surrounding  tissue it may cause tissue 
irritation, damage or tissue death 
• Convulsions that may occur with high blood pressure 
• Loss of facial nerve control (or paralysis), for example, of the throat muscles, or the 
eye muscles 
• Damage to the optic nerve resulting in blindness 
• Paralysis, foot drop, change in gait 
• Development of other cancers 
• Change in the levels of certain drugs 
• Changes in the level of sodium in the blood 
• You should not receive vincristine if you have the demyelinating form of Charcot-
Marie-Tooth syndrome (loss of muscle tissue and touch sensation,) 
 
Doxorubicin Common Side Effects: 
 
Common side effects are those that have occurred in greater than or equal to 30% of 
patients who have received Doxorubicin:  
• Fatigue, weakness 
• Temporary decrease in white blood cells that could cause increased your risk of 
infections 
• Low platelets that may affect the ability of your blood to clot 
• Nausea and vomiting shortly after dosing, which can be severe 
• Thin hair, brittle hair, complete hair loss that is reversible  
• Painful sores in the throat or mouth that may cause difficulty in swallowing  
• Red discoloration of urine  
• Blood clotting disorders and anemia (lack of red blood cells)  
 
Doxorubicin Less Common Side Effects: 
 
Less common side effects are those that have occurred in 10-29% of patients who have 
received Doxorubicin: 
• Diarrhea, loss of appetite, dehydration, weight loss 
• Injection site reactions including swelling, pain, redness or tissue damage. If 
doxorubicin leaks into the surrounding tissue it may lead to tissue death 
• Flushing of the face 
• Sensitivity to light 
• Peeling of skin on hands or soles of feet 
• Skin rash 
• Darkening of the finger or toe nails, or nail loss 


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• Eye infections 
• Itching 
• Dehydration 
• Fever, chills, hives 
• Problems with fertility* 
* You should not assume that you cannot get pregnant or that you cannot get someone 
else pregnant.  
Rarely, the following side effects of Doxorubicin have been seen in humans:   
• Treatment related acute leukemia or myelodysplasia 
• Damage to large intestine 
• Doxorubicin can damage the heart muscle and may cause heart problems, including 
possibly fatal heart failure. Heart problems may occur during doxorubicin therapy or 
months to years after receiving this medication. Your risk of developing heart 
problems depends on your dose, medical history (including previous heart disease, 
radiation therapy in the chest area), and previous use of this and other drugs.  
• Allergic reactions, such as fever, urticaria (hives) and anaphylaxis (acute allergic 
reaction) occur rarely. 
• Severe tissue damage may occur if doxorubicin leaks out of the vein into the 
surrounding tissue 
 
Possible Discomforts And Risks Of Dexamethasone 
Some of the more serious risks and side effects of receiving Dexamethasone include: 
• Allergic reactions.  Get emergency medical help if you have any of these signs of 
an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, 
or throat. 
• Problems with your vision; 
• Swelling, rapid weight gain, feeling short of breath; 
• Severe depression, unusual thoughts or behavior, seizure (convulsions); 
• Bloody or tarry stools, coughing up blood; 
• Pancreatitis (severe pain in your upper stomach spreading to your back, nausea 
and vomiting, fast heart rate); 
• Low potassium (confusion, uneven heart rate, extreme thirst, increased urination, 
leg discomfort, muscle weakness or limp feeling); or 
• Dangerously high blood pressure (severe headache, blurred vision, buzzing in 
your ears, anxiety, confusion, chest pain, shortness of breath, uneven 
heartbeats, seizure). 
 
You should call your doctor at once if you have any of these serious side effects above.   
 
Less serious side effects may include: 
• Sleep problems (insomnia), mood changes, irritability; 
• Acne, dry skin, thinning skin, bruising or discoloration; 
• Slow wound healing; 


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• Increased sweating; 
• Headache, dizziness, spinning sensation; 
• Nausea, stomach pain, bloating; 
• Muscle weakness;  
• Increased appetite, weight gain, changes in the shape or location of body fat 
(especially in your arms, legs, face, neck, breasts, and waist). 
 
C3. OTHER RISKS OF THIS RESEARCH STUDY 
 
Other procedures that are part of the study also involve some risks: 
 
Blood Draw:  In addition to the risks of all study drugs, routine needle sticks for blood 
samples may cause pain, bruising and rarely, infection at the site where blood is drawn.   
Bone Marrow Biopsy or Aspirate:  Possible side effects of bone marrow aspirate and 
biopsy include bleeding, infection, bruising, discomfort and/or pain at the biopsy site and 
possible side effects from the local anesthetic (pain or bruising at the injection site). 
Multi Gated Acquisition (MUGA) Scan: MUGA scan is a radioactive heart scan to see 
how well your heart pumps blood. A radioactive agent is injected into a vein, after which 
you lie on a table. A special camera that detects radioactivity takes pictures of your 
heart. The MUGA scan procedure has minimal if any risks. The test is painless except 
for a brief sting from the needle used to inject the tracer into your vein. Allergic reactions 
to the radioactive tracer are rare. Occasionally, some soreness or swelling may develop 
at the injection site. The radioactive agent is completely gone from the body within a few 
days of the test.  
Echocardiogram (ECHO): ECHO is a noninvasive scan of the heart using sound 
waves. This test will be used to see how well your heart pumps blood. This test has no 
known risks or side effects. 
C4. REPRODUCTIVE RISKS 
 
Risks to women who could become pregnant 
The drugs in this study might affect a baby, before or after the baby is born. We do not 
know if the drugs causes harm to a baby, so we do not want anyone who might be 
pregnant to enter the study. You should not become pregnant or nurse a baby while in 
this study. Unless you cannot have children because of surgery or other medical 
reasons (you had an effective tubal ligation, or had the ovaries or the uterus removed; 
or you are post-menopausal), you must use two effective methods of birth control from 
the time of signing the informed consent form, for the entire study drug treatment period 
(including interruptions in treatment), and for 90 days after completing study drug 
treatment.  You must tell the study doctor right away if you think you are pregnant. You 
will be asked to have a pregnancy test to be sure you are not pregnant at the start of the 
study.  


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You must have a negative pregnancy test prior to enrolling in the study. 
 
Unless you cannot have children because of surgery or other medical reasons (you had 
an effective tubal ligation, or had the ovaries or the uterus removed; or you are post-
menopausal), you must use two effective methods of birth control from the time of 
signing the informed consent form, for the entire study drug treatment period (including 
interruptions in treatment), and for 90 days after completing study drug treatment.  It is 
strongly recommended that at least one of these two methods be highly effective (see 
examples below). 
 
Highly effective methods 
Other effective methods (barrier 
methods) 
Intra-uterine devices (IUD)         
Latex or non-latex condom with or 
without a spermicidal agent 
Hormonal (birth control pills/oral 
contraceptives, injectable 
contraceptives, contraceptive patches, 
or contraceptive implants) 
Diaphragm with spermicide; Cervical 
cap with a spermicide; Sponge with a 
spermicide 
If one of the highly effective methods cannot be used, using two effective 
methods at the same time are recommended.  
 
Risks of fathering a child 
You should not father a baby while taking part in this study because it is unknown if the 
drugs in this study could affect a baby. If your partner is able to become pregnant, one 
or both of you must use some form of effective birth control. Even if you are surgically 
sterilized (i.e. have had a vasectomy) you must agree to use an appropriate method of 
barrier contraception (latex or non-latex condom with a spermicidal agent) during the 
entire study drug treatment period, and for 90 days after completing study drug 
treatment.  You must tell the study doctor right away if you think your partner is 
pregnant. 
 
Highly effective methods 
Other effective methods (barrier 
methods) 
Vasectomy         
Latex or non-latex condom  with or 
without a spermicidal agent   
 
Diaphragm with spermicide; Cervical 
cap with spermicide; Sponge with 
spermicide 
If one of the highly effective methods cannot be used, using two effective 
methods at the same time are recommended.  
All subjects (male or female):  If you or your partner becomes pregnant during this 
study, you must tell the study doctor immediately.  The doctor will advise you of the 
possible risks to your unborn child and discuss options for managing the pregnancy with 


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you.  For female subjects who become pregnant while on this study, the study drug will 
be stopped immediately and the pregnancy will be followed until conclusion. 
 
If you do not understand what any of these discomforts and risks mean, please ask the 
study doctor or study staff to explain these terms to you. 
 
 
C5. ARE THERE ANY BENEFITS TO TAKING PART IN THE STUDY? 
 
This study may or may not help you, but we hope the information from this study will 
help us develop better treatments for adults with relapsed or refractory acute 
lymphoblastic leukemia/lymphoma, lymphoblastic lymphoma or mixed phenotype acute 
leukemia. 
 
D1. ARE THERE ANY COSTS TO BEING IN THE STUDY? 
 
Most of the medical care that you will receive in this study is considered routine care for 
your condition and would be recommended whether you join the study or not.  Costs for 
routine care will be billed to you or your insurance carrier.  Activities / costs that are part 
of the study that will not be billed to you or your insurance company are: Ixazomib, 
processing, of research samples. Some insurers will not pay for drugs, tests or 
hospitalization that are part of research studies, so check with your insurer before you 
join this study. If you have questions regarding study costs, please contact Dr. Atallah. 
 
D2. WILL I BE PAID FOR PARTICIPATING IN THE STUDY? 
 
There is no payment for being in this study.  You will not receive payments of any kind 
for discoveries, patents or products that may be developed from this study. 
 
D3. WHAT OTHER HEALTHCARE CHOICES DO I HAVE? 
 
You do not have to join this study. You are free to say yes or no. If you do not join this 
study, your doctor can discuss other healthcare choices with you.  
Your other choices may include: 
• 
Getting treatment or care for your cancer without being in a study. 
• 
Joining a different research study 
• 
Getting no treatment 
• 
Getting comfort care, also called palliative care.  This type of care helps reduce 
pain, tiredness, appetite problems, and other problems caused by the cancer.  It 
does not treat the cancer directly, but instead tries to improve how you feel.  
Comfort care tries to keep you as active and comfortable as possible.  
 
D4. WILL I BE GIVEN NEW INFORMATION ABOUT THE STUDY? 


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If we learn any important new information about the drug that might change your mind 
about being in the study, we will tell you about it right away.  You can then decide if you 
want to stay in the study. 
D5. WHAT HAPPENS IF I AM HARMED BECAUSE I TOOK PART IN THE STUDY?  
 
No funds have been set aside to pay any costs if you become ill or are harmed because 
of this study. If you think that you have become ill or were harmed because of this 
study, let the study doctors know right away by calling 414-805-6800.  By signing this 
form, you do not give up your right to seek payment for harm you receive while 
participating in this study. 
 
If you think that you have become ill or were harmed because of this study, let the study 
doctors know right away by calling 414-805-6800. 
 
By signing this form, you do not give up your right to seek payment for harm you receive 
while participating in this study. 
 
D6. WHO CAN ANSWER MY QUESTIONS ABOUT THE STUDY? 
 
• 
If you have more questions about this study at any time, you can call Dr. Atallah at 
414-805-6800. 
• 
If you have questions about your rights as a study participant, want to report any 
problems or complaints, obtain information about the study, or offer input, you can 
call the MCW/Froedtert Hospital Research Subject Advocate at 414-955-8844. 
 
E. PERMISSION TO COLLECT, USE AND SHARE HEALTH INFORMATION 
 
E1. What health information will be collected and used for this study? 
To do this research study, we need your permission to collect and use some of your 
health information, or you cannot be in the study. This information may come from 
questions we ask, forms we ask you to fill out, or your medical record, as described 
below. We will only collect and use information needed for the study.  
 
The health information to be collected and used for this study is:  
All or portions of your medical chart: 
 Hospital/Medical Records 
 Physician/Clinical Records 
 Lab and/or Pathology Reports 
 Radiology Reports 
 Biological Samples 
 Interview/Questionnaires 
 


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E2. Who will see the health information collected for this study? 
The only MCW/Froedtert Hospital employees allowed to handle your health information 
are those on the study team, those on the Institutional Review Board (IRB) and those 
who check on the research activities to make sure the hospital’s rules are followed. 
 
The study team may share your information with people who don’t work at 
MCW/Froedtert Hospital because they planned, pay for, or work with us on this study.  
The federal Privacy Rule may no longer protect your health information once it leaves 
MCW/Froedtert Hospital.  For this study, we plan to share information with those 
doctors, researchers or government representatives working with us on this study at the 
institutions or companies listed here: 
 
 
U.S. Food and Drug Administration, Rockville, MD     
Millennium and its collaborators or designees 
Representatives of Central Laboratories  
Any Independent ethics committee, which approved this study 
Other Regulatory Agencies and/or Their Designated Representatives   
Those required by law 
 
We may record your research information, including results of tests and procedures 
done for research, in your Froedtert Hospital and/or Medical College of Wisconsin 
medical record.  As a result, this research information may be seen by people allowed 
to see your medical records for healthcare operations or treatment, by those you allow 
to see your medical records by giving written permission, and by others when required 
by law. 
 
We will not use your personal health information for a different study without your 
permission or the permission of a hospital research review board (IRB). Once all 
personal identification is removed, the information might be used or released for other 
purposes without asking you. Results of the study may be presented in public talks or 
written articles, but no information will be presented that identifies you. 
  
E3. What are the risks of sharing this health information? 
One risk of taking part in a research study is that more people will handle your personal 
health information collected for this study. The study team will make every effort to 
protect the information and keep it confidential, but it is possible that an unauthorized 
person might see it. Depending on the kind of information being collected, it might be 
used in a way that could embarrass you or affect your ability to get insurance. If you 
have questions, you can talk to the study doctor about whether this could apply to you.  
 
E4. How long will you keep the health information for this study? 
If you sign this form, we plan to keep your information without any end-date in case we 
need to check it again for this study. 
 


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E5. Can I cancel my permission to share this health information? 
If you change your mind later and do not want us to collect or share your health 
information, you need to send a letter to: 
 
Ehab Atallah, MD  
Froedtert & Medical College of Wisconsin 
Division of Hematology and Oncology 
9200 W. Wisconsin Avenue 
Milwaukee, WI  53226 
 
The letter must say that you have changed your mind and do not want the researcher to 
collect and share your health information. At that time, we may decide that you cannot 
continue to be part of the study. We may still use the information we have already 
collected. 
 
 
 
F1. FOR MORE INFORMATION ABOUT THE STUDY 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site 
at any time. 
 
You can look up this study by referring to the ClinicalTrials.gov number (NCT01887587) 
or by asking the study team for a printed copy.    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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CONSENT TO PARTICIPATE IN THE STUDY 
 
By signing my name below, I confirm the following: 
• I have read (or had read to me) this entire consent document.  All of my questions 
have been answered to my satisfaction. 
• The study’s purpose, procedures, risks and possible benefits have been explained to 
me.   
• I agree to let the study team use and share the health information and other 
information gathered for this study. 
• I voluntarily agree to participate in this research study.  I agree to follow the study 
procedures as directed.  I have been told that I can stop at any time. 
 
IMPORTANT: You will receive a signed and dated copy of this consent form.  Please 
keep it where you can find it easily.  It will help you remember what we discussed today. 
 
 
 
 
Subject's Name please print  
Subject's Signature 
Date    
 
 
 
Name of Legally Authorized 
Representative (if applicable)  
please print  
Signature of Legally Authorized 
Representative 
Date 


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IRB Approval Period: 8/11/2015 – 12/9/2015  
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MCW Version: 08-13-15 
EFFECTIVE 
 
8/14/2015 
 
MCW/FH IRB
 
 
 
Name of Witness (if applicable) please 
print  (for short form consent process, or 
consent of blind or illiterate subject) 
Signature of Witness 
 
Date 
 
 
 
* Name of person discussing/ 
obtaining consent please print  
Signature of person 
discussing/obtaining consent
Date 
* A member of the study team trained and authorized by the Principal Investigator to act on her/his behalf 
in obtaining informed consent according to the protocol.  In all research study protocols the Principal 
Investigator is responsible and accountable for the study.