Conditions: Acute Leukemia Chronic Leukemia Myelodysplastic Syndrome Lymphomas Multiple Myeloma
Keywords: hematologic malignancies
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 29
Healthy volunteers: no

Brief summary:
In an attempt to reduce relapse risk and improve outcomes following haploidentical transplantation for patients with high risk hematologic malignancies, the investigators will implement several strategies to augment the well documented effect of NK cell alloreactivity seen in HLA-mismatched transplantation. These strategies include (1) choosing potential haploidentical donors for optimal NK-alloreactivity, (2) utilizing proteasome inhibition post-transplant with MLN9708 to both sensitize tumor cells to NK cytotoxicity and protect against graft-versus-host disease (GVHD), and (3) eliminating mycophenolate mofetil from the post-transplant immunosuppression regimen to improve NK cell reconstitution following haploidentical peripheral blood stem cell transplantation.

Detailed description:
Overview of Study Design:

In an attempt to reduce relapse risk and improve outcomes following haploidentical transplantation for patients with high risk hematologic malignancies, the investigators will implement several strategies to augment the well documented effect of NK cell alloreactivity seen in HLA-mismatched transplantation. These strategies include (1) choosing potential haploidentical donors for optimal NK-alloreactivity, (2) utilizing proteasome inhibition post-transplant with MLN9708 to both sensitize tumor cells to NK cytotoxicity and protect against graft-versus-host disease (GVHD), and (3) eliminating mycophenolate mofetil from the post-transplant immunosuppression regimen to improve NK cell reconstitution following haploidentical peripheral blood stem cell transplantation.

Patients will receive a nonmyeloablative haploidentical transplant using a T-cell replete allograft and post-transplant cyclophosphamide as previously described at our center (Bashey et al. J Clin Oncol. 2013; 31(10):1310-6). MLN9708 will be administered once weekly for 3 weeks on a 28 day cycle for one-year post-transplant. Post-transplant immunosuppression will consist of tacrolimus only (MLN9708 will substitute for mycophenolate mofetil as the second GVHD prophylactic medication).

The primary endpoint of this trial will be the risk of relapse and/or progression at one-year post-transplant. Experience from the literature suggests that following a nonmyeloablative haploidentical transplant using post-transplant cyclophosphamide (haplo-pCy), the risk of relapse is approximately 50% at one year post-transplant. It is hoped that under this protocol, this rate will be at most 25%. Thus the investigators statistically formalize this study by testing the null hypothesis that p, the PFS rate is 0.25 or less versus the alternative hypothesis that p is greater than 0.5. A sample size of 25 patients gives 90% power with an alpha=0.05, using the formula for a one sample binomial (two-sided) test of a proportion.

Arms:
arm 1: All patients will receive a haploidentical donor transplant using a conditioning regimen of Fludarabine (Flu), cyclophosphamide (cy) and total body irradiation (TBI) followed by MLN9708.

Interventions: intervention 1: MLN9708
Intervention descriptions: intervention 1: MLN9708 will be given weekly x 3 weeks every 28 day cycles, for up to 12 cycles starting at D+5 post-transplant.

Protocol document:
Prot_SAP_000.pdf: 
Blood & Marrow Transplant Program at 
Clinical Study Protocol X16035 
Northside Hospital 
 
 
 
1 
 
CLINICAL STUDY PROTOCOL  
X16035 
 
A Phase II Trial of Nonmyeloablative Haploidentical Peripheral Blood Stem Cell 
Transplantation Followed By Maintenance Therapy With the Novel Oral Proteasome 
Inhibitor, MLN9708,  in Patients with High-risk Hematologic Malignancies 
 
 
 
 
 
 
Indication: 
High Risk Hematologic Malignancies 
Phase: 
Phase II 
 
Protocol History 
Original 
 
 
07 February 2014 
Amendment   
 
22April 2014 
Amendment 
 
 
22December 2014 
Amendment 
 
 
06March 2015 
 
Principal Investigator  
Scott R. Solomon, MD 
 
Co-Investigators 
 
H. Kent Holland, MD 
 
 
 
 
Lawrence E. Morris, Jr, MD 
 
 
 
 
Asad Bashey, MD, PhD 
 
 
 
 
Melhem Solh, MD 
 
Investigative Site 
 
Blood and Marrow Transplant Program at Northside Hospital 
5670 Peachtree Dunwoody Rd. NE  Suite 1000 
Atlanta, GA  30342 
404-255-1930 
 
 
 
 
 
 
This is an investigator-initiated study.  The principal investigator Scott R. Solomon, MD, (who 
may also be referred to as the sponsor-investigator), is conducting the study and acting as the 
sponsor.  Therefore, the legal/ethical obligations of the principal investigator include both those 
of a sponsor and those of an investigator. 


Blood & Marrow Transplant Program at 
Clinical Study Protocol X16035 
Northside Hospital 
 
 
 
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PROTOCOL SUMMARY  
Study Title:  A Phase II Trial of Nonmyeloablative Haploidentical Peripheral Blood Stem Cell 
Transplantation Followed By Maintenance Therapy With the Novel Oral Proteasome 
Inhibitor, MLN9708,  in Patients with High-risk Hematologic Malignancies 
Phase:  II 
Number of Patients:  25 
Study Objectives  
Primary 
 To estimate the incidence of relapse/progression at one-year post-transplant. 
Secondary 
 To obtain estimates of overall survival (OS), event-free survival (EFS), non-relapse mortality 
(NRM), engraftment, acute and chronic graft-versus-host disease (GVHD). 
 Characterize additional hematologic and non-hematologic toxicities of MLN9078 when given 
post haploidentical transplant. 
 Characterize donor hematopoietic chimerism in peripheral blood at days ~30, ~60, and ~90 
after HSCT. 
 
Overview of Study Design:   
In an attempt to reduce relapse risk and improve outcomes following haploidentical transplantation 
for patients with high risk hematologic malignancies, we will implement several strategies to 
augment the well documented effect of NK cell alloreactivity seen in HLA-mismatched 
transplantation. These strategies include (1) choosing potential haploidentical donors for optimal 
NK-alloreactivity, (2) utilizing proteasome inhibition post-transplant with MLN9708 to both 
sensitize tumor cells to NK cytotoxicity and protect against graft-versus-host disease (GVHD), and 
(3) eliminating mycophenolate mofetil from the post-transplant immunosuppression regimen to 
improve NK cell reconstitution following haploidentical peripheral blood stem cell transplantation. 
Patients will receive a nonmyeloablative haploidentical transplant using a T-cell replete allograft and 
post-transplant cyclophosphamide as previously described at our center (Bashey et al. J Clin Oncol. 
2013; 31(10):1310-6).  MLN9708 will be administered once weekly for 3 weeks on a 28 day cycle 
for one-year post-transplant. Post-transplant immunosuppression will consist of tacrolimus only 
(MLN9708 will substitute for mycophenolate mofetil as the second GVHD prophylactic 
medication). 
The primary endpoint of this trial will be the risk of relapse and/or progression at one-year post-
transplant. Experience from the literature suggests that following a nonmyeloablative haploidentical 
transplant using post-transplant cyclophosphamide (haplo-pCy), the risk of relapse is approximately 
50% at one year post-transplant.  It is hoped that under this protocol, this rate will be at most 25%. 
Thus we statistically formalize this study by testing the null hypothesis that p, the PFS rate is 0.25 or 
less versus the alternative hypothesis that p is greater than 0.5. A sample size of 25 patients gives 
90% power with an alpha=0.05, using the formula for a one sample binomial (two-sided) test of a 
proportion. 


Blood & Marrow Transplant Program at 
Clinical Study Protocol X16035 
Northside Hospital 
 
 
 
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Correlative samples will be drawn at baseline, day 30, 60, 90, 6mo, 12 months for lymphocyte 
subsets.  Additional PBMCs will be collected and frozen for future immune reconstitution studies.  
Approximately 30-50ml of blood will be collected at each time point. 
Study Population:   
Eligible patients will be at least 18 years of age, with adequate performance status and organ 
function, and have a high risk hematologic malignancy (acute lymphoblastic leukemia/lymphoma in 
complete remission, acute myeloid leukemia in complete remission, relapsed Burkitt 
leukemia/lymphoma in complete remission, multiple myeloma (relapsed disease and/or presence of 
del17p), relapsed lymphoma including marginal zone, follicular, and chemotherapy-sensitive diffuse 
large B cell, T cell, Mantle cell, and Hodgkin’s.  Full details of disease inclusion is located in section 
5.1. Key Exclusion Criteria will be poor performance status, inadequate organ function, or lack of 
suitable haploidentical donor. 
Duration of Study:  # months from FPI to LPI: 24 months 
# months from LPI to LPO: 12 months. 
# months to complete study: 36 months  
 
 


Blood & Marrow Transplant Program at 
Clinical Study Protocol X16035 
Northside Hospital 
 
 
 
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STUDY OVERVIEW  
 
 
 
Days –6, -5 
Fludarabine 30 mg/M2 IV qd 
 
Cyclophosphamide (CTX) 14.5 mg/kg IV qd 
 
 
 
 
 
 
 
Days –4 -2 
Fludarabine 30 mg/M2 IV qd 
 
 
 
 
Day –1 
TBI 200 cGy 
 
 
 
 
Day 0 
Infuse unmanipulated PBSCs 
 
 
 
 
Days 3, 4 
CTX 50 mg/kg IV q d 
 
(hydration/Mesna) 
(First dose of cyclophosphamide must be administered 48-72 hr after infusion of PBCs) 
 
 
 
Day 5    
Begin Tacrolimus and  
                MLN9708 4mg weekly x 3doses q28days, up to 12 monthly cycles 
 
 
 
 
Day 30, 60, 90 
Assess Chimerism in peripheral blood 
 
 
 
 
 
Day 180 
Discontinue Tacrolimus 
 
 
 


Blood & Marrow Transplant Program at 
Clinical Study Protocol X16035 
Northside Hospital 
 
 
 
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SCHEDULE OF EVENTS 
 
Test 
Screen 
Month 1 
(4 
weekly 
visits) 
Month 
2 (4 
weekly 
visit) 
Month 
3 (4 
weekly 
visits) 
Month 
4 
Month 
5 
Month 
6 
Months 
7-11 
Month 
12 
End of 
Study  
Months 
18, 24 
and 36 
H & P 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with 
differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PFT* 
X 
 
 
 
 
 
 
 
 
 
 
ECHO* 
X 
 
 
 
 
 
 
 
 
 
 
EKG* 
X 
 
 
 
 
 
 
 
 
 
 
IDMs including 
Hepatitis & 
HIV* 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
**(FOCBP) 
X 
 
 
 
 
 
 
 
 
 
 
GVHD 
assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity 
Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Bone marrow 
biopsy & 
aspirate  
 
 
 
X 
 
 
X 
 
X 
X 
X 
CT/PET for 
NHL/HD for 
disease 
assessment 
 
 
 
X 
 
 
X 
 
X 
X 
X 
Research 
Sample*** 
 X 
X (Day 
30) 
X (Day 
60) 
X (Day 
90) 
 
 
X 
 
X 
 
 
Survival 
 
 
 
 
 
 
 
 
 
 
X 
New 
malignancy 
assessment 
 
 
 
 
 
 
 
 
 
 
X 
*Testing that is done for transplant is acceptable if done within 6 weeks of the start of study drug.  
**Women with a uterus <50 or women >50 but < one year without a menstrual cycle) are considered 


Blood & Marrow Transplant Program at 
Clinical Study Protocol X16035 
Northside Hospital 
 
 
 
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FOCBP. 
*** Research samples will be collected for lymphocyte subsets.  Additional PBMCs will be collected 
to be frozen for future immune reconstitution studies. Approximately 30-50ml of blood will be 
collected at each time point.  


Blood & Marrow Transplant Program at 
Clinical Study Protocol X16035 
Northside Hospital 
 
 
 
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TABLE OF CONTENTS 
PROTOCOL SUMMARY ....................................................................................................... 2 
STUDY OVERVIEW DIAGRAM .......................................................................................... 4 
SCHEDULE OF EVENTS ...................................................................................................... 5 
LIST OF TABLES ................................................................................................................... 9 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ........................................... 10 
1. BACKGROUND AND STUDY RATIONALE ............................................................... 14 
1.1 Scientific Background .................................................................................................. 14 
1.1.1 Disease Under Treatment ...................................................................................... 17 
1.1.2 MLN9708 .............................................................................................................. 18 
1.2 Preclinical Experience ................................................................................................. 18 
1.3 Clinical Experience ...................................................................................................... 18 
1.4 Pharmacokinetics and Drug Metabolism ..................................................................... 18 
1.5 Clinical Trial Experience Using the Oral Formulation of MLN9708 ......................... 19 
1.6 Relapsed and/or Refractory Multiple Myeloma .......................................................... 23 
1.7 Newly Diagnosed Multiple Myeloma (NDMM) ......................................................... 26 
1.8 Study Rationale ............................................................................................................ 28 
1.9 Potential Risks and Benefits ........................................................................................ 29 
2. STUDY OBJECTIVES ...................................................................................................... 33 
2.1 Primary Objectives ...................................................................................................... 33 
2.2 Secondary Objectives .................................................................................................. 33 
3. STUDY ENDPOINTS ....................................................................................................... 33 
3.1 Primary Endpoints ....................................................................................................... 33 
3.2 Secondary Endpoints ................................................................................................... 33 
4. STUDY DESIGN............................................................................................................... 33 
4.1 Overview of Study Design ........................................................................................... 33 
4.2 Number of Patients ...................................................................................................... 35 
4.3 Duration of Study ......................................................................................................... 35 
4.4 Correlative Samples ..................................................................................................... 35 
5. STUDY POPULATION .................................................................................................... 35 
5.1 Inclusion Criteria ......................................................................................................... 35 
5.2 Exclusion Criteria ........................................................................................................ 37 
5.3 Criteria for donor selection .......................................................................................... 39 
6. TREATMENT PLAN/STUDY DRUG ............................................................................. 39 
6.1 Transplant Regimen ..................................................................................................... 39  
6.2 MLN9708 Administration ........................................................................................... 42 
6.3 Dose-Modification Guidelines ..................................................................................... 43 
 6.3.1 Recommended MLN9708 Criteria for Beginning or Delaying a Subsequent 
Treatment Cycle & Dose Modifications for Treatment Associated Toxicity  ..... 43 
6.4 Excluded Concomitant Medications and Procedures .................................................. 46 
6.5 Permitted Concomitant Medications and Procedures .................................................. 47 
6.6 Precautions and Restrictions ........................................................................................ 47 
6.7 Management of Clinical Events ................................................................................... 48 
6.8 Preparation, Reconstitution, and Dispensing ............................................................... 51 
6.9 Packaging and Labeling ............................................................................................... 51 


Blood & Marrow Transplant Program at 
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6.10 Storage, Handling, and Accountability ...................................................................... 51 
6.11 Study Compliance ...................................................................................................... 52 
6.12 Termination of Treatment and/or Study Participation ............................................... 52 
7. STATISTICAL AND QUANTITATIVE ANALYSES .................................................... 53 
7.1 Statistical Methods ....................................................................................................... 53 
7.1.1 Determination of Sample Size .............................................................................. 53 
7.1.2 Stopping Criteria ................................................................................................... 53 
8. ADVERSE EVENTS ......................................................................................................... 54 
8.1 Definitions ................................................................................................................... 54 
8.1.1 Pretreatment Event Definition .............................................................................. 54 
8.1.2 Adverse Event Definition...................................................................................... 54 
8.1.3 Serious Adverse Event Definition......................................................................... 55 
8.1.4 Adverse Event of Special Interest Definition ....................................................... 56 
8.2 Procedures for Reporting Serious Adverse Events ...................................................... 56 
8.3 Procedures for Reporting AESIs .................................................................................. 58 
8.4 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events .......... 59 
9. ADMINISTRATIVE REQUIREMENTS ......................................................................... 59 
9.1 Good Clinical Practice ................................................................................................. 59 
9.2 Ethical Considerations ................................................................................................. 59 
9.3 Patient Information and Informed Consent ................................................................. 60 
9.4 Patient Confidentiality ................................................................................................. 60 
9.5 Investigator Compliance .............................................................................................. 60 
9.6 On-site Audits .............................................................................................................. 61 
9.7 Investigator and Site Responsibility for Drug Accountability ..................................... 61 
9.8 Product Complaints ...................................................................................................... 61 
9.9 Closure of the Study .................................................................................................... 62 
9.10 Record Retention ....................................................................................................... 62 
10. USE OF INFORMATION ............................................................................................... 62 
11. DISEASE EVALUATION…………………………………………………………….. 63 
12. REFERENCES ................................................................................................................ 71 
13. APPENDICES ................................................................................................................. 79 
13.1 Karnofsky Performance Status .. ……………………………………………………79 
13.2 Group B KIR Haplotype Determination .................................................................... 80 
13.3 Sample SAE Form ..................................................................................................... 80 
13.4 Millennium Pregnancy Reporting Form .................................................................... 80 
 
 


Blood & Marrow Transplant Program at 
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Northside Hospital 
 
 
 
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LIST OF TABLES  
Table 1-1: Ongoing Studies of Oral MLN9708 
Table 1-2: Summary of Most Common (At Least 10% of Total) All Grade Treatment-Emergent 
Adverse Events (Oral MLN9708 Single-Agent [C16003/4/7/9] Safety Population) 
Table 1-3: Summary of Most Common (At Least 10% of Total) All Grade Treatment-Emergent 
Adverse Events (Oral MLN9708 Combination-Agent [C16005/6/8] Safety Population) 
Table 1-4: Study C16004, Oral MLN9708, Single Agent, Given Weekly: Most Common TEAEs 
as of 30 April 12 (N=52) 
Table 1-5: Study C16007, Oral MLN9708, Single Agent Given Weekly, Most Common TEAEs 
as of 30April 12 (N=14) 
Table 1-6: Study C16005: Oral MLN97087 Given Weekly in Combination With Lenalidomide 
and Dexamethasone, Most Common TEAEs as of 30 April 2012 
Table 6-1: MLN908 Dose Adjustments 
Table 6-2: MLN9708 Dose Adjustments for Hematologic Toxicities 
Table 6-3: MLN9708 Treatment Modification (Delays, Reductions, and Discontinuations) Due 
to Adverse Events (Non-Hematologic Toxicities) 
Table 11-1: Response Criteria for Lymphoma 
 
 


Blood & Marrow Transplant Program at 
Clinical Study Protocol X16035 
Northside Hospital 
 
 
 
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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
Common abbreviations used in oncology protocols are provided below.  Program-specific or 
protocol-specific abbreviations must be added to this list, and unnecessary abbreviations 
removed, as applicable.  Abbreviations that are retained should not be changed.  
Abbreviation 
Term 
5-HT3 
5-hydroxytryptamine 3 serotonin receptor 
AE 
adverse event 
ALL 
acute lymphoblastic leukemia 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myelogenous leukemia 
ANC 
absolute neutrophil count 
API 
active pharmaceutical ingredient 
aPTT 
activated partial thromboplastin time 
Ara-C 
Cytarabine 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration versus time curve 
AUC24 hr 
area under the plasma concentration versus time curve from zero to 24 hours 
AUCinf 
area under the plasma concentration versus time curve from zero to infinity 
AUCτ 
area under the plasma concentration versus time curve from zero to next dose 
BCRP 
breast cancer resistance protein 
hCG
beta-human chorionic gonadotropin 
BID 
bis in die; twice a day 
BM 
bone marrow 
BSA 
body surface area 
BUN 
blood urea nitrogen 
BZD 
Benzodiazepines 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CL 
clearance, IV dosing 
CLP 
plasma clearance 
CLTotal 
total clearance 
Cmax 
single-dose maximum (peak) concentration   
CNS 
central nervous system 


Blood & Marrow Transplant Program at 
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Northside Hospital 
 
 
 
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Abbreviation 
Term 
CO2 
carbon dioxide 
CR 
complete remission  
CRM 
continual reassessment method 
CRP 
C-reactive protein 
CSF-1R 
colony-stimulating factor 1 receptor 
CT 
computed tomography 
Ctrough 
single-dose end of dosing interval (trough) concentration 
CV 
cardiovascular  
CYP 
cytochrome P450 
DLT 
dose-limiting toxicity 
DME 
drug metabolizing enzymes 
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) 
EU 
European Union 
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 
HDPE 
high-density polyethylene 
hERG 
human ether-à-go-go related gene 
HIV 
human immunodeficiency virus 
HNSTD 
highest nonseverely toxic dose 


Blood & Marrow Transplant Program at 
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Northside Hospital 
 
 
 
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Abbreviation 
Term 
IB 
Investigator’s Brochure 
IC50 
concentration producing 50% inhibition 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
IRB 
institutional review board 
ITT 
intent-to-treat 
IV 
intravenous; intravenously 
IVRS 
interactive voice response system 
Ki 
inhibition constant 
KPS 
Karnofsky Performance Status 
LDH 
lactate dehydrogenase 
LFT 
liver function test(s) 
MedDRA 
Medical Dictionary for Regulatory Activities 
Millennium 
Millennium Pharmaceuticals, Inc., and its affiliates 
MRI 
magnetic resonance imaging 
MRU 
medical resource utilization 
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 
PCR 
polymerase chain reaction 
PD 
progressive disease (disease progression) 
Pgp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PO 
per os; by mouth (orally) 
PR 
partial remission  
PRO 
patient-reported outcome 
PSA 
prostate-specific antigen 
QD 
quaque die; each day; once daily 


Blood & Marrow Transplant Program at 
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Northside Hospital 
 
 
 
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Abbreviation 
Term 
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 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SC 
Subcutaneous 
SD 
stable disease 
SmPC 
Summary of Product Characteristics 
t1/2 
terminal disposition half-life 
TGI 
tumor growth inhibition 
Tmax 
single-dose time to reach maximum (peak) concentration 
UK 
United Kingdom 
ULN 
upper limit of the normal range 
US 
United States 
Vz 
volume of distribution in the terminal phase 
WBC 
white blood cell 
WHO 
World Health Organization 
 


Blood & Marrow Transplant Program at 
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Northside Hospital 
 
 
 
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1.    
BACKGROUND AND STUDY RATIONALE 
1.1    
Scientific Background 
Allogeneic HSCT is a potentially curative treatment for a variety of hematologic malignancies 
and non-malignant hematologic disorders1.  Of all the potential sources of allografts, HSCT from 
a HLA-matched sibling has generally produced the best overall outcomes2. Unfortunately, only 
about a third of candidates for HSCT have HLA-matched siblings.  For patients who lack HLA-
matched siblings, there are three alternative sources of stem cells for HSCT: 1) volunteer 
unrelated donors; 2) umbilical cord blood; and 3) partially HLA-matched, or haploidentical, 
related donors3.  Since any patient shares exactly one HLA haplotype with each biological parent 
or child and half of siblings, an eligible haploidentical donor can be identified rapidly in nearly 
all cases.  However, haploidentical HSCT has been associated with significant risks of graft 
rejection and severe GVHD4-6, which are manifestations of excessive alloreactivity by host7 and 
donor T cells8, respectively.  The risk of severe GVHD may be reduced in intensively 
conditioned recipients of grafts that have been rigorously depleted of T cells, but the risks of 
serious infection and death from prolonged immune compromise in these patients remains high9-
14. Mortality from CMV disease was 14% in a recent study of nonmyeloablative transplantation 
using HLA-haploidentical donors15. Fukuda, et al. reported an incidence of 15% invasive mold 
infections in nonmyeloablative transplants from HLA-matched related or unrelated donors with a 
mortality rate of 56%16. In order to reduce the toxicity of haploidentical HSCT, methods to 
selectively inhibit alloreactivity while preserving immunity to infection and the malignancy are 
clearly required17.  
Cyclophosphamide (Cy) is a highly immunosuppressive antineoplastic agent that has an 
established role in conditioning for HSCT.  Typically, the drug is administered prior to 
transplantation to prevent graft rejection by suppressing the host immune system.  However, pre-
transplantation conditioning with Cy increases the risk of GVHD following allogeneic T cell 
infusion in mouse models18.  In contrast, administration of a properly timed, high dose of Cy 
after HSCT inhibits both graft rejection and GVHD19-22.    
Based on these murine studies, investigators at Johns Hopkins University developed a non-
myeloablative conditioning regimen for transplantation of non-T cell-depleted marrow from 
partially HLA-matched, or haploidentical, bone marrow from first-degree relatives23.  This study 
demonstrated the optimal titration of post-transplantation Cy dose, given in conjunction with pre-
transplantation fludarabine and total body irradiation (TBI), to achieve a regimen that had an 
acceptably low risk of graft rejection and GVHD, the two major complications of haploidentical 


Blood & Marrow Transplant Program at 
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15 
 
HSCT.  All patients received mycophenolate mofetil (MMF) and tacrolimus, beginning 24 hours 
after post-transplant Cy administration for GVHD prophylaxis.  A total of 88 patients with poor 
risk hematologic malignancies were studied. The median times to neutrophil and platelet 
recovery for all patients were 15 and 24 days, respectively. Graft failure occurred in a total of 
15/84 patients (18%). All but two patients with graft failure experienced recovery of autologous 
hematopoiesis with median times to neutrophil and platelet engraftment of 24 days (range 11-48 
days) and 44 days (range 15-395 days), respectively. 
The cumulative incidences of grades II-IV and III-IV acute GVHD by day 200 were 35% and 
10%. The cumulative incidence of chronic and extensive chronic GVHD in the first year after 
transplantation for the entire population was 22% and 14%, respectively. The cumulative 
incidences of NRM at 180 days and 1 year after transplantation were 13% and 19%, respectively. 
The cumulative incidences of relapse at 1 and 2 years after transplantation were 50% and 57%, 
respectively. At a median follow-up of survivors of 817 days (range, 112-1808 days), the 
actuarial overall survival at 1 and 2 years were 45% and 35%, respectively. The actuarial EFS at 
1 and 2 years were 32% and 24%, respectively. Furthermore, CMV reactivation was observed in 
20 of 60 (33%) high-risk patients, and proven or probable invasive mold infections post-
transplant, all caused by Aspergillus sp, were observed in 6 of 88 (6.8%) patients, of whom two 
had infection prior to transplant. Two patients died from Aspergillus infection, one while 
persistently neutropenic following graft failure. There was no CMV-associated mortality. 
From these results, it was concluded that (1) post-transplantation immunosuppression with high 
dose Cy, tacrolimus, and MMF was associated with an acceptably low incidence of graft 
rejection, severe acute GVHD, and extensive chronic GVHD, (2) there was effective clinical 
immune reconstitution as demonstrated by the low incidence of severe opportunistic infections, 
and (3) relapse represented the major cause of treatment failure.  Strategies to decrease the 
relapse risk are clearly needed.   
Clinical data from haploidentical transplantation (haplo-HSCT) has revealed that NK cells are 
responsible for remarkably favorable effects in adults with AML and more recently, in children 
with high-risk ALL24-27.  The emergence of the concept of NK cell alloreactivity has represented 
an important advance in the field of haplo-HSCT, underlining for the first time that not only 
adaptive immunity, but also innate immunity is a crucial element for a successful clinical 
outcome. Indeed, it has become evident that the therapeutic effect of haplo-HSCT is in part 
dependent on the graft-versus-leukemia (GVL) effect exerted by NK cells which originate from 
the donor allograft.   


Blood & Marrow Transplant Program at 
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Northside Hospital 
 
 
 
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Each NK cell expresses one or more inhibitory receptors (KIR), which through interactions with 
self-HLA class I molecules, prevent NK cell-mediated attack against healthy, autologous cells. 
On the other hand, cells in which HLA class I expression is compromised (for example, after 
tumor transformation or viral infection) become susceptible to NK-mediated killing.  Thus, in an 
autologous setting, NK cells can kill only cells that do not express sufficient HLA class I 
molecules, whereas in a nonself environment, NK cells may kill allogeneic cells when they 
express inhibitory KIRs that are not engaged by any of the HLA class I alleles present on 
allogeneic target cells. As a NK-mediated, alloreactive response depends on the failure of KIRs 
to engage their HLA class I ligands, alloreactive NK cells have been said to see “missing self” on 
allogeneic target cells. Alloreactivity in haplo-HSCT is operating through the mechanism of 
missing-self recognition, provided that the donor expresses a KIR ligand that is missing in the 
recipient's HLA genotype and expresses the specific inhibitory KIR, leading to a KIR/KIR ligand 
mismatch in the donor-versus-recipient direction. 
A number of activating forms of KIRs (e.g., KIR2DS1, KIR2DS2, and KIR3DS1) have been 
recently described, which are highly homologous in the extracellular domain to their inhibitory 
counterparts and present a short cytoplasmic tail lacking ITIM (immunoreceptor tyrosine-based 
inhibition motifs) .  Inhibitory/activating KIRs as well as HLA are two polymorphic gene 
systems. As they are encoded on separate chromosomes, they segregate independently. Over 350 
different KIR genotypes have been described, which highlights the great variability in the KIR 
gene family. Combinations of HLA class I and KIR variants influence resistance to infections, 
susceptibility to autoimmune diseases, and complications of pregnancy, as well as outcome after 
hematopoietic stem cell transplantation.  All HLA/KIR combinations can be divided in two basic 
KIR haplotypes: group A haplotypes, which have a fixed number of genes that encode inhibitory 
receptors (with the exception of the activating receptor KIR2DS4), and group B haplotypes, 
which have variable gene contents, including additional activating receptor genes.  Recent 
studies have suggested that donor group B haplotypes yield significantly better protection against 
leukemic relapses, as compared with group A, and improved disease-free survival in patients 
undergoing T cell-depleted HSCT for AML28-30.  
Research has shown that NK cell cytotoxicity can be potentiated in vitro by pre-exposing tumor 
cells to the proteasome inhibitor, Bortezomib31.  Pretreatment of tumor cells with Bortezomib 
has been shown to increase NK-mediated tumor control in multiple cancer types including 
myeloma, leukemia, renal cell carcinoma, prostate cancer, breast cancer, squamous cell and 
hepatocellular carcinoma32-37.  Enhanced NK cell killing effect is in part dependent on the up-
regulation of receptors on the tumor surface for tumor necrosis factor related apoptosis inducing 
ligand (TRAIL) and to drug-induced augmentation of tumor caspase-8 activity, leading to 


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enhanced tumor killing via perforin/granzyme mediated NK-tumor cytotoxicity32.  Other 
mechanisms of action include down-regulation of class I HLA on tumor cells34, as well as 
selectively induced the expression of the tumor cells NKG2D ligands, MICA and MICB33,38.   
In animal models, systemic proteasome inhibition has been shown to significantly inhibit acute 
GVHD while preserving graft-versus-tumor (GVT) responses in advanced tumor-bearing mice 
after allogeneic BMT with no observed adverse effects on myeloid recovery and donor 
chimerism39.  Bortezomib has been shown to decrease T-helper 1 responses among alloreactive 
T-lymphocytes40, while preserving regulatory T cells41,42 and T cell responses against 
pathogens43.  Clinical studies utilizing a short course of bortezomib with tacrolimus/methotrexate 
for GVHD prophylaxis demonstrated low rates of GVHD in HLA-mismatched unrelated donor 
transplants, while improving T cell and NK cell reconstitution44. 
It is therefore hypothesized that proteasome inhibition can improve the results of haploidentical 
transplantation by both preventing GVHD and augmenting GVT through its enhancement of 
alloreactive NK cell function.  MLN9708 is a selective, orally bioavailable, second-generation 
proteasome inhibitor, which has a shorter proteasome dissociation half-life and improved 
pharmacokinetics, pharmacodynamics, and antitumor activity compared with bortezomib.  In 
clinical studies of patients with myleoma, MLN9708 has shown comparable clinical activity and 
a better safety profile when compared to bortezomib45.  Benefits of MLN9708 include the 
convenience of once weekly oral fixed dosing as well as a significantly decreased risk of 
peripheral neuropathy, which is one of the biggest impediment to long-term administration of 
bortezomib.  We further hypothesize that the combination of tacrolimus and MLN9708 will 
provide sufficient GVHD prophylaxis making it possible to eliminate the need for 
mycophenolate mofetil, which has been shown to significantly decrease NK cell proliferation 
and cytotoxic function46. 
1.1.1    Disease Under Treatment 
High risk hematologic malignancies with standard indication for nonmyeloablative 
haploidentical transplantation include acute lymphoblastic leukemia/lymphoma in complete 
remission, acute myeloid leukemia in complete remission, relapsed Burkitt leukemia/lymphoma 
in complete remission, multiple myeloma (relapsed disease and/or presence of del17p), relapsed 
lymphoma including marginal zone, follicular, and chemotherapy-sensitive diffuse large B cell, 
T cell, Mantle cell, and Hodgkin’s. Specific disease criteria are listed in section 5.1 Inclusion 
Criteria. 


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1.1.2         MLN9708  
1.2    
Preclinical Experience 
Please refer to the current MLN9708 Investigator’s Brochure (IB) and Safety Management 
Attachment (SMA). 
1.3    
Clinical Experience 
As of 30 April 2012, 382 patients have been treated with MLN9708 across 9 enrolling, sponsor-
led phase 1 or phase 1/2 studies evaluating both twice-weekly and weekly dosing schedules.  
MLN9708 is available as an intravenous and oral formulation. Regardless of the route of 
administration in the twice-weekly dosing schedule, MLN9708 is given on Days 1, 4, 8, and 11 
of a 21-day cycle; in the weekly dosing schedule, the drug is given on Days 1, 8, and 15 of a 28-
day cycle. To date, the development of oral MLN9708 has focused on multiple myeloma 
[relapsed and/or refractory and newly diagnosed] and a different yet related plasma cell 
dyscrasia, systemic light chain (AL) amyloidosis. A clinical pharmacology study looking at 
drug-drug interactions (DDIs), the effect of food, and bioavailability also uses the oral 
formulation. Details of these trials can be found in ClinicalTrials.gov and the MLN9708 IB.   
1.4   
Pharmacokinetics and Drug Metabolism 
Clinical IV and PO pharmacokinetic (PK) data show that MLN9708 (measured as the 
biologically active boronic acid form of MLN9708 [MLN2238]) has multi-exponential 
disposition with a rapid initial phase that is largely over by 4 hours.  Oral MLN9708 is rapidly 
absorbed with a median time to first maximum plasma concentration (Tmax) of approximately 0.5 
to 2.0 hours and terminal t1/2 after multiple dosing of approximately 5 to 7 days47. 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 BSA48.  Based on these data, a 
recommendation was made for fixed dosing in clinical trials.  An absolute bioavailability of 67% 
was determined for MLN9708 using the population PK analysis.  See the IB for information on 
the PK for IV doses of MLN9708. 
Metabolism appears to be the major route of elimination for MLN9708, with negligible urinary 
excretion of the parent drug (< 3% of dose).  In vitro studies of liver microsomes show that 
MLN9708 is metabolized by multiple cytochrome P450 enzymes (CYPs) and non-CYP 
enzymes/proteins.  The rank order of relative biotransformation activity of the 5 major human 


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CYP isozymes is 3A4 (34.2%) > 1A2 (30.7%) > 2D6 (14.7%) > 2C9 (12.1%) > 2C19 (< 1%).  
MLN9708 is not an inhibitor of CYPs 1A2, 2C9, 2C19, 2D6, or 3A4, nor is it a time-dependent 
inhibitor of CYP3A4/5.  The potential for MLN9708 treatment to produce 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 because of the potential for first-pass metabolism when 
MLN9708 is administered via the PO route and because of the moderate contribution of 
CYP3A4- and CYP1A2-mediated metabolism of MLN9708 in human liver microsomes.  
MLN9708 may be a weak substrate of P-glycoprotein (P-gp), breast cancer resistance protein 
(BCRP), and multidrug resistance associated protein (MRP2) efflux pump transporters.  
MLN9708 is not an inhibitor of P-gp, BCRP, and MRP2.  The potential for DDIs with substrates 
or inhibitors of P-gp, BCRP, and MRP2 is, therefore, inferred to be low. 
1.5    
Clinical Trial Experience Using the Oral Formulation of MLN9708 
In the 7 studies actively enrolling patients to investigate oral MLN9708 in patients with differing 
malignancies (multiple myeloma, AL amyloidosis, nonhematologic cancers, and lymphoma), a 
total of 242 patients have been treated as of 30 April 2012. These patients have been treated with 
different doses of MLN9708, either as a single agent treatment or in combination with currently 
clinically available treatments. Information regarding the ongoing studies, patient populations, 
and doses investigated are included in Table 1-1. 
 


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Table 1-1   
Ongoing Studies of Oral MLN9708 
Trial/ 
Population 
Description 
Doses Investigated 
C16003 
RRMM 
N = 58 
PO, twice weekly (TW), single agent 
0.24-2.23 mg/m2, TW 
MTD:  2.0 mg/m2 
DLT:  rash, thrombocytopenia 
C16004 
RRMM 
N = 52 
PO, weekly (W), single agent 
0.24-3.95 mg/m2, W 
MTD:  2.97 mg/m2 
DLT:  rash, nausea, vomiting, diarrhea 
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 
RP2D*:  4.0 mg fixed (switched to fixed dosing in 
phase 2, relevant to 2.23 mg/m2) 
C16006 
NDMM 
N = 28 
PO, TW (Arm A- 42 day cycle) and W 
(Arm B- 28 day cycle), combination 
with melphalan and prednisone 
Arm A*:  3-3.7 mg, fixed dose, TW 
DLT: rash, thrombocytopenia, subileus 
Arm B*:  5.5 mg, fixed dose, W 
DLT: Esophageal ulcer 
C16007 
RRAL 
N = 6 
PO, W, single agent 
4-5.5 mg, fixed dose*, W 
MTD: 4 mg 
DLT: thrombocytopenia, dirrhea, dyspnea, acute 
rise in creatinine, cardiac arrest 
 
C16008 
NDMM 
N=11 
PO, TW, combination with LenDex 21 
day cycle 
3.0-3.7 mg fixed dose* W 
MTD: 4 mg 
 
C16009 
Solid 
tumors, 
Lymphomas 
N = 22 
PO, W, single agent 
5.5 mg fixed dose* W 
C16010 
RRMM 
N = 1 
PO, W, combination with LenDex 
4.0 mg fixed dose* W 
TB-
MC010034 
RRMM 
N = 5 
PO, W, single agent in 1s part of study 
then in combination with LenDex in 2nd 
part 
3.0 mg fixed dose* W 
DLT: thrombocytopenia, nausea, hypertension, 
diarrhea 
Abbreviations:  RRAL = Relapsed or refractory Primary systemic light chain (AL) amyloidosis; BSA = body 
surface area ; DLT = dose-limiting toxicity; IV = intravenuously; LenDex = lenalidomide plus 
dexamethasone; MTD = maximum tolerated dose; NDMM = newly diagnosed multiple myeloma; PO = 
orally; RRMM = relapsed and/or refractory multiple myeloma; RP2D = recommended phase 2 dose 
* Approximate body surface area (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 MLN9708 
The emerging safety profile indicates that oral MLN9708 is generally well tolerated with 
predominant toxicities largely reversible, able to be monitored by routine clinical examinations 
and manageable by dose reductions, discontinuation, or standard supportive care. From 
experience from phase 1 through 2 studies the major toxicities can be managed to allow repeat 
treatment cycles over periods extending beyond 24 months.  
In the 4 ongoing studies (C16003, C16004, C16007, and C16009) investigating single-agent oral 
MLN9708 in patients with differing malignancies (multiple myeloma, AL amyloidosis, 
nonhematologic cancers, and lymphoma), a total of 146 patients have been treated as of 30 April 
2012. These patients have been treated with different doses of MLN9708 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 MLN9708 Studies (C16003, C16004, C16007, and C16009) is 
shown in Table 1-2. 
Table 1-2 
Summary of Most Common (At Least 10% of Total) All Grade Treatment-
Emergent Adverse Events (Oral MLN9708 Single-Agent [C16003/4/7/9] 
Safety Population) 
Primary System Organ Class  
Preferred Term and Incidence 
N=146 
n (%) 
Subjects with at Least One Adverse Event 135 (92) 
 
Gastrointestinal disorders 102 (70) 
Nausea 68 (47); Diarrhoea 55 (38); Vomiting 51 (35); 
Abdominal pain 21 (14); Constipation 21 (14) 
General disorders and administration site conditions 98 
(67) 
Fatigue 71 (49); Pyrexia 31 (21); Oedema peripheral 15 
(10) 
Blood and lymphatic system disorders 77 (53) 
Thrombocytopenia 60 (41); Anaemia 30 (21); 
Neutropenia 23 (16); Leukopenia 15 (10) 
Nervous system disorders 63 (43) 
Headache 20 (14); Dizziness 18 (12) 
Metabolism and nutrition disorders 60 (41) 
Decreased appetite 39 (27) Dehydration 21 (14) 
Respiratory, thoracic and mediastinal disorders 60 (41) 
Cough 22 (15); Dyspnoea 21 (14) 
Skin and subcutaneous tissue disorders 60 (41) 
Rash macular 17 (12) 
Musculoskeletal and connective tissue disorders 56 
(38) 
Arthralgia 20 (14); Back pain 17 (12) 
Infections and infestations 54 (37) 
Upper respiratory tract infection 21 (14) 
Source: MLN9708 Investigator’s Brochure Edition 6 
Treatment emergent is defined as any AE that occurs after administration of the first dose of any study drug through 
30 days after the last dose of any study drug, any event that is considered drug-related regardless of the start 
date of the event, or any event that is present at baseline but worsens in intensity or is subsequently considered 
by the investigator to be drug-related.  
Subject Incidence: A subject counts once for each preferred term. Percentages use the number of treated subjects as 
the denominator 


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In the 3 studies actively enrolling patients to investigate oral MLN9708 in combination with 
standard combination regimens in patients with newly diagnosed multiple myeloma, a total of 96 
patients have been treated as of 30 April 2012. These patients have been treated with different 
doses of MLN9708 in combination with lenalidomide and dexamethasone in 2 trials (C16005 
and C16008) and with melphalan and prednisone in 1 trial (C16006). The most frequent (at least 
10%) adverse events occurring in the pooled safety population from Studies C16005, C16006, 
and C16008 is shown in Table 1-3. In combinations trials, related is defined as possibly related 
to any drug in the combination regimen, not just specifically related to MLN9708. 
Table 1-3 
Summary of Most Common (At Least 10% of Total) Treatment- Emergent 
Adverse Events (Oral MLN9708 Combination Agent [C16005/6/8] Safety 
Population) 
 
Primary System Organ Class  
Preferred Term and Incidence 
N= 96 n (%) 
Subjects with at Least One Adverse Event 135 (92) 
 
 
Gastrointestinal disorders 70 (73) 
Nausea 32 (33); Constipation 29 (30); Vomiting 25 (26) 
Diarrhoea 22 (23) 
General disorders and administration site conditions 64 
(67) 
Fatigue 37 (39); Oedema peripheral 20 (21); Pyrexia 19 
(20) 
Skin and subcutaneous tissue disorders 57 (59) 
Rash 13 (14) 
Nervous system disorders 46 (48) 
Neuropathy peripheral 13 (14); Dysgeusia 12 (13) 
Dizziness 11 (11) 
Musculoskeletal and connective tissue disorders 45 
(47) 
Back pain 18 (19); Muscle spasms 10 (10) 
Blood and lymphatic system disorders 42 (44) 
Thrombocytopenia 28 (29); Anaemia 22 (23);  
Neutropenia 19 (20) 
Infections and infestations 40 (42) 
Upper respiratory tract infection 17 (18);  
Metabolism and nutrition disorders 38 (40) 
Decreased appetite 11 (11) 
Respiratory, thoracic and mediastinal disorders 34 (35) 
Dyspnoea 13 (14); Cough 11 (11) 
Psychiatric disorders 23 (24) 
Insomnia 15 (16) 
Source: MLN9708 Investigator’s Brochure Edition 6. 
Treatment emergent is defined as any AE that occurs after administration of the first dose of any study drug through 
30 days after the last dose of any study drug, any event that is considered drug-related regardless of the start 
date of the event, or any event that is present at baseline but worsens in intensity or is subsequently considered 
by the investigator to be drug-related. 
Subject Incidence: A subject counts once for each preferred term. Percentages use the number of treated subjects as 
the denominator. 
 
The clinical experience with MLN9708 also shows early signs of antitumor activity as evidenced 
by at least a 50% reduction in disease burden in some patients and prolonged disease 


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stabilization in others across all ongoing trials. The antitumor activity has been seen with single-
agent MLN9708, when combined with established therapies, and across the malignancies studied 
(advanced solid tumors49, non-Hodgkin’s disease, Hodgkin’s disease50, relapsed and/or 
refractory multiple myeloma [RRMM; 51,52], relapsed or refractory systemic light chain 
amyloidosis [RRAL; 53], and newly diagnosed multiple myeloma [NDMM; 54-56] to date. 
Though additional data are needed to characterize the clinical benefit of this drug, the emerging 
data supports the ongoing development of MLN9708. 
Of particular relevance to this study (C16011) is the clinical experience from Studies C16004 
and C16007 in which single-agent MLN9708 is administered weekly in patients with RRMM or 
RRAL, respectively.  
1.6    
Relapsed and/or Refractory Multiple Myeloma 
Study C16004 is an open-label, dose-escalation, phase 1 study of MLN9708 administered 
weekly on Days 1, 8, and 15 of a 28-day cycle in adult patients with RRMM. Patients with MM 
enrolled in the dose-escalation component of the study have relapsed following at least 2 lines  of 
therapy, which must have included bortezomib, thalidomide (or lenalidomide), and 
corticosteroids. The dose-escalation phase of the trial has completed. In this study, 2 of 3 patients 
experienced protocol-defined DLTs (Grade 3 rash and Grade 3 nausea, vomiting, and diarrhea) 
at a dose of 3.95 mg/m2. As per protocol, subsequent patients were treated at 1 dose level below 
(2.97mg/m2) where 1 of 6 patients experienced a DLT (Grade 3 nausea, vomiting, and diarrhea). 
The MTD of weekly oral MLN9708 was determined to be 2.97 mg/m2. 
Once the MTD was established, cohorts of patients representing the heterogeneous patient 
population currently seen in clinical practice were enrolled in order to further evaluate the safety, 
tolerability, efficacy, PK, and pharmacodynamics of oral MLN9708. The MTD expansion 
cohorts enrolling are: 
1. Relapsed and Refractory expansion cohort [refractory is defined as disease progression 
while on therapy or within 60 days after the last dose of therapy]; 
2. Carfilzomib expansion cohort 
3. Proteasome Inhibitor-Naïve expansion cohort 
4. VELCADE-Relapsed expansion cohort 


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Final study results are not available for this ongoing trial, but preliminary data suggest 
MLN9708 has antitumor activity in heavily pretreated MM patients, with durable 
responses/disease control, and is generally well tolerated57, 58. 
As of the 30 April 2012 data cut, these patients are considered heavily pretreated as evidenced by 
a median number of 4 (range 1–13) prior lines of therapy, with 66% refractory to the last line of 
therapy. Patients have received a median of 2 cycles of therapy (range, 1- 11). Five patients have 
achieved objective response: 1 patient achieved a VGPR and 4 patients achieved a PR. 
Additionally, 15 patients achieved durable disease stabilization for up to 9.5 months. At data cut-
off, 15 patients remain on treatment; discontinuation of treatment was primarily due to 
progressive disease (69%). 
A summary of the safety profile of patients treated in Study C16004 is outlined in Table 1-4. 
Overall, 92% of patients experienced a TEAE of any grade and of any cause. Peripheral 
neuropathy was limited to Grade 1/ 2 in 6 patients, with 3 patients reporting baseline Grade 1 PN 
at study entry. 
 
Table 1-4    
Study C16004, Oral MLN9708, Single Agent, Given Weekly:  Most 
Common TEAEs as of 30 April 12 (N= 52) 
Most Common (> 20%) Any Grade and Irrespective 
of Cause 
Thrombocytopenia (54%) 
Fatigue (48%) 
Nausea (44%), diarrhea (44%) 
Vomiting (37%) 
Decreased appetite (33%) 
Rash* (31%) 
Anemia (25%) 
Neutropenia (23%) 
Drug-Related Grade  3 in > 5% of patients 
 
Thrombocytopenia (38%) 
Diarrhea and neutropenia 17% (each), fatigue and 
lymphopenia 10% (each), nausea and decreased 
appetite 8% (each) and vomiting 6% 
 
Source: MLN9708 Investigator’s Brochure Edition 6 
* Rash includes preferred terms of rash macular, rash, maculo-papular, rash morbilliform, rash pruritic, 
pruritus,, rash erythematous, exfoliative rash, and rash popular 
 
Dose reductions required were due to AEs that included rash, neutropenia, thrombocytopenia, 
diarrhea, nausea, vomiting, dehydration, hypotension, increase in serum creatinine, abdominal 
pain, ileus, fatigue, and pneumonia. The AEs reported for the 5 patients who were required to 


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discontinue treatment included Grade 2 MLN9708-related nausea/vomiting in 1 patient treated 
above the MTD, Grade 3 MLN9708-related diarrhea in a second patient, related Grade 3 
thrombocytopenia, related Grade 2 dyspnea, and not related Grade 4 elevation in creatinine (1 
patient each). There were no on-study deaths.  
Study C16007 is evaluating single agent weekly , Day 1, 8, and 15 of a 28-day cycle, oral dosing 
in patients with RRAL after at least 1 prior therapy. The objectives of this study are to determine 
the safety, tolerability, and MTD, as well as to determine hematologic and organ response rates 
in this patient population. The starting dose level was selected from Study C16004 as previously 
described. In Study C16007 the dose was switched from the BSA-based dosing to the fixed dose, 
thereby the 4.0 mg fixed starting dose in Study C16007 corresponds to the 2.23 mg/m2 dose (one 
dose level below MTD) from Study C16004. This study is currently enrolling patients in the 
dose-expansion portion of the trial. 
As of 30 April 2012, 14 patients have been treated in this study. At the first dose level of 4.0 mg, 
1 of 6 patients experienced a protocol-defined DLT (that is, thrombocytopenia that lasted more 
than 2 weeks, which met the definition of a DLT due to the delay in starting Cycle 2). As per 
protocol, the dose was escalated to 5.5 mg for the next cohort of patients where 2 of 5 patients 
experienced a DLT (Grade 3 diarrhea, n=1; and Grade 2 dyspnea, Grade 2 acute rise in serum 
creatinine, and Grade 4 cardiac arrest, n=1). The latter patient did not appear to have cardiac AL 
amyloidosis by echocardiogram on study entry, but did have substantial renal involvement. After 
the occurrence of this DLT, diagnoses included cardiac involvement and CHF. The MTD of 
weekly oral MLN9708 was determined to be 4.0 mg. Following the establishment of the MTD, 
patients are currently being enrolled in to 1 of 2 cohorts: proteasome inhibitor naïve or 
proteasome inhibitor exposed59. 
As of the 30 April 2012 data cut, the patients enrolled in the study are considered heavily 
pretreated, as evidenced by a median number of 3 prior lines of therapy (range 1–7), with 38% 
and 46% of patients having been previously treated with bortezomib and lenalidomide, 
respectively. To be eligible for the study, patients must have amyloid involvement of the heart, 
kidney, or both; at the data cut the organ involvement distribution was 6, 4, and 4 patients, 
respectively. Patients have received a median of 2.5 cycles of therapy (range, 1-12). Eight 
patients remain on treatment. Early signs of activity have been reported. There were 11 patients 
who have received at least 1 cycle of therapy with completed response assessments (9 in the 4.0 
mg [MTD] cohort and 2 in the 5.5 mg cohort). The overall hematologic response rate at MTD is 
56% (5 patients achieved a hematologic response [4 VGPR and 1 PR]; 3 patients showed no 
change, and 1 patient had an early progression.  


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A summary of the safety profile of patients treated in Study C16007 is outlined in Table 1-5. 
Overall, 86% of patients experienced a TEAE of any grade and of any cause. 
Table 1-5    
Study C16007, Oral MLN9708, Single Agent Given Weekly  Most 
Common TEAEs as of 30April 12 (N = 14) 
Most Common (> 20%) 
Any Grade and Irrespective of Cause 
Nausea (50%) 
Fatigue (36%) 
Thrombocytopenia (29%) 
Diarrhea (29%) 
Decreased Appetite (21%) 
Peripheral Edema (21%) 
Dyspnea (21%) 
Abdominal pain (21%) 
Drug-Related Grade  3 in more than 3 Patients  
Thrombocytopenia 5 patients, rash 3 patients, 
dehydration 2 patients, fatigue 2 patients 
 
Source: MLN9708 Investigator’s Brochure Edition 6 
 
One patient discontinued study drug administration due to a TEAE (patient with DLT of acute 
rise in serum creatinine, dyspnea, and cardiac arrest treated at 5.5 mg, as noted above). No death 
has been reported. 
The potential risks reported with MLN9708 use, pooled from all studies using the oral 
formulations, were anticipated based on preclinical data and previous experience with 
VELCADE and are noted in the MLN9708 IB, SMA, and ICF documents. Regardless of whether 
MLN9708 is administered on the once weekly or twice weekly dosing schedule, there is 
consistency among the type of TEAEs reported, despite some differences in the frequency and 
severity of the reported events. While the predominant potential toxicities may be severe in some 
cases, they are largely reversible, and can be managed by routine clinical monitoring and 
standard medical interventions, which may include dose reductions and supportive care. Please 
refer to the MLN9708 IB and SMA for further information. 
1.7    
Newly Diagnosed Multiple Myeloma (NDMM) 
In Study C16005, MLN9708 is given weekly (Days 1, 8, and 15), in combination with 
lenalidomide (Days 1-21), and dexamethasone (Days 1, 8, 15, and 22) in a 28-day cycle.  
Enrollment to this study is closed.   


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Clinical data as of 30 April 2012 is available.  The MTD in Study C16005 was determined to be 
2.97 mg/m2 given weekly in a 28-day cycle with LenDex.  The DLTs were urticarial rash, 
dizziness, nausea, orthostatic hypotension, vomiting, diarrhoea, and syncope.  The recommended 
phase 2 dose (RP2D) estimation was established following evaluation of the available data from 
the phase 1 portion of the trial which included, but was not limited to, analyses of efficacy results 
and adverse events (Grade 3/4 AEs, SAEs, all grades peripheral neuropathy, and treatment 
discontinuation).  Given that the dose of MLN9708 at 2.97 mg/m2 compromised the maximal 
dosing of lenalidomide and that the dose of 2.23 mg/m2 is very tolerable and clinically active, 
Millennium designated 2.23 mg/m2 as the RP2D after evaluation of the data and discussion with 
investigators.  The RP2D of 2.23 mg/m2 has been translated into a fixed dose of 4.0 mg based on 
the results from the population PK analysis.  Enrollment in this study has been completed; final 
study results are not available, but preliminary data suggests oral MLN9708 given weekly plus 
lenalidomide and dexamethasone in a 28-day cycle appears well tolerated with manageable 
toxicity and encouraging antitumor activity.   
In Study C16005, 15 of 15 (100%) patients in the dose escalation portion of the study 
experienced at least 1 TEAE irrespective of grade or causality.  At the MTD across all dose 
expansion cohorts 49 of 53 patients (including 3 patients from the dose escalation cohort [92%]) 
reported at least 1 TEAE irrespective of grade or causality.  In the MTD cohorts, fatigue was the 
most common AE reported (38%).  Other common AEs reported include nausea (32%), 
constipation (30%), upper respiratory infection (23%), and peripheral oedema (21%).  Skin 
toxicity, primarily erythematous rash, occurred in 62% of patients (of note, rash is an 
overlapping toxicity with MLN9708 and lenalidomide).  Peripheral neuropathy was reported in 
13% of patients; Grade 3 in 1 patient.   
A summary of the overall safety profile of patients treated in Study C16005 is outlined in Table 
1-6.  Overall, 100% of 65 patients experienced at least one TEAE of any grade and of any cause.   
Table 1-6    
Study C16005:  Oral MLN9708 Given Weekly in Combination With 
Lenalidomide and Dexamethasone, Most Common TEAEs as of 30 
April 2012 
Most Common (> 20%) Any Grade and Irrespective of 
Cause 
Fatigue (37%) 
Nausea (34%) 
Constipation (31%) 
Vomiting (28%) 
Diarrhoea (26%) 
Thrombocytopenia (23%) 
Upper respiratory tract infection (22%) 


Blood & Marrow Transplant Program at 
Clinical Study Protocol X16035 
Northside Hospital 
 
 
 
28 
 
Anaemia and oedema peripheral ( 20% each) 
Drug-Relateda Grade  3 in  2 Patients  
Nausea, vomiting (n=3 each)  
Thrombocytopenia, lymphopenia, rash pruritic (n=2 each ) 
 
Source: MLN9708 Investigator’s Brochure Edition 6. 
a 
Related means to ANY drug in the study drug combination. 
 
The most common drug-related SAEs reported in Study C16005 as of 30 April 2012 include 
pneumonia, infection, diverticulitis, localised infection, gastrointestinal haemorrhage, respiratory 
syncytial virus (RSV) pneumonia faecaloma, pyrexia, pneumonia respiratory syncytial viral, 
non-cardiac chest pain, peripheral oedma, asthenia, hyponatraemia vomiting, diarrhoea, nausea, 
chest pain, dehydration, anemia, dizziness, peripheral sensory neuropathy, orthostatic 
hypotension, embolism, muscular weakness, acute renal failure, blood creatinine increased, 
maculopapular rash, atrial fibrillation, syncope, hypotension, and deep vein thrombosis, and back 
pain.   
As of the clinical data cutoff, 4 patients have discontinued treatment due to TEAEs including 
gastrointestinal hemorrhage, angioedema, syncope, and RSV pneumonia. 
One death was reported for a patient with RSV pneumonia; the event was deemed by the 
investigator to be related to treatment with MLN9708.   
1.8 
Study Rationale 
In an attempt to reduce relapse risk and improve outcomes following haploidentical 
transplantation for patients with high risk hematologic malignancies, we will implement several 
strategies to augment the well documented effect of NK cell alloreactivity seen in HLA-
mismatched transplantation. These strategies include (1) choosing potential haploidentical 
donors for optimal NK-alloreactivity, (2) utilizing proteasome inhibition post-transplant with 
MLN9708 to both sensitize tumor cells to NK cytotoxicity and protect against graft-versus-host 
disease (GVHD), and (3) eliminating mycophenolate mofetil from the post-transplant 
immunosuppression regimen to improve NK cell reconstitution following haploidentical 
peripheral blood stem cell transplantation. 
Patients will receive a nonmyeloablative haploidentical transplant using a T-cell replete allograft 
and post-transplant cyclophosphamide as previously described at our center (Bashey et al. J Clin 
Oncol. 2013; 31(10):1310-6).  MLN9708 will be administered once weekly for 3 weeks on a 28 
day cycle for one-year post-transplant. Post-transplant immunosuppression will consist of 


Blood & Marrow Transplant Program at 
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Northside Hospital 
 
 
 
29 
 
tacrolimus only (MLN9708 will substitute for mycophenolate mofetil as the second GVHD 
prophylactic medication). 
1.9    Potential Risks and Benefits 
MLN9708 
Please refer to the current MLN9708 Investigator’s Brochure (IB) and Safety Management 
Attachment (SMA). 
MLN9708 is a modified dipeptide boronic acid proteasome inhibitor similar to VELCADE, 
which has a known safety profile [VELCADE PI]. The most frequent AEs reported to date in the 
ongoing MLN9708 phase 1 studies were anticipated based on preclinical data and previous 
experience with VELCADE, and are noted in the IB, the Safety Management Attachment, and 
the informed consent documents. However, it is possible that MLN9708 will have toxicities that 
were not previously observed in or predicted from such sources. Patients will be monitored 
closely for anticipated toxicities.  
MLN9708 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 
trials49,50,51,52,54,55,56. 
This study will be conducted in compliance with the protocol, good clinical practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonisation (ICH) 
guidelines. 
Cyclophosphamide (Cytoxan®) 
Cyclophosphamide is an alkylating agent which prevents cell division primarily by cross-linking 
DNA strands. Cyclophosphamide is cell cycle nonspecific. Cyclophosphamide for injection is 
available in 500mg, 1gram, and 2000 mg vials which are reconstituted with 100 ml sterile water 
for injection. The concentration of the reconstituted product is 20 mg/ml. The calculated dose 
will be diluted further in 500-1000 ml of Dextrose 5%  in water or NS. Each dose will be infused 
over 1-2 hr (depending on the total volume). Clinical toxicities of cyclophosphamide include 
alopecia, nausea and vomiting, headache and dizziness, hemorrhagic cystitis, cardiotoxicity, 
immunosuppression, myelosuppression, pulmonary fibrosis, increased hepatic enzymes and 
syndrome of inappropriate anti-diuretic hormone (SIADH). 


Blood & Marrow Transplant Program at 
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Northside Hospital 
 
 
 
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Mesna (sodium-2-mercapto ethane sulphonate) 
Mesna is a prophylactic agent used to prevent hemorrhagic cystitis induced by the 
oxasophosphorines (cyclophosphamide and ifosphamide). It has no intrinsic cytotoxicity and no 
antagonistic effects on chemotherapy. Mesna binds with acrolein, the urotoxic metabolite 
produced by the oxasophosphorines, to produce a non-toxic thioether and slows the rate of 
acrolein formation by combining with 4-hydroxy metabolites of oxasophosphorines. Mesna is 
available in 1000 mg vials containing a 100 mg/ml solution. Mesna will be diluted and 
administered per institutional standards. Mesna will be utilized per standard of care for the day 3 
and day 4 post transplant cyclophosphamide doses, not for the pre-transplant doses. At the doses 
used for uroprotection mesna is virtually non-toxic. However, adverse effects which may be 
attributable to mesna include nausea and vomiting, diarrhea, abdominal pain, altered taste, rash, 
urticaria, headache, joint or limb pain, hypotension and fatigue.  
Fludarabine (Fludara®) 
Fludarabine phosphate is purine antimetabolite that, after administration, undergoes rapid 
conversion in plasma to the nucleoside 2-fluoro ara-A (F-araA). F-araA subsequently enters cells 
where it is phosphorylated to F-araATP and the monophosphate F-araAMP.  Once activated, F-
araATP inhibits DNA polymerase and ribonucleotide reductase. The monophosphate F-araAMP, 
once incorporated into DNA, is an effective DNA chain terminator. Fludarabine monophosphate, 
50 mg/vial, is reconstituted with 2 ml of sterile water, resulting in a 25mg/ml solution. The 
desired dose is further diluted to concentrations of 0.04-1 mg/ml in normal saline or 5% dextrose 
(50-100ml) for injection and will be administered by IV infusion over 30 minutes. Following IV 
administration, the drug is metabolized to 2-F-araA and widely distributed in tissues.  2-F-araA 
is excreted primarily in urine and has a terminal elimination half-life of 7 to 12 hours. Clinical 
toxicities of fludarabine monophosphate include: myelosuppression, primarily lymphopenia and 
granulocytopenia, alopecia, rash, dermatitis, nausea, vomiting, anorexia, stomatitis, diarrhea, 
somnolence, fatigue, peripheral neuropathy, mental status changes, cortical blindness, 
hepatocellular toxicity with elevation in serum transaminases, and interstitial pneumonitis. These 
effects are reversible when the drug is discontinued.  
Tacrolimus 
Tacrolimus, also known as FK-506, is a macrolide immunosuppressant. It inhibits lymphocytes 
by forming a complex with FKBP-12, calcium, and calmodulin, leading to the decrease in the 
phosphatase activity of calcineurin. This drug is used with corticosteroids for prophylaxis of 
organ rejection in patients receiving allogeneic liver, kidney, or heart transplants. Its use is also 


Blood & Marrow Transplant Program at 
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31 
 
currently being investigated in bone marrow, pancreas, pancreatic islet cell and small bowel 
transplantation. This drug is well-absorbed orally. Tacrolimus is extensively metabolized by the 
mixed-function oxidase system, primary the cytochrome P450 system (CYP3A). A metabolic 
pathway leading to the formation of 8 possible metabolites has been proposed.  Demethylation 
and hydroxylation were identified as the primary mechanisms of biotransformation in vitro.  . 
The metabolized products are excreted in the feces and urine. Nephrotoxic drugs, antifungals, 
calcium channel blockers, cimetidine, danazol, erythromycin, methylprednisone and 
metoclopramide increase the bioavailabilty of FK-506. In contrast, phenobarbital, phenytoin, 
rifamycins and carbamazepine decrease FK-506 levels. Adverse reactions include tremor, 
headache, diarrhea, hypertension, nausea, and renal dysfunction. 
Total Body Irradiation 
Patients as part of their BMT preparative regimen will receive 200 cGy of TBI in one fraction on 
day -1.   The prescription point is located at the midplane of the body at the level of the 
umbilicus.  The dose uniformity as measured by the dose to the reference point (umbilicus) is 
kept within + 10% of the prescribed dose.  An interruption in the radiotherapy regimen should 
only be considered if the patient has developed potentially life threatening complications that 
preclude continuation of the radiotherapy schedule.  The dose rate will be less than 10cGy/min at 
the prescription point and should be   recorded for each treatment as well as the total time of the 
treatment in order to compute the effective dose rate per treatment field.  
Graft Failure 
A risk of participating in this research protocol is that shifting part of the standard HSCT dose of 
cyclophosphamide after the graft infusion may damage the graft. The consequences of damaging 
the graft may include delayed hematologic recovery or graft failure. The risk of delayed 
hematologic recovery does not appear to be severe, based on prior experience with 
nonmyeloablative haploidentical transplantation. However, the risks of delayed hematologic 
recovery in this study cannot be directly extrapolated from referenced studies due to the 
inclusion of the investigational drug, MLN9708, in this protocol. Primary graft failure in the 
setting of a nonmyeloablative preparative regimen is usually not a fatal complication, as 
autologous hematopoietic recovery is usually expected.  
 
Acute and Chronic GVHD 


Blood & Marrow Transplant Program at 
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32 
 
The second major risk in participating in this research protocol is the risk of developing acute 
and/or chronic GVHD. The degree of GVHD varies from mild cutaneous reactions to extensive 
widespread and systemic involvement of skin, liver, and gastrointestinal tract.  The incidence of 
fatal infection is greater in patients developing GVHD due to the immunosuppressive nature of 
GVHD and its associated treatments. The development of grade 3 or higher acute GVHD is 
considered clinically significant and associated with increased morbidity and non-relapse 
mortality. The likelihood of surviving severe GVHD is to a large part dependent on the age of 
the patient and the patient’s overall condition. For the majority of the patients eligible for this 
trial who have high-risk hematologic malignancies, a moderate increase in GVHD may be 
accompanied by an increased graft-versus-malignancy (GVM) benefit, so that the same long-
term relapse free survival is maintained.  
Regimen-related toxicities  
Toxicities directly related to the administration of high-dose chemotherapy and TBI include 
gastrointestinal toxicity (nausea, vomiting, mucositis), alopecia, infertility (which may be 
permanent), interstitial pneumonitis, idiopathic cardiomyopathy, hemorrhagic cystitis, hepatic 
venoocclusive disease, or multi-organ failure which may be fatal. 
Infection 
Infection is a major cause of morbidity in allo HSCT and is a major concern in these patients.  
Infections may be bacterial, viral, parasitic, or fungal.  Often, these infections are life-
threatening, particularly when caused by viral or fungal organisms, and are associated with high 
mortality in the transplant population. 


Blood & Marrow Transplant Program at 
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2.    
STUDY OBJECTIVES 
 
2.1    
Primary  Objectives 
 To estimate the incidence of relapse/progression at one-year post-transplant. 
2.2    
Secondary Objectives 
 To obtain estimates of overall survival (OS), event-free survival (EFS), non-relapse 
mortality (NRM), engraftment, acute and chronic graft-versus-host disease (GVHD). 
 Characterize additional hematologic and non-hematologic toxicities of MLN9708 when 
given post haploidentical transplant. 
 Characterize donor hematopoietic chimerism in peripheral blood at days ~30, ~60, and 
~90 after HSCT. 
3.    
STUDY ENDPOINTS 
3.1    
Primary Endpoints  
 Relapse/Progression 
3.2    
Secondary Endpoints 
 OS, EFS, NRM, engraftment, acute and chronic GVHD 
 Unexpected toxicities attributable to MLN9708  
 Donor hematopoietic chimerism  
4.    
STUDY DESIGN  
4.1    
Overview of Study Design 
Patients will be required to meet institutional guidelines for transplantation and follow the 
institutional standard for post-transplant care.  At a minimum, patients will need to be seen for 
study related purposes according to the following schedule. Other tests and exams will be done 
according to physician preference.  


Blood & Marrow Transplant Program at 
Clinical Study Protocol X16035 
Northside Hospital 
 
 
 
34 
 
 
Test 
Screen 
Month 1 
(4 
weekly 
visits) 
Month 
2 (4 
weekly 
visit) 
Month 
3 (4 
weekly 
visits) 
Month 
4 
Month 
5 
Month 
6 
Months 
7-11 
Month 
12 
End of 
Study  
Months 
18, 24 
and 36 
H & P 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with 
differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PFT* 
X 
 
 
 
 
 
 
 
 
 
 
ECHO* 
X 
 
 
 
 
 
 
 
 
 
 
IDMs 
including 
Hepatitis & 
HIV* 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
**(FOCBP) 
X 
 
 
 
 
 
 
 
 
 
 
GVHD 
assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity 
Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Bone marrow 
biopsy & 
aspirate  
 
 
 
X 
 
 
X 
  
X 
X 
X 
CT/PET for 
NHL/HD for 
disease 
assessment 
 
 
 
X 
 
 
X 
  
X 
X 
X 
Research 
Sample*** 
 X 
X (Day 
30) 
X (Day 
60) 
X (Day 
90) 
 
 
X 
 
X 
 
 
Survival 
 
 
 
 
 
 
 
 
 
 
X 
New 
malignancy 
assessment 
 
 
 
 
 
 
 
 
 
 
X 
 
*Testing that is done for transplant is acceptable if done within 6 weeks of the start of study drug. 


Blood & Marrow Transplant Program at 
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Northside Hospital 
 
 
 
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**Women with a uterus <50 or women >50 but < one year without a menstrual cycle) are considered 
FOCBP. 
*** Research samples will be collected for lymphocyte subsets.  Additional PBMCs will be collected 
to be frozen for future immune reconstitution studies. Approximately 30-50ml of blood will be 
collected at each time point.    
 
MLN9708 will be given weekly x 3 weeks every 28 day cycles, for up to 12 cycles starting at 
D+5 post-transplant.   
4.2    
Number of Patients 
Twenty-five (25) patients will be enrolled on this study.  Should a patient sign consent and either 
not be transplanted or elect not to start MLN9708, they will be considered a screen failure.  
Patients who have begun high dose chemotherapy and decide not to start MLN9708 will be 
placed on mycophenolate mofetil 15 mg/kg actual body weight orally three times daily 
(maximum total daily dose of 3 grams) through day +35 in addition to tacrolimus for GVHD 
prevention.    
4.3   Duration of Study 
Patients have the potential to continue on active study treatment for up to 12 months post-
transplant depending on disease assessment.  Adverse events will be collected for 30 days post 
the last dose of study drug given.  Patients will be followed for survival per institutional 
guidelines at a minimum of 18, 24 and 36 months post-transplant.    
4.4 
Correlative Samples  
Patients will be asked to participate in optional research.  Correlative samples will be drawn 
at baseline, day 30, 60, 90, 6mo, 12 months for flow cytometric analysis for T cell and NK 
cell recovery.   Additional PBMCs will be collected and frozen for future immune 
reconstitution studies, including T cell receptor spectratyping and flow cytometric 
measurement of naïve, memory, and regulatory T cell reconstitution. Approximately 30-50ml 
of blood will be collected at each time point.     
5.      STUDY POPULATION 
5.1    INCLUSION CRITERIA 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 


Blood & Marrow Transplant Program at 
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Northside Hospital 
 
 
 
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1. Availability of a 3/6 – 5/6 matched (HLA-A, B, DR) related donor   
 Donor must have negative HLA cross-match in the host vs. graft direction. 
 Donor must be willing to donate mobilized peripheral blood stem cells 
2. Male or female patients Age ≥ 18 years 
3. Karnofsky status ≥ 70% *(Appendix 1) 
4. Voluntary written consent must be given before performance of any study related procedure 
not part of standard medical care, with the understanding that consent may be withdrawn by 
the patient at any time without prejudice to future medical care. 
5. One of the following high-risk malignancies: 
Chronic Myelogenous Leukemia 
 Chronic myelogenous leukemia in chronic phase, resistant and/or intolerant to 
tyrosine kinase inhibitors (OR) 
 Chronic myelogenous leukemia in accelerated phase (OR) 
 Chronic myelogenous leukemia with blast crisis that has entered into a second 
chronic phase following induction chemotherapy.   
Acute Myelogenous Leukemia 
 2nd or subsequent complete remission (OR) 
 Primary induction chemotherapy failure, but subsequently entered into a complete 
remission (OR) 
 1st complete remission with poor risk cytogenetics or molecular markers; or arising 
from preceding hematological disease  
Myelodysplastic Syndrome 
 Treatment-related 
 Monosomy 7 or complex cytogenetics 


Blood & Marrow Transplant Program at 
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 IPSS score of 1.0 or greater   
 Chronic myelomonocytic leukemia (CMML)  
Acute lymphocytic leukemia/lymphoblastic lymphoma 
 2nd or subsequent complete remission (OR) 
 Primary induction chemotherapy failure, but subsequently entered into a complete 
remission (OR) 
 1st complete remission with poor risk cytogenetics  
Chronic Lymphocytic Leukemia / Prolymphocytic Leukemia 
 Duration of remission <12 months after receiving chemotherapy with a nucleoside 
analog (OR) 
 High risk features (i.e. 17p deletion), (OR)  
 Second or subsequent relapse 
Hodgkin’s or Non-Hodgkin’s Lymphoma (including low-grade, mantle cell, and 
intermediate-grade/diffuse) 
 Previously treated disease that has either relapsed or failed to respond adequately to 
conventional-dose therapy or autologous transplantation (AND) 
 Chemoresponsive to most recent salvage therapy 
Multiple Myeloma 
 Presence of a poor risk cytogenetic abnormality [i.e. 17p, t(4;14)] 
 Relapse post autologous transplant 
5.2 
    
Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
1. 
Patients will not be excluded on the basis of sex, racial or ethnic background.  


Blood & Marrow Transplant Program at 
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Northside Hospital 
 
 
 
38 
 
2. 
Prior allogeneic transplant 
3. 
Poor cardiac function: left ventricular ejection fraction <40% 
4. 
Poor pulmonary function: FEV1, FVC, or DLCO <50% predicted  
5. 
Poor liver function: bilirubin >2.5 mg/dl (not due to hemolysis, Gilbert’s or primary 
malignancy), AST/ALT > 3X ULN 
6. 
Poor renal function: Creatinine >2.0 mg/dl or creatinine clearance (calculated creatinine 
clearance is permitted) < 40 mL/min 
7. 
Ongoing or active systemic infection, active hepatitis B or C virus infection, or known 
human immunodeficiency virus (HIV) positive. 
8. 
Women of childbearing potential who currently are pregnant or who are not practicing 
adequate contraception 
9. 
Patients who have any debilitating medical or psychiatric illness which would preclude 
their giving informed consent or their receiving optimal treatment and follow-up.  
10. Systemic treatment, within 14 days before the first dose of MLN9708, with strong 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. 
11. Patient has  Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical examination 
during the screening period. 
12. Participation in other clinical trials, including those with other investigational agents not 
included in this trial, within 21days of the start of this trial and throughout the duration of 
this trial.  
13. Infection requiring systemic antibiotic therapy or other serious infection within 14 days 
before study enrollment. 
14. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled 
hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, 
unstable angina, or myocardial infarction within the past 6 months. 


Blood & Marrow Transplant Program at 
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Northside Hospital 
 
 
 
39 
 
15. Known allergy to any of the study medications, their analogues, or excipients in the various 
formulations of any agent. 
16. Known GI disease or GI procedure that could interfere with the oral absorption or tolerance 
of MLN9708 including difficulty swallowing. 
5.3    
Criteria for donor selection 
1. 
Donors will be family members haploidentically matched to the recipient at least 5/10 loci 
(HLA-A, B, C, DR, DQ).  Half siblings are permitted as donors. 
2. 
Donors must be willing to donate mobilized peripheral blood progenitor cells. 
3. 
Donors will be selected to avoid both a positive HLA crossmatch in the host-versus-graft 
(HVG) direction and/or high titer donor specific antibodies as determined by the pre-
transplant panel reactive antibody (PRA) testing.   
4. 
Donors will be selected preferentially to maximize NK alloreactivity in the following order 
of preference.  Priority will be given to donors with inhibitory Kir-ligand mismatches in the 
GVH direction.  In the setting of multiple possible NK alloreactive donors, preference will 
be given to donors having a group “B” Kir haplotype.  If no NK alloreactive donors are 
available, preference will be given to donors with the highest group B haplotype content28 
(appendix 2).  
6.    
TREATMENT PLAN / STUDY DRUG 
6.1   Transplant Regimen 
Peripheral Blood Stem Cell Collection  
Peripheral blood stem cells will be collected by institutional guidelines following standard G-
CSF-based mobilization and infused on day 0.  Cryopreservation of the stem cell product prior to 
infusion is permissible. 
Stem Cell Processing 
Minor ABO incompatible stem cell grafts will be plasma reduced and washed.  Major ABO 
incompatible stem cell products will not require manipulation.   


Blood & Marrow Transplant Program at 
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Northside Hospital 
 
 
 
40 
 
Preparative Regimen 
 Fludarabine 30 mg/m2 infused over 30 minutes once daily on days -6, -5, -4, -3 and -2 
(total dose, 150 mg/m2). 
 Cyclophosphamide 14.5mg/kg/d infused over 1-2 hours once daily on days -6 and -5 
 TBI 200 cGy to be administered in 1 fraction on day -1.   
Stem Cell Infusion (Day of Transplant) day 0. 
 
Post-transplant Cyclophosphamide 
 Cyclophosphamide 50mg/kg will be given on D+3 post-transplant (within 72 hr of 
PBSC infusion) and on D+4 post-transplant. Cyclophosphamide will be given as an IV 
infusion over 2 hours. Hydration and Mesna will be given according to the institution’s 
standard of care.   
Chemotherapy Dosing:   
Fludarabine dose will be based on actual body weight.  Cyclophosphamide pre-transplantation 
dose is based on the lesser of adjusted ideal body weight or actual body weight.  
Cyclophosphamide post-transplantation dosing weight is based on the lesser of actual or ideal 
body weight.   
 Ideal Body Weight (IBW) Formulas: 
 
 
Males IBW = 50 kg + 2.3 kg/inch over 5 feet 
 
 
Females IBW = 45.5 + 2.3 kg/inch over 5 feet 
 
 
For patients less than 5 feet, subtract 2.3 kg/inch 
 Adjusted Ideal Body Weight (AIBW) Formula: 
 
 
AIBW = IBW + [(0.25) x (ABW – IBW)] 
 Doses of Fludarabine will be adjusted as needed according to creatinine clearance: 
 
 
Creatinine Clearance =  (140-Age) x IBW ( x 0.85 for females) 


Blood & Marrow Transplant Program at 
Clinical Study Protocol X16035 
Northside Hospital 
 
 
 
41 
 
 
 
 
 
 
 
 
72 x Serum Creatinine 
 
CHEMOTHERAPEUTIC 
AGENT 
Calculated 
Creatinine 
Clearance 
46-60 ml/min 
Calculated 
Creatinine 
Clearance  
31-45 ml/min 
 
Fludarabine 
 
80% of total 
dose 
 
75% of total 
dose 
 
Growth factor support:  Patients will receive G-CSF (Filgrastim) 5 mcg/kg/d SQ starting day +5 
and continuing until the ANC >1000/mm3 x 3 days or 1500/mm3 x 1 day. 
Supportive Care: Antibiotic prophylaxis and other supportive care measures will be implemented 
according to institutional guidelines. Ciprofloxacin is not permitted while receiving MLN9708 
due to its inhibition of CYP1A2; however alternative floroquinolones are acceptable 
(levofloxacin, moxifloxacin, gatifloxacin).  Broad-spectrum azole anti-fungal medications such 
as voriconazole, posaconazole, or itraconazole are not permitted while receiving MLN9708 due 
to its inhibition of CYP3A4.  Acceptable anti-fungal prophylaxis medications include the 
echinocandins (i.e. Micafungin) or liposomal Amphotericin (i.e. Ambisome). 
Post-transplant immunosuppression: 
 It is crucial that NO immunosuppressive agents are given until 24 hours after the 
completion of the post-transplant Cyclophosphamide.  This includes steroids as anti-
emetics. 
 Tacrolimus 0.03mg/kg/day infuse over 24 hours starting on day+5 (adjusted to maintain a 
trough level of 5-15 ng/ml) and switched to oral (twice-daily divided dose) on day 21 or 
when able to tolerate p.o.  Tacrolimus will be discontinued on day +180, in the absence 
of clinically significant GVHD. 


Blood & Marrow Transplant Program at 
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Northside Hospital 
 
 
 
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MLN9708 (Ixazomib®): 
 MLN9708 will be administered orally weekly x 3doses q28days, up to 12 monthly 
cycles, starting at day +5 post-transplant (see section 6.2).   
 It will be given at a fixed dose of 4mg po with dose adjustment for hematologic or non-
hematopoietic toxicity (see section 6.3). 
6.2   MLN9708 Administration 
MLN9708 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 sub-investigator(s).  Patients 
should be monitored for toxicity, as necessary, and doses of MLN9708 should be modified as 
needed to accommodate patient tolerance to treatment; this may include symptomatic treatment, 
dose interruptions, and adjustments of MLN9708 dose (see Section 6.3). 
Capsules of MLN9708 will also be referred to as study drug.  Study drug will be supplied by 
Millennium as capsules of 2.3, 3.0 and 4.0 mg MLN9708. MLN9708 will be administered at a 
fixed dose of 4mg orally weekly x 3doses, q28days, up to 12 monthly cycles, starting at day +5 
post-transplant, with dose adjustment for hematologic or non-hematopoietic toxicity (see Section 
6.3).  
Patients should be instructed to swallow MLN9708 capsules whole, with water, and not to break, 
chew, or open the capsules.  Study drug should be taken on an empty stomach (no food or drink) 
at least 1 hour before or 2 hours after a meal.  Each capsule should be swallowed separately with 
a sip of water.  A total of approximately 8 ounces (240 mL) of water should be taken with the 
capsules.   
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 doseIn case 
of vomiting repeat doses should be given as follows: 
1. If vomiting occurs within 30 minutes of taking a dose and the capsule is   found then the 
entire dose should be repeated.  Repeat dosing should occur as soon as nausea has 
resolved. Unexpected delays in repeat dosing are acceptable as long as dosing is complete 
at least 72 hours before the next scheduled dose.   


Blood & Marrow Transplant Program at 
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43 
 
2. If  vomiting occurs within 30 minutes of taking a dose and no capsule  is found then 50% 
of the dose should be repeated.  Patients assigned dose level -2 (2.3mg) will receive 
1.5mg as the repeat dose.  Repeat dosing should occur as soon as nausea has resolved. 
Unexpected delays in repeat dosing are acceptable as long as dosing is complete at least 
72 hours before the next scheduled dose.   
3. If vomiting occurs 30-60 minutes after a dose then 50% of the dose should be repeated, 
regardless of vomitus contents.  Patients assigned dose level -2 (2.3mg) will receive 
1.5mg as the repeat dose. Repeat dosing should occur as soon as nausea has resolved. 
Unexpected delays in repeat dosing are acceptable as long as dosing is complete at least 
72 hours before the next scheduled dose.   
4. If vomiting occurs more than 60 minutes after a dose the patient should not repeat the 
dose but should resume dosing at the time of the next scheduled dose.   
MLN9708 Destruction 
Investigational MLN9708 (expired or end of study) should be destroyed on site according to the 
institution’s standard operating procedure.  Removal and destruction of all drug will be 
documented on drug accountability logs. 
6.3    Dose-Modification Guidelines  
6.3.1 
Recommended MLN9708 Criteria for Beginning or Delaying a Subsequent 
Treatment Cycle & Dose Modifications for Treatment Associated Toxicity 
Treatment with MLN9708 will use a cycle length of 28 days. Cycle #1 will begin regardless of 
ANC or platelet count and continue for the full cycle.  During cycle #1, MLN9708 will only be 
held or dose modified for grade 3-4 non-hematologic toxicity, judged to be related to study drug.  
If MLN9708 is held during cycle #1, mycophenolate 15mg/kg three times daily (3 grams 
maximum daily dose) may be given at MD discretion.  For any new cycle of treatment to begin, 
the patient must meet the following criteria: 
 ANC must be ≥ 1,000/mm3 (can be supported with growth factor support). 
 Platelet count must be ≥ 50,000/mm3. 
 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-cited criteria for initiation of the next cycle of treatment, 
dosing should be delayed until resolution of toxicity per tables 6-2 and 6-3.. The maximum delay 


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before treatment should be discontinued will be 4 weeks or at the discretion of the Principal 
Investigator. 
For dosing recommendations upon recovery, refer to Table 6-2 and Table 6-3. 
Table 6-1 MLN908 Dose Adjustments 
 
Dose Level 
Dose (mg) 
Starting Dose 
4.0 mg 
-1 
3.0 mg 
-2 
2.3 mg 
-3 
Discontinue 
Dosage adjustments for hematologic toxicity are outlined in Table 6-2. 
Table 6-2    
MLN9708 Dose Adjustments for Hematologic Toxicities 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Criteria 
Action 
 If ANC <1.0 x 109/L or platelet count 
<50x109/L prior to the start of a new 
cycle (other than cycle 1) 
 OR 
 If platelet count falls to ≤30 x 109/L or 
ANC≤0.50 x 109/L after initiating a cycle 
but before day 15 
 Hold MLN9708 until resolution as per 
section 6.2 
 Upon recovery, MLN9708 may be 
reinitiated with 1 dose level reduction  
 If platelet count falls to ≤30 x 109/L or 
 Reduce MLN9708 by 1 dose level at the 


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ANC≤0.50 x 109/L after day 15 but 
recovers in time for the start of the next 
cycle 
start of the next cycle 
 
Treatment modifications due to MLN9708-related AEs are outlined in Table 6-3. 
Table 6-3    
MLN9708 Treatment Modification (Delays, Reductions, and 
Discontinuations) Due to Adverse Events (Non-Hematologic Toxicities) 
Adverse Event (Severity) 
Action on Study Drug 
Further Considerations 
Peripheral Neuropathy: 
Grade 1 peripheral neuropathy 
 
 No action 
 
Grade 1 signs and symptoms:  
asymptomatic; without pain or loss 
of function; clinical or diagnostic 
observations only60 
 
 
New or worsening Grade 1 
peripheral neuropathy with pain or 
Grade 2 (other than cycle 1) 
 Hold study drug until 
resolution to Grade ≤ 1 or 
baseline 
Grade 2 signs and symptoms:  
Moderate symptoms; limiting 
instrumental activities of daily 
living (ADL)60 
 
 
New or worsening Grade 2 
peripheral neuropathy with pain 
(other than cycle 1) or Grade 3 
(any cycle) 
 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 
indicated60 
New or worsening Grade 4 
peripheral neuropathy 
 Discontinue study drug 
 
 
 
Grade 2 Rash 
 
Symptomatic 
recommendations as per 
section 6.6 
The investigator and project 
clinician may discuss 
considerations for dose 
modifications and symptom 
management. 
 
Grade 3 nonhematologic toxicity 
judged to be related to study drug 
 
 Hold study drug until 
resolution to Grade < 1 or 
baseline 
 
Symptomatic recommendations 
noted in Section 6.7 


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Table 6-3    
MLN9708 Treatment Modification (Delays, Reductions, and 
Discontinuations) Due to Adverse Events (Non-Hematologic Toxicities) 
Adverse Event (Severity) 
Action on Study Drug 
Further Considerations 
If not recovered to 
< Grade 1 or baseline 
within 4 weeks 
 
 Reduce study drug to next 
lower dose upon return to 
< Grade 1 or baseline 
 
Subsequent recurrence 
Grade 3 that does not 
recover to < Grade 1 or 
baseline within 4 weeks 
 Hold study drug until 
resolution to Grade < 1 or 
baseline 
 Reduce study drug to next 
lower dose  
Monitor closely, take appropriate 
medical precautions, and provide 
appropriate symptomatic care 
 
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  
 
Dose Re-Escalation: 
 If MLN9708 is reduced for any nonhematologic toxicity judged related to study drug, the 
dose may not be re-escalated.   
 If MLN9708 is reduced for hematologic toxicity, the dose may be re-escalated at the 
discretion of the principal investigator. 
6.4    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 DDI with a strong inhibitor would increase MLN2238 exposure. 
 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 to use.  A DDI with a strong 
inducer would decrease MLN2238 exposure. 


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 Strong CYP3A inducers:  rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, and 
phenobarbital 
The use of NSAIDS should be avoided 
The dietary supplements St John’s wort and Ginkgo biloba are not permitted. 
The following procedures are prohibited during the study: 
 Any antineoplastic treatment with activity against hematologic malignancies except for 
drugs in this treatment regimen  
 Radiation therapy (the requirement for local radiation therapy generally indicates disease 
progression).    
6.5 Permitted Concomitant Medications and Procedures  
 G-CSF (filgrastim) will be given post transplant as described in section 6.1.  
Erythropoietin, if used, should follow published guidelines and/or institutional practice. 
 Supportive measures consistent with optimal patient care may be given throughout the 
study.  
6.6    Precautions and Restrictions  
Fluid deficits should be corrected before and throughout treatment. 
Nonsteroidal anti-inflammatory drugs (NSAIDs) induced prevalence of nephrotoxicity is 
relatively low; however, given the wide use of these agents many persons are at risk, including 
for example, patients with cardio-renal disease, dehydration, and the aging kidney. NSAIDs 
should be avoided with impaired renal function given reported NSAID-induced renal failure in 
patients with decreased renal function.  
Pregnancy 
It is not known what effects MLN9708 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 criteria:  
 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, at the same time, from the time of signing the informed consent form 
through 90 days after the last dose of study drug, AND 
 Agree to practice true abstinence when this is in line with the preferred and usual lifestyle 
of the subject.  (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-
ovulation methods] and withdrawal are not acceptable methods of contraception.) 
Male patients, even if surgically sterilized (i.e., status post-vasectomy), must agree to 1 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 (e.g., calendar, ovulation, symptothermal, post-
ovulation methods] and withdrawal are not acceptable methods of contraception.) 
6.7  
 Management of Clinical Events  
Adverse drug reactions such as thrombocytopenia, diarrhea, fatigue, nausea, vomiting, and rash 
have been associated with MLN9708 treatment. Management guidelines regarding these events 
are outlined below. Further details of management of MLN9708 AEs are described in Section 6 
of the MLN9708 IB.  
Use of MLN9708 in the setting of graft-versus-host disease (GVHD) 
In the setting of grade II-IV acute GVHD or moderate-severe cGVHD, MLN9708 should be 
discontinued.  Upon resolution of GVHD, consideration could be given to restarting 
investigational drug at the discretion of the principal investigator.  
Prophylaxis Against Risk of Infection 
If lymphopenia is noted, patients may be at an increased risk of infection.  In particular, 
lymphopenia can be associated with reactivation of herpes zoster and herpes simplex viruses.  


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Antiviral therapy such as acyclovir or valacyclovir may be initiated as clinically indicated.  Other 
antivirals are also acceptable. 
Nausea and/or Vomiting 
Standard anti-emetics, including 5-HT3 antagonists, are recommended for emesis occurring upon 
treatment initiation; prophylactic anti-emetics may also be considered.  .  Fluid deficits should be 
corrected before initiation of study drug and during treatment. 
Diarrhea 
Diarrhea should be managed according to clinical practice, including the administration of anti-
diarrheals once infectious causes are excluded.  Fluid intake should be maintained to avoid 
dehydration.  Fluid deficits should be corrected before initiation of treatment and during 
treatment. Prophylactic anti-diarrheals are not generally recommended. 
Erythematous Rash With or Without Pruritus 
As with VELCADE, rash with or without pruritus has been reported with MLN9708, primarily at 
the higher doses tested. The rash may range from some erythematous areas, macular and/or small 
papular bumps that may or may not be pruritic over a few areas of the body or more generalized, 
has been transient and has resolved either spontaneously or with standard symptomatic measures 
such as oral or topical steroids and/or antihistamines. Prophylactic measures should also be 
considered if a patient develops a rash (e.g., using a thick, alcohol-free emollient cream on dry 
areas of the body).  A rare risk is Stevens-Johnson Syndrome, a severe, life-threatening or deadly 
rash with skin peeling and mouth sores, which should be managed symptomatically according to 
standard medical practice.  
Thrombocytopenia 
Thrombocytopenia has been reported to date primarily at the higher doses tested.  Blood counts 
should be monitored regularly as outlined in the protocol with additional testing obtained 
according to standard clinical practice.  Thrombocytopenia may be severe but has been 
manageable with platelet transfusions according to standard clinical practice. Thrombocytopenia 
nadirs commonly recover without intervention by the beginning of the next scheduled cycle. 
MLN9708 administration should be modified as noted as per dose modification 
recommendations in Table 6-2 when thrombocytopenia occurs.  Therapy can be reinitiated at a 
reduced level upon recovery of platelet counts. A rare risk is thrombotic thrombocytopenic 
purpura (TTP), a rare blood disorder where blood clots form in small blood vessels throughout 


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the body characterized by thrombocytopenia, petechiae, fever, or possibly more serious signs and 
symptoms. TTP should be managed symptomatically according to standard medical practice. 
Neutropenia 
Neutropenia has been reported with MLN9708.  Blood counts should be monitored regularly as 
outlined in the protocol with additional testing obtained according to standard clinical practice.  
Neutropenia may be severe but has been manageable with G-CSF according to standard clinical 
practice.  Neutropenic nadirs commonly recover without intervention by the beginning of the 
next scheduled cycle or with a short delay in treatment.  MLN9708 administration should be 
modified when neutropenia occurs, as noted in the dose modification recommendations in Table 
6-2.  Therapy can be reinitiated at a reduced level upon recovery of absolute neutrophil counts. 
Fluid Deficits 
Dehydration should be avoided because MLN9708 may cause vomiting, diarrhea, and 
dehydration.  Acute renal failure has been reported with MLN9708.  Fluid deficits should be 
corrected before initiation of study drug and during treatment and as needed during therapy.  
Until further information is available, intake of NSAIDs while on this protocol should be 
avoided. 
Hypotension 
Symptomatic hypotension and orthostatic hypotension have been reported with MLN9708. 
Blood pressure should be closely monitored while the patient is on study treatment and fluid 
deficit should be corrected as needed, especially in the setting of concomitant symptoms such as 
nausea, vomiting, diarrhea, or anorexia. Patients taking medications and/or diuretics to manage 
their blood pressure (for either hypo- or hypertension) should be managed according to standard 
clinical practice, including considerations for dose adjustments of their concomitant medications 
during the course of the trial.  
Posterior Reversible Encephalopathy Syndrome  
One case of posterior reversible encephalopathy syndrome (PRES) has been reported with 
MLN9708.  While this case ultimately resolved, PRES has also been reported rarely with another 
proteasome inhibitor, VELCADE.  PRES is characterized by headache, seizures and visual loss, 
as well as abrupt increase in blood pressure.  Prompt diagnosis and initiation of antihypertensive 
and anticonvulsant therapy are important to prevent irreversible end-organ damage. 


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6.8  
Preparation, Reconstitution, and Dispensing 
MLN9708 is an anticancer drug and as with other potentially toxic compounds caution should be 
exercised when handling MLN9708 capsules. 
6.9  
Packaging and Labeling 
The study drug MLN9708 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.   
MLN9708 capsules should be stored unopened at 2°C to 8°C (36°F-46°F).  The capsules are 
individually packaged in cold form foil-foil blisters in a child-resistant package.  The 0.2-, 0.5-, 
and 2.0 mg capsules are in 1  4 blister strips that are individually perforated.  The strips (1  4) 
are placed in cartons containing 6 strips (24 total capsules) of the same strength. The 2.3-, 3.0-, 
and 4.0 mg capsules are supplied as a 1 x 3 blister card in a child-resistant cardboard wallet. 
6.10  
Storage, Handling, and Accountability 
Upon receipt at the investigative site, MLN9708 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, MLN9708 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. 


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Because MLN9708 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. 
In case of contact with the powder (e.g., 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 MLN9708, including that MLN9708 is to be taken as intact 
capsules. 
6.11      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. 
6.12   
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 


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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. 
7.    
STATISTICAL AND QUANTITATIVE ANALYSES 
Statistical Methods 
7.1.1     Determination of Sample Size 
The primary endpoint of this trial will be the risk of relapse and/or progression at one-year post-
transplant.  Experience from the literature suggests that following a nonmyeloablative 
haploidentical transplant using post-transplant cyclophosphamide (haplo-pCy), the risk of relapse 
is approximately 50% at one year post-transplant61.  It is hoped that under this protocol, this rate 
will be at most 25%. Thus we statistically formalize this study by testing the null hypothesis that 
p, the PFS rate is 0.25 or less versus the alternative hypothesis that p is greater than 0.5. A 
sample size of 25 patients gives 90% power with an alpha=0.05, using the formula for a one 
sample binomial (two-sided) test of a proportion.  Accrual will continue unless a stopping 
criterion is met.  We expect that patients will be accrued over 2 years. 
7.1.2    Stopping Criteria 
NRM: As outlined in Section 1 (Background), the overall non-relapse mortality (NRM) on the 
nonmyeloablative haploidentical HSCT trial utilizing post-transplantation Cy, MMF and 
tacrolimus is approximately 19% at one year. Consequently a NRM incidence that is 
convincingly greater than 20% would raise concerns for excessive toxicity. This trigger would be 
met if NRM occurs in 3 out of the first 5 patients, 5 of the first 10 patients, or 6 of the first 15 
patients. If the stopping criterion is met, accrual to the trial will be temporarily halted until a 
decision regarding either modification or termination of the trial could be made. 
Severe acute GVHD (aGVHD): As outlined in Section 1 (Background), the expected incidence 
of severe aGVHD (Grades III-IV)) on the nonmyeloablative haploidentical HSCT utilizing post-
transplantation Cy, MMF and tacrolimus is approximately 10%. The working hypothesis of this 
trial is that the overall toxicity of fully ablative haploidentical HSCT is not significantly greater 
than haploidentical HSCT after nonmyeloablative conditioning utilizing post-transplantation Cy. 
Consequently, an incidence of severe aGVHD convincingly greater than 15% would raise 
concerns for excessive toxicity. This trigger would be met if severe aGVHD occurs in 3 of the 
first 5 patients, 4 of the first 10 patients, or 5 of the first 15 patients. If the stopping criterion is 


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met, accrual to the trial will be temporarily halted, until a decision regarding either modification 
or termination of the trial could be made.  
Engraftment Failure:  As outlined in Section 1 (Background), the incidence of engraftment 
failure on the nonmyeloablative haploidentical HSCT trial utilizing post-transplantation Cy, 
MMF and tacrolimus is approximately 18%. Consequently a graft failure incidence that is 
convincingly greater than 20% would raise concerns for excessive toxicity. This trigger would be 
met if graft failure occurs in 3 out of the first 5 patients, 5 of the first 10 patients, or 6 of the first 
15 patients. If the stopping criterion is met, accrual to the trial will be temporarily halted until a 
decision regarding either modification or termination of the trial could be made.  
Excessive Toxicity (defined as toxicities CTCAE v.3 grade 4 or higher considered probably 
or definitely related to the study drug): There is significant potential and/or expected toxicity 
that occurs in the first 4 weeks following allogeneic transplant, including severe cytopenias 
(neutropenia, anemia, thrombocytopenia), renal insufficiency, hypokalemia, hypomagnesaemia, 
hepatic sinusoidal obstruction syndrome, nausea, vomiting, diarrhea, mucositis/enteritis, fever, 
life-threatening infections, thrombotic microangiopathy, graft rejection, and graft-versus-host 
disease.  However, excessive toxicity that is convincingly greater than 15% would raise 
concerns. This trigger would be met if grade ≥4 toxicity, probably or definitely related to study 
drug, occurs in the first four weeks in 3 out of the first 5 patients, 4 of the first 10 patients, or 5 of 
the first 15 patients. If the stopping criterion is met, accrual to the trial will be temporarily halted 
until a decision regarding either modification or termination of the trial could be made.  
8.    
ADVERSE EVENTS   
Definitions 
8.1.1    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. 
8.1.2       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 


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(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product whether or not it is related to the medicinal product.  
This includes any newly occurring event, or a previous condition that has increased in severity or 
frequency since the administration of study drug. 
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline.   
8.1.3    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 abuse; any 
organism, virus, or infectious particle (e.g., prion protein transmitting Transmissible 
Spongiform Encephalopathy), pathogenic or nonpathogenic, is considered an infectious 
agent.   


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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. 
8.1.4    Adverse Event of Special Interest Definition 
Adverse Events of Special Interest (AESIs) are a subset of AEs that are to be reported to 
Millennium on a quarterly basis by the sponsor-investigator. Millennium will provide the current 
list of AESIs and updates to the list will be distributed to the sponsor-investigator as appropriate 
8.2    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 date the participant receives the first dose of study drug through 30 days after administration 
of the last dost of MLN9708. Any SAE that occurs at any time during treatment with MLN9708 
or for 60 days after the completion of MLN9708 treatment that the sponsor-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).    


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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, Scott R. Solomon, 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 to Millennium Pharmacovigilance: 
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 
 
The protocol may include language to specify expected adverse events which will not be 
considered serious and will not require expedited reporting. 
The sponsor-investigator must fax 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 
 Intensity of the event(s): Sponsor-investigator’s or sub-investigator’s 
determination.  Intensity for each SAE, including any lab abnormalities, will be 
determined by using the NCI CTCAE version specified in the protocol, as a 
guideline, whenever possible.  The criteria are available online at 
http://ctep.cancer.gov/reporting/ctc.html. 
 Causality of the event(s): Sponsor-investigator’s or sub-investigator’s 
determination of the relationship of the event(s) to study drug administration.  
Follow-up information on the SAE may be requested by Millennium.   


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 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 or study drug(s), 
including, but not limited to, telephone conversation logs within 24 hours but no later than 4 
calendar days of such communication. 
 
SAE and Pregnancy Reporting Contact Information 
SAE and Pregnancy Reporting Contact Information 
Cognizant Contacts Fax Number: 1-800-963-6290 
Email: takedaoncocases@cognizant.com 
Suggested Reporting Form:   
• 
SAE Report Form (a sample is provided in Appendix 13.3) 
• 
US FDA MedWatch 3500A:  
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
8.3    
Procedures for Reporting AESIs 
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 nonserious AEs 


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(including AESIs), the investigator must determine both the intensity of the event and the 
relationship of the event to study drug administration. 
AESIs must be reported to Millennium on a quarterly basis. 
8.4    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 immediately 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 in Appendix 12.)   
9.    
ADMINISTRATIVE REQUIREMENTS 
9.1    
Good Clinical Practice 
The study will be conducted in accordance with the International Conference on Harmonisation 
(ICH) for Good Clinical Practice (GCP) and the appropriate regulatory requirement(s).  The 
investigator will be thoroughly familiar with the appropriate use of the study drug as described in 
the protocol and Investigator’s Brochure.  Essential clinical documents will be maintained to 
demonstrate the validity of the study and the integrity of the data collected.  Master files should 
be established at the beginning of the study, maintained for the duration of the study and retained 
according to the appropriate regulations.   
9.2    
Ethical Considerations 
The study will be conducted in accordance with applicable regulatory requirement(s) and will 
adhere to GCP standards.  The IRB/IEC will review all appropriate study documentation in order 
to safeguard the rights, safety and well-being of the patients.  The study will be conducted only 


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at sites where IRB/IEC approval has been obtained.  The protocol, Investigator’s Brochure, 
informed consent form, advertisements (if applicable), written information given to the patients 
(including diary cards), safety updates, annual progress reports, and any revisions to these 
documents will be provided to the IRB/IEC by the investigator.  Millennium requests that 
informed consent documents be reviewed by Millennium or designee prior to IRB/IEC 
submission.   
9.3    
Patient Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from either 
the patient or his/her guardian or legal representative before study participation.  The method of 
obtaining and documenting the informed consent and the contents of the consent must comply 
with the ICH-GCP and all applicable regulatory requirements. 
9.4    
Patient Confidentiality 
In order to maintain patient privacy, all data capture records, drug accountability records, study 
reports and communications will identify the patient by initials and the assigned patient number.  
If requested, the investigator will grant monitor(s) and auditor(s) from Millennium or its 
designees and regulatory authority(ies) access to the patient’s original medical records for 
verification of data gathered on the data capture records and to audit the data collection process.  
The patient’s confidentiality will be maintained and will not be made publicly available to the 
extent permitted by the applicable laws and regulations. 
9.5    
Investigator Compliance 
The investigator will conduct the study in compliance with the protocol given approval/favorable 
opinion by the IRB/IEC and the appropriate regulatory authority(ies).  Changes to the protocol 
will require approval from Millennium and written IRB/IEC approval/favorable opinion prior to 
implementation, except when the modification is needed to eliminate an immediate hazard(s) to 
patients.  The IRB/IEC may provide, if applicable regulatory authority(ies) permit, expedited 
review and approval/favorable opinion for minor change(s) in ongoing studies that have the 
approval /favorable opinion of the IRB/IEC.  The investigator will submit all protocol 
modifications to Millennium and the regulatory authority(ies) in accordance with the governing 
regulations.  
Any departures from the protocol must be fully documented in the source documents.   


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9.6    
On-site Audits 
Regulatory authorities, the IEC/IRB and/or Millennium may request access to all source 
documents, data capture records, and other study documentation for on-site audit or inspection.  
Direct access to these documents must be guaranteed by the investigator, who must provide 
support at all times for these activities. 
9.7    
Investigator and Site Responsibility for Drug Accountability 
Accountability for the study drug at all study sites is the responsibility of the principal 
investigator.  The investigator will ensure that the drug is used only in accordance with this 
protocol.  Drug accountability records indicating the drug’s delivery date to the site, inventory at 
the site, use by each patient, and amount returned to Millennium or a designee or disposal of the 
drug (if applicable and if approved by Millennium) will be maintained by the clinical site.  
Accountability records will include dates, quantities, lot numbers, expiration dates (if 
applicable), and patient numbers.   
9.8    
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.  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 PPD (refer to Section 8.2). 


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9.9    
Closure of the Study 
This study may be prematurely terminated, if in the opinion of the investigator or Millennium, 
there is sufficient reasonable cause.  Written notification documenting the reason for study 
termination will be provided to the investigator or Millennium by the terminating party.   
Circumstances that may warrant termination include, but are not limited to: 
 Determination of unexpected, significant, or unacceptable risk to patients 
 Failure to enter patients at an acceptable rate 
 Insufficient adherence to protocol requirements 
 Insufficient, incomplete and/or unevaluable data 
 Determination of efficacy based on interim analysis 
 Plans to modify, suspend or discontinue the development of the drug 
9.10    Record Retention 
The investigator will maintain all study records according to the ICH-GCP and applicable 
regulatory requirement(s).   
10.    USE OF INFORMATION 
All information regarding MLN9708 supplied by Millennium to the investigator is privileged 
and confidential information.  The investigator agrees to use this information to accomplish the 
study and will not use it for other purposes without consent from Millennium.  It is understood 
that there is an obligation to provide Millennium with complete data obtained during the study.  
The information obtained from the clinical study will be used toward the development of 
MLN9708 and may be disclosed to regulatory authority(ies), other investigators, corporate 
partners, or consultants as required. 
Upon completion of the clinical study and evaluation of results by Millennium, the hospital or 
institution and/or investigator may publish or disclose the clinical trial results pursuant to the 
terms contained in the applicable Clinical Trial Agreement.    
 


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11.  DISEASE EVALUATION62, 63 
Relapse of Malignancy – Testing for recurrent malignancy in the blood, marrow or other sites 
will be used to assess relapse after transplantation.  For the purpose of this study, relapse is 
defined by either morphological or cytogenetic evidence of acute leukemia consistent with pre-
transplant features, or radiologic evidence (including the recurrence of fluoro-deoxyglucose 
[FDG]-avid lesions on PET scan) of progressive lymphoma.  When in doubt, the diagnosis of 
recurrent or progressive lymphoma should be documented by tissue biopsy.   
Minimal Residual Disease – Minimal residual disease is defined by the sole evidence of 
malignant cells by flow cytometry, or fluorescent in situ hybridization (FISH), or Southern blot, 
or Western blot, or polymerase chain reaction (PCR), or other techniques, in absence of 
morphological or cytogenetic evidence of disease in blood or marrow.  Since the frequency of 
testing for minimal residual disease is highly variable among centers, and the sensitivity is highly 
variable among laboratory techniques, evidence of minimal residual disease alone will not be 
sufficient to meet the definition of relapse in the context of this trial.  However, minimal residual 
disease that progresses (see above) will be considered as relapse and the date of relapse will be 
the date of detection of minimal residual disease that prompted an intervention by the treating 
physician.  Data on tapering immunosuppression, administering chemotherapy or biological 
agents to in response to detection of minimal residual disease will be captured in the case report 
forms. 
Acute Leukemia – Relapse will be diagnosed when there is: 
1. The reappearance of leukemia blast cells in the peripheral blood; or, 
2. > 5% blasts in the marrow, not attributable to another cause (e.g., bone marrow 
regeneration); or 
3. The development of extramedullary leukemia or leukemic cells in the cerebral spinal 
fluid or 
4. The reappearance of cytogenetic abnormalities present prior to transplantation 
 


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Lymphoma – Relapse will be diagnosed when there is: 
1. Appearance of any new lesion more than 1.5 cm in any axis during or at the end of 
therapy, even if other lesions are decreasing in size.  Increased FDG uptake in a 
previously unaffected site should only be considered relapsed or progressive disease after 
confirmation with other modalities.  In patients with no prior history of pulmonary 
lymphoma, new lung nodules identified by CT are mostly benign.  Thus, a therapeutic 
decision should not be made solely on the basis of the PET without histologic 
confirmation. 
2. At least a 50% increase from nadir in the sum of the product diameters (SPD) of any 
previously involved nodes, or in a single involved node, or the size of other lesions (e.g., 
splenic or hepatic nodules).  To be considered progressive disease, a lymph node with a 
diameter of the short axis of less than 1.0 cm must increase by  50% and to a size of 1.5 
x 1.5 cm or more than 1.5 cm in the long axis.  
Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the 
lesion was PET positive before therapy unless the lesion is too small to be detected with 
current PET systems (<.1.5 cm in its long axis by CT). 
 
Institution of any therapy to treat persistent, progressive or relapsed disease, including 
withdrawal of immunosuppressive therapy or DLI, will be considered evidence of 
relapse/progression regardless of whether the criteria described above are met. 


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TABLE 11.1 RESPONSE CRITERIA FOR LYMPHOMA64 
 
 
Response Criteria for Acute Leukemia 
Remission is defined as < 5% blasts with no morphological characteristics of acute leukemia 
(e.g., Auer Rods) in a bone marrow with > 20% cellularity, peripheral blood counts showing 
ANC >1000/l, including patients in CRp. 
Response Criteria for Lymphoma 
Response criteria for lymphoma are described in Table 11.1 
Response Criteria for Multiple Myeloma 
Stringent Complete Response (sCR): 
 SCR requires, in addition to CR (defined below), all of the following 
 Normal free light chain ration (FLC) 
 Absence of clonal cells in bone marrow by immunohistochemistry or 
immunofluorescence 


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Complete Response (CR) requires all of the following: 
 Absence of the original monoclonal paraprotein in serum and urine by routine 
electrophoresis and by immunofixation.  The presence of new monoclonal bands is 
consistent with oligoclonal immune reconstitution does not exclude CR: 
 Less than 5% plasma cells in a bone marrow aspirate and also on trephine bone biopsy, if 
biopsy is performed;  
 No increase in size or number of lytic bone lesions on radiological investigations 
(development of a compression fracture dose not exclude CR)*; and, 
 Disappearance of soft tissue plasmacytomas. 
*If not clinically indicated, radiographs are not required to document CR.  
Patients in whom some, but not all, the criteria for CR are fulfilled are classified as partial 
responses (see below), providing the remaining criteria satisfy the requirements for partial 
response.  This includes patients in whom routine electrophoresis is negative but in whom 
immunofixation has not been performed. 
Near Complete Response (nCR): represents disease detected only by immunofixation and it is 
defined as65,66 
 
Presence of the original monoclonal paraprotein in serum and urine by immunofixation 
 Less than 5% plasma cells in a bone marrow aspirate and also on trephine bone biopsy, if 
biopsy is performed;  
 No increase in size or number of lytic bone lesions on radiological investigations 
(development of a compression fracture dose not exclude CR) 
 Very Good Partial Response (VGPR) requires, in addition to PR (defined below), all of 
the following:Serum or urine paraprotein detectable by immunofixation but not on 
electrophoresis, 
OR 
 Greater than or equal to 90% reduction in serum paraprotein plus urine paraprotein 
<100mg/24 hours 


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Partial Response (PR) requires one of the following: 
 Greater than or equal to 50% reduction in the level of the serum monoclonal paraprotein 
and/or reduction in 24 hour urinary monoclonal paraprotein either by greater than or 
equal to 90% or to <200mg/24 hours in light chain deisease. 
 If the only measurable non-bone marrow parameter is FLC, greater than or equal to 50% 
reduction in the difference between involved and uninvolved FLC levels or a 50% 
decrease in level or involved FLC with 50% decrease in ratio.  
 If the bone marrow is the only measurable parameter, greater than or equal to 50% 
reduction in bone marrow plasma cells given that the baseline count was greater or equal 
to 30%. 
 Greater than or equal to 50% reduction in the size of soft tissue plasmacytomas (by 
radiography or clinical examination). 
 
Stable Disease (SD) 
 Patients who do not meet criteria for sCR, CR, VGPR, PR or progressive disease are 
considered to have stable disease (SD). 
 
Progression (PD) from CR or sCR requires one or more of the following: 
 A reappearance of serum monoclonal paraprotein, with a level of at least 0.5 g/dL. 
 24-hour urine protein electrophoresis with at least 200 mg paraprotein/24 hours. 
 Abnormal FLC levels of >10 mg/dl, only in patients without measurable paraprotein in 
the serum and urine.  
 At least 10% plasma cells in a bone marrow aspirate or on trephine biopsy. 
 Definite increase in the size of existing bone lesions or soft tissue plasmacytomas. 
 Development of new bone lesions or soft tissue plasmacytomas.  
 Development of hypercalcemia (corrected serum Ca >11.5 mg/dL or >2.8 mmol/L) not 
attributable to any other cause. 
 
Progressive Disease (PD) for patients not in CR or sCR, progressive disease requires one or 
more of the following: 
 >25% increase in the level of the serum monoclonal paraprotein, which must also be an 
absolute increase of at least 0.5 g/dL. 
 >25% increase in 24-hour urine protein electrophoresis, which must also be an absolute 
increase of at least 200 mg/24 hours. 


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 Absolute increase in the difference between involved and uninvolved FLC levels 
(absolute increase must be >10 mg/dl), only in patients without measurable paraprotein in 
the serum and urine.  
 >25% increase in plasma cells in a bone marrow aspirate or on trephine biopsy, which 
must also be an absolute increase of at least 10%. 
 Definite increase in the size of existing bone lesions or soft tissue plasmacytomas. 
 Development of new bone lesions or soft tissue plasmacytomas.  
 Development of a compression fracture does not exclude continued response and may not 
indicate progression. 
 Development of hypercalcemia (corrected serum Ca >11.5 mg/dL or >2.8 mmol/L) not 
attributable to any other cause. 
 
Response Criteria for CML67 
Complete Hematologic response or remission (all must be present): 
 Platelet count <450,000/ uL 
 WBC count <10,000/UL 
 No immature neutrophils 
 <5% basophils 
 Spleen not palpable 
Cytogenetic Response 
 No response >95% Ph+ cells 
 Minor Response 36-95% Ph+ cells 
 Major Response <35% Ph+ cells 
 
Molecular response/remission  
 
 Major response  >3 log reduction 
 
Complete response no BCR-ABL transcript detectable 
 


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Response Criteria for CLL68  
Complete response  
Requires all of the following for a period of at least three months from completion of therapy:  
• Absence of lymphadenopathy > 1.5 cm on physical exam and CT scan;  
• No hepatomegaly or splenomegaly on physical exam (CT scan may be used to assess);  
• No clonal B-cells in the blood by flow cytometry;  
• Normal CBC as exhibited by polymorphonuclear leukocytes ≥ 1500/μL, platelets > 
100,000/μL, hemoglobin > 11.0 g/dL (untransfused); lymphocyte count < 5,000/μL;  
• Bone marrow aspirate and biopsy must be normocellular for age with < 30% of nucleated cells 
being lymphocytes. Flow cytometry/immunohistochemistry should be performed on bone 
marrow. Lymphoid nodules may be present but must be T-cell in origin. If these are 
demonstrated to be clonal B-cells, patients should be considered a partial response. Additionally, 
if bone marrow is positive by two color flow cytometry for CLL cells it should be considered a 
partial response. If the marrow is hypocellular a bone marrow should be performed in 2-3 
months. If blood counts (polymorphonuclear leukocytes < 1500/μL, platelets < 100,000/μL) fail 
to recover at the time of the response evaluation but there is otherwise no evidence of CLL 
otherwise, a repeat determination should be performed at the time of count recovery 
(polymorphonuclear leukocytes ≥ 1500/μL, platelets > 100,000/μL) but no later than six months.  
• Patients who fulfill the criteria for CR after induction with the exception of a persistent 
cytopenia (CR with incomplete recovery, CRi) that is believed to be treatment related will be 
considered a CRi. As stated above, patients falling into this category should ideally undergo a 
repeat bone marrow when counts recover fully. If the bone marrow at this time reveals no CLL, 
these patients will be considered to be in complete remission at that time. Additionally, patients 
who fulfill the criteria of CR with exception of having bone marrow lymphoid CLL nodules will 
be considered a CRi and assessed prospectively for the similarity to outcome with CR.  
Partial Response  
Requires a ≥ 50% decrease in peripheral lymphocyte count from pre-treatment value, ≥ 50% 
reduction in lymphadenopathy of as many as 6 measurable lymph nodes, and/or ≥ 50% reduction 
in splenomegaly/hepatomegaly for a period of at least two months. Patients may have bone 
marrow lymphoid nodules of B-cell origin. Additionally, these patients must have one of the 
following:  
• Polymorphonuclear leukocytes ≥ 1,500/μL or 50% improvement from pre-treatment value;  


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• Platelets > 100,000/μL or 50% improvement from pre-treatment value;  
• Hemoglobin > 11.0 g/dL (untransfused) or 50% improvement from pre-treatment value  
Progressive Disease  
Characterized by any one of the following events:  
• ≥ 50% increase in the products of at least two lymph nodes on two consecutive determinations 
two weeks apart (at least one lymph node must be ≥ 2 cm); appearance of new palpable lymph 
nodes.  
• ≥ 50% increase in the size of the liver and/or spleen as determined by measurement below the 
respective costal margin; appearance of palpable hepatomegaly or splenomegaly, which was not 
previously present.  
• ≥ 50% increase in the absolute number of circulating lymphocytes to at least 5,000/μL.CALGB 
100701/BMT CTN 0804 03/15/13 50   
• Transformation to a more aggressive histology (i.e., Richter’s syndrome or prolymphocytic 
leukemia with ≥ 56% prolymphocytes).  
• Patients not fulfilling the above criteria for progressive disease but demonstrating a decrease in 
hemoglobin > 2 g/dL (or < 10 g/dL), decrease > 50% in platelet or granulocyte count will not be 
rated as progressive disease because these may occur as both a consequence of therapy and of 
underlying CLL. A bone marrow biopsy in such settings is strongly encouraged.  
Stable Disease  
Patients who do not fulfill the criteria for complete or partial response as defined above but do 
not exhibit progressive disease will be considered as having stable disease. 


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27. Moretta A., Locatelli F., Moretta L. Human NK cells: from HLA class I-specific killer 
Ig-like receptors to the therapy of acute leukemias. Immunol. Rev. 2008; 224:58–69. 
28. Cooley S, Weisdorf DJ, Guethlein LA, et al. Donor selection for natural killer cell 
receptor genes leads to superior survival after unrelated transplantation for acute 
myelogenous leukemia. Blood. 2010;116(14):2411-9. 
29. Symons HJ, Leffell MS, Rossiter ND, et al. Improved survival with inhibitory killer 
immunoglobulin receptor (KIR) gene mismatches and KIR haplotype B donors after 
nonmyeloablative, HLA-haploidentical bone marrow transplantation. Biol Blood Marrow 
Transplant. 2010;16(4):533-42. 


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30. Kröger N, Zabelina T, Berger J, et al.  Donor KIR haplotype B improves progression-free 
and overall survival after allogeneic hematopoietic stem cell transplantation for multiple 
myeloma.  Leukemia. 2011;25(10):1657-61. 
31. Hallett WH, Ames E, Motarjemi M, et al.  Sensitization of tumor cells to NK cell-
mediated killing by proteasome inhibition.  J Immunol. 2008 Jan 1;180(1):163-70. 
32. Lundqvist A, Abrams SI, Schrump DS. et al. Bortezomib and depsipeptide sensitize 
tumors to tumor necrosis factor-related apoptosis-inducing ligand: a novel method to 
potentiate natural killer cell tumor cytotoxicity. Cancer Res. 2006;66:7317-25 
33. Armeanu S, Krusch M, Baltz KM, et al.  Direct and natural killer cell-mediated antitumor 
effects of low-dose bortezomib in hepatocellular carcinoma. Clin Cancer Res. 2008 Jun 
1;14(11):3520-8. 
34. Shi J, Tricot GJ, Garg TK, et al. Bortezomib down-regulates the cell-surface expression 
of HLA class I and enhances natural killer cell-mediated lysis of myeloma.  Blood. 2008 
Feb 1;111(3):1309-17. 
35. Wu X, Shao Y, Tao Y, et al. Proteasome inhibitor lactacystin augments natural killer cell 
cytotoxicity of myeloma via downregulation of HLA class I.  Biochem Biophys Res 
Commun. 2011 Nov 11;415(1):187-92. 
36. Ames E, Hallett WH, Murphy WJ.  Sensitization of human breast cancer cells to natural 
killer cell-mediated cytotoxicity by proteasome inhibition.  Clin Exp Immunol. 2009 
Mar;155(3):504-13. 
37. Jardine L, Hambleton S, Bigley V, et al.  Sensitizing primary acute lymphoblastic 
leukemia to natural killer cell recognition by induction of NKG2D ligands.  Leuk 
Lymphoma. 2013 Jan;54(1):167-73. 
38. Valés-Gómez M, Chisholm SE, Cassady-Cain RL, et al.  Selective induction of 
expression of a ligand for the NKG2D receptor by proteasome inhibitors.  Cancer Res. 
2008 Mar 1;68(5):1546-54. 
39. Sun K, Welniak LA, Panoskaltsis-Mortari A, et al.  Inhibition of acute graft-versus-host 
disease with retention of graft-versus-tumor effects by the proteasome inhibitor 
bortezomib. Proc Natl Acad Sci U S A. 2004 May 25;101(21):8120-5. 


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40. Blanco B, Pérez-Simón JA, Sánchez-Abarca LI, et al.  Bortezomib induces selective 
depletion of alloreactive T lymphocytes and decreases the production of Th1 cytokines.  
Blood. 2006 May 1;107(9):3575-83. 
41. Blanco B, Pérez-Simón JA, Sánchez-Abarca LI, et al.  Treatment with bortezomib of 
human CD4+ T cells preserves natural regulatory T cells and allows the emergence of a 
distinct suppressor T-cell population.  Haematologica. 2009 Jul;94(7):975-83. 
42. Kim JS, Lee JI, Shin JY, et al.  Bortezomib can suppress activation of rapamycin-
resistant memory T cells without affecting regulatory T-cell viability in non-human 
primates.  Transplantation. 2009 Dec 27;88(12):1349-59. 
43. Blanco B, Sánchez-Abarca LI, Caballero-Velázquez T, et al.  Depletion of alloreactive T-
cells in vitro using the proteasome inhibitor bortezomib preserves the immune response 
against pathogens.  Leuk Res. 2011 Oct;35(10):1412-5. 
44. Koreth J, Stevenson KE, Kim HT, et al.  Bortezomib-based graft-versus-host disease 
prophylaxis in HLA-mismatched unrelated donor transplantation.  J Clin Oncol. 2012 
Sep 10;30(26):3202-8. 
45. Kumar SK, Berdeja JG, Niesvizky R, et al.  A Phase 1/2 Study of Weekly MLN9708, an 
Investigational Oral Proteasome Inhibitor, in Combination with Lenalidomide and 
Dexamethasone in Patients with Previously Untreated Multiple Myeloma (MM).  Blood 
(ASH Annual Meeting Abstracts) 2012 120: Abstract 332 
46. Ohata K, Espinoza JL, Lu X, et al.  Mycophenolic acid inhibits natural killer cell 
proliferation and cytotoxic function: a possible disadvantage of including mycophenolate 
mofetil in the graft-versus-host disease prophylaxis regimen.  Biol Blood Marrow 
Transplant. 2011 Feb;17(2):205-13. 
47. Gupta, N., et al., 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(21): p. abstr 
1813. 
48. Gupta, N., M. Saleh, and K. Venkatakrishnan. Flat-Dosing Versus BSA-Based Dosing for 
MLN9708, An Investigational Proteasome Inhibitor: Population Pharmacokinetic (PK) 
Analysis of Pooled Data From 4 Phase-1 Studies in 53rd ASH Annual Meeting and 
Exposition. 2011. San Diego, CA. 


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49. Chow, L.Q., et al. MLN9708, an investigational proteasome inhibitor, in patients with 
solid tumors; Updated phase 1 results in Head and Neck Symposium. 2012. Phoenix, AZ 
50. Assouline, S., et al. Once-weekly MLN9708, an investigational proteasome inhibitor, in 
patients with relapsed/refractory lymphoma: results of a phase 1 dose-escalation study in 
17th EHA Annual Congress. 2012. Amsterdam, the Netherlands. 
51. Lonial, S., et al. Phase I study of twice-weekly dosing of the investigational oral 
proteasome inhibitor MLN9708 in patients (pts) with relapsed and/or refractory multiple 
myeloma (MM) in ASCO Annual Meeting. 2012. Chicago, Illinois. 
52. Kumar, S., et al. Oral weekly MLN9708, an investigational proteasome inhibitor, in 
combination with lenalidomide and dexamethasone in patients (pts) with previously 
untreated multiple myeloma (MM): A phase I/II study in ASCO Annual Meeting. 2012. 
Chicago, Illinois. 
53. Merlini, G., et al. MLN9708, a Novel, Investigational Oral Proteasome Inhibitor, in 
Patients with Relapsed or Refractory Light-Chain Amyloidosis (AL): Results of a Phase 1 
Study in 54th ASH Annual Meeting and Exposition. 2012. Atlanta, Georgia. 
54. Kumar, S. et al. A Phase 1/2 Study of Weekly MLN9708, an Investigational Oral 
Proteasome Inhibitor, in Combination with Lenalidomide and Dexamethasone in Patients 
with Previously Untreated Multiple Myeloma (MM) in 54th ASH Annual Meeting and 
Exposition. 2012. Atlanta, Georgia. 
55. Richardson, P.G., et al. MLN9708, an investigational proteasome inhibitor, in 
combination with lenalidomide and dexamethasone in previously untreated multiple 
myeloma patients (pts): 
Evaluation of weekly and twice-weekly dosing in 17th EHA Annual Congress. 2012. 
Amsterdam, the Netherlands. 
56. San Miguel, J., et al. Oral MLN9708, an an investigational proteasome inhibitor, in 
combination with melphalan and prednisone in patients with previously untreated 
multiple myeloma: a phase 1 study in 17th EHA Annual Congress. 2012. Amsterdam, the 
Netherlands. 
57. Kumar S., et al. Weekly Dosing of the Investigational Oral Proteasome Inhibitor 
MLN9708 in Patients with Relapsed and/or Refractory Multiple Myeloma: Results From 
a Phase 1 Dose Escalation Study in 53rd ASH Annual Meeting and Exposition. 2011. San 


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Diego, CA 
58. Kumar S., et al. Weekly dosing of the investigational oral proteasome inhibitor MLN9708 
in patients (pts) with relapsed/refractory multiple myeloma (MM): A phase I study in 
ASCO Annual Meeting. 2012. Chicago, Illinois. 
59. Sanchorawala V., et al. Poster Presentation: Phase 1 study of MLN9708, a novel, 
investigational oral proteasome inhibitor, in patients with relapsed or refractory light-
chain amyloidosis. XIII International Symposium on Amyloidosis, Groningen, The 
Netherlands 2012. 
60. Common Terminology Criteria for Adverse Events (CTCAE). 2010. 
61. Luznik L, O'Donnell PV, Symons HJ, et al.  HLA-haploidentical bone marrow 
transplantation for hematologic malignancies using nonmyeloablative conditioning and 
high-dose, posttransplantation cyclophosphamide.  Biol Blood Marrow Transplant. 2008 
Jun;14(6):641-50. 
62. Disease evaluation criteria for leukemia and lymphoma taken from BMT CTN 1101 
Multi-Center, Phase III, Randomized Trial of Reduced Intensity Conditioning (RIC) and 
Transplantation of Double Unrelated Umbilical Cord Blood versus HLA-Haploidentical 
Related Donor Bone Marrow for Patients with Hematologic Malignancies 
63. Disease evaluation criteria for multiple myeloma taken from BMT CTN 0702 A Trial of 
Single Autologous Transplant with or without Consolidation Therapy versus Tandem 
Autologous Transplant with Lenalidomide Maintenance for Patients with Multiple 
Myeloma 
64. Lahuerta JJ, Martinez-Lopez J Sema Jdl, Blade J, Grande C, Alegre A, et al.  Remission 
status defined by immunofixation vs electrophoresis after autologous transplantation has 
a major impact on the outcome of multiple myeloma patients. British Journal of 
Haematology. 2000; 109(2):438-46. 
65. Richardson PG, Barlogie B, Berensoin J, Singhai S, Jagannath S, Irwin D, et al.  A Phase 
2 Study of Boretzomib in Relapsed, Refractory Myeloma.  N Engl J Med. 
2003:348(26):2609-17. 
66. Cheson, B.D. et al.  Revised response criteria for malignant lymphoma.  J Clin Oncol 
5:579-586, 2007. 


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67. Response criteria for CML taken from CIBMTR 2011 Tandem Meeting presentation 
68. Response criteria for CLL taken from CIBMTR 100701 Phase II Study of Reduced-
Intensity Allogeneic Stem Cell Transplant For High-Risk Chronic Lymphocytic 
Leukemia (CLL) 


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13. APPENDICES 
13.1   Appendix 1: Karnofsky Performance Status Scale 
Index 
Specific Criteria 
General 
100 
Normal, no complaints, no evidence of disease. 
 
Able to carry on normal activity; no 
special care needed. 
90 
Able to carry on normal activity, minor signs or 
symptoms of disease. 
80 
Normal activity with effort, some signs or 
symptoms of disease. 
70 
Care for self, unable to carry on normal activity 
or to do work. 
Unable to work, able to live at 
home and care for most personal 
needs, varying amount of assistance 
needed. 
60 
Requires occasional assistance from others but 
able to care for most needs. 
50 
Requires considerable assistance from others 
and frequent medical care 
40 
Disabled, requires special care and assistance. 
Unable to care for self, requires 
institutional or hospital care or 
equivalent, disease may be rapidly 
progressing. 
 
30 
Severely disabled, hospitalization indicated, but 
death not imminent. 
20 
Very sick, hospitalization necessary, active 
supportive treatment necessary. 
10 
Moribund 
0 
Dead 
 


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13.2   
Appendix 2: Group B KIR Haplotype Determination 
Group A and B KIR haplotypes have distinctive centromeric (Cen) and telomeric (Tel) gene-
content motifs. With the goal of developing a donor selection strategy to improve transplant 
outcome, Cooley et al., compared the contribution of these motifs to the clinical benefit 
conferred by B haplotype donors28.  Compared to A haplotype motifs, centromeric and telomeric 
B motifs both contributed to relapse protection and improved survival, but Cen-B homozygosity 
had the strongest independent effect.  
 
A donor KIR B-content group calculator is available through the Immuno Polymorphism 
Database (IPD) project, established by the HLA Informatics Group of the Anthony Nolan 
Research Institute in close collaboration with the European Bioinformatics Institute; and can be 
accessed through the following website: http://www.ebi.ac.uk/ipd/kir/donor_b_content.html. 
   
 
 
 
13.3    
Sample SAE Form 
(A sample Serious Adverse Event Form is attached.) 
 
13.4  Millennium Pregnancy Reporting Form 
(A sample Pregnancy Form  is attached)  

ICF_001.pdf: 
 
 
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Northside Hospital Informed Consent 
 
A Phase II Trial of Nonmyeloablative Haploidentical Peripheral Blood Stem Cell 
Transplantation Followed By Maintenance Therapy With the Novel Oral Proteasome 
Inhibitor, MLN9708,  in Patients with High-risk Hematologic Malignancies 
 
Principal Investigator: 
 
Scott Solomon, M.D. 
 
 
 
Associate Investigators: 
 
Lawrence Morris, M.D. 
 
 
 
 
 
Kent Holland, M.D. 
 
 
 
 
 
Asad Bashey, M.D., PhD 
 
 
 
 
 
Melhem Solh, MD 
 
 
 
 
 
 
Blood and Marrow Transplant Group of Georgia 
(BMTGA) 
5670 Peachtree Dunwoody Road, Ste 1000 
 
 
 
 
 
Atlanta, GA 30342 
 
 
 
 
 
404-255-1930 
 
WHAT IS THE PURPOSE OF THE STUDY? 
You are being asked to take part in a research study because you have a blood cancer or blood 
disorder that may be treatable with a stem cell transplant (SCT) from a relative or an unrelated 
donor (allogeneic transplant).  However, you do not have a brother or sister or an unrelated donor 
who is a complete tissue match.  Tissue typing shows that you do have a family member who is a 
partial match (haploidentical donor).  A complete tissue match is when another person has the 
exact same HLA makeup that you, as the transplant recipient do. HLA stands for Human 
Leukocyte Antigen.  HLA are proteins (markers) found on most cells in your body. Your 
immune system uses these markers to recognize which cells belong in your body and which do 
not. When a person is said to be a complete match, their HLA markers look identical to your 
markers and the risks of complications following bone marrow or stem cell transplant may be 
decreased.  When HLA markers do not match completely, they are said to be a partial match or 
mismatch.  
 
Two of the major complications of SCT are graft-versus-host disease (GVHD) and graft 
rejection.  GVHD occurs when cells of the donor’s immune system injure your normal tissues.  


 
 
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GVHD can cause rash, diarrhea, or liver damage, and can be severe enough to cause death.  
Acute GVHD usually occurs within the first 100 days post transplant and most often affects the 
liver, skin and gut.  Chronic GVHD usually occurs after 100 days post transplant and can affect 
the liver, skin and gut as well as any other organ such as the eyes, mouth or lungs.  However, 
cells of the donor’s immune system can also attack cancer cells and prevent the cancer from 
coming back.  Graft rejection occurs when your immune system destroys all the cells of your 
donor’s bone marrow. 
 
Previous studies from this institution have shown that using cyclophosphamide (a type of 
chemotherapy) both before and after a transplant from a partially matched (haploidentical) 
family donor can reduce your risk of developing complications after transplant including graft 
rejection and GVHD.  Using this approach, our group and others have shown that the risk of 
complications following haploidentical transplantation is no higher than what is seen following 
transplants from a fully matched donor. 
 
However, another important risk of an allogeneic stem cell transplant is that your disease may 
come back (relapse).  We are conducting this research study to find out whether an 
investigational drug called MLN9708 (ixazomib citrate) can be used safely and effectively as 
part of your transplant process to prevent your disease from relapsing. MLN9708 is a type of 
targeted drug known as a proteasome inhibitor.  It is a once-weekly oral version of a currently 
available drug called bortezomib (Velcade®), which is FDA approved for the treatment of 
multiple myeloma and mantle cell lymphoma.  In addition to its ease of use, being an oral drug, 
MLN9708 may also be more effective and better tolerated than Velcade®, and clinical trials are 
currently being performed in patients with multiple myeloma.  In this trial, we are using 
MLN9708 to help improve the results of haploidentical transplantation. Many of the risks and 
benefits of transplant are related to effects of the donor’s immune system: either against your 
normal tissues (GVHD) or against the cancer cells, the so called graft-versus-malignancy (GVM) 
effect.   Natural killer (NK) cells have been shown to be an important part of the donor immune 
system and the GVM effect – they can directly kill cancer cells and help to prevent relapse.  
Drugs like MLN9708 and Velcade® have been shown to improve the cancer killing ability of 
NK cells.  These drugs have also been shown in animal models to decrease the risk of GVHD.  It 
is hoped, in this protocol, that MLN9708 will decrease your chance of relapse by improving the 
GVM effect, while minimizing your risk of GVHD.   


 
 
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The word “investigational” means that MLN9708 is not approved by the U.S. Food and Drug 
Administration (FDA). The FDA is allowing the use of MLN9708 in this study. The 
chemotherapy and other drugs used in this study are FDA approved for use in SCT.  
 
This is an investigator-initiated study.  The principal investigator, Scott R. Solomon, MD (who 
may also be referred to as the sponsor-investigator), is conducting the study and acting as the 
sponsor.  Therefore, the legal/ethical obligations of the principal investigator include both those 
of a sponsor and those of an investigator. 
 
This consent form will provide you with information about this research study.  Before you 
decide to take part, you should understand enough about the risks and benefits of participating to 
make an informed decision.  This process is known as informed consent.  Please ask the study 
doctor or the study staff to explain any words or information that you do not clearly understand.  
You may take home an unsigned copy of this consent form to think about or discuss with family or 
friends before making your decision.  You will be asked to sign this form if you wish to 
participate. 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
This study will be conducted only at the Blood and Marrow Transplant Program at Northside 
Hospital.  We anticipate enrolling 25 patients over the course of 2 years.  
 
HOW LONG WILL I BE IN THIS STUDY? 
You have an opportunity to receive MLN9708 for up to 12 months after your transplant.  Once 
you have received your first dose of study treatment, you will be followed throughout your 
treatment plan and will continue for 30 days after your last dose of treatment to monitor your 
health for any adverse reactions.  You will continue to follow up with either BMTGA or your 
referring physician as part of routine transplant follow up indefinitely. The follow up obtained 
after transplant is to determine disease free survival, presence of graft-versus-host disease, 
engraftment (if donor cells are functioning appropriately in your bone marrow) and quality of life 
after the transplant.   These are standard evaluations for transplant recipients.   
   
WHAT WILL HAPPEN TO ME ON THIS STUDY? 
If you agree to be in this study, you will be evaluated at Northside Hospital and the Blood and 
Marrow Transplant Group of GA (BMTGA).  This evaluation may include the following tests 
and/or procedures:  


 
 
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• Medical history and physical examination 
• Bone marrow biopsy and aspiration - A bone marrow aspiration is a procedure in which 
an area of the hip bone is numbed, and a small sample of bone marrow is withdrawn. A 
bone marrow biopsy is similar to a bone marrow aspiration, except a sample of bone is 
removed through a needle. 
• Various blood tests including a complete blood count (CBC) and chemistry panel to see 
how well your organs are functioning.  Approximately 6.5 tablespoons of blood are taken 
for all blood tests.  
• Additional blood tests called infectious disease markers (IDMs) that test for HIV (human 
immunodeficiency virus, the virus that causes AIDS [Acquired Immune Deficiency 
Syndrome]), hepatitis and other transmittable diseases.  State law requires that the results 
of positive tests for HIV (Human Immunodeficiency Virus) and hepatitis be reported to a 
local health agency.   
• Electrocardiogram or ECG (tracing of the electric activity of the heart) 
• CT/PET (Computed tomography/Positron emission tomography) scans to determine the 
extent of your disease if you have Non-Hodgkin’s Lymphoma or Hodgkin’s Disease 
• ECHO (echocardiogram) or MUGA (multi-gated acquisition scan) which is a test to see 
how well your heart is functioning 
• Pulmonary Function Tests (PFTs) to determine how well your lungs are working 
• Serum Pregnancy test for women of child bearing potential  
• Approximately two ounces of extra blood will be drawn at six separate times (pre-
transplant, one, two, three, six and twelve months post-transplant) to determine how the 
investigational drug, MLN9708, affects the recovery of your immune system following 
transplant.  These research samples are optional and you may choose not to allow us to 
collect these samples but still participate in this research study.  You will be asked about 
your willingness to provide these extra samples toward the end of this consent form.  You 
will be able to agree or disagree to provide these samples.    
 
All of these tests, with the exception of the additional blood samples for research, are considered 
routine and would be done prior to transplant whether or not you participate in this study. 
 
If you are found to be eligible, and you choose to join this study, a central venous catheter will 
be placed under your collarbone, if you do not already have one.  This catheter will be used for 
many things during the transplant including chemotherapy, fluids, antibiotics and other 
medications, blood transfusions, and intravenous feeding (if necessary).   


 
 
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You will be given Fludarabine for 5 consecutive days prior to your stem cell infusion by IV 
(intravenous) infusion. These days will be considered day -6 to day -2 of the study.  You will 
receive 2 doses of cyclophosphamide on days -6 and -5.  You will then receive Total Body 
Irradiation (TBI) on day -1.   
 
Your stem cell infusion day will be considered Day 0.  Your donor’s stem cells will be collected 
by apheresis.  Apheresis is a process which removes the donor’s blood, pulls out the stem cells 
that will be given to you and returns the blood back to the donor’s body.  After the stem cells are 
processed, they will be given to you through your catheter on the inpatient bone marrow unit.  
 
You will then receive Cyclophosphamide on days 3 and 4 after your transplant and begin a drug 
called tacrolimus on Day 5 that will aid in the prevention of graft rejection and GVHD.  On day 
5 you will also start weekly treatments of MLN9708.  MLN9708 will be given orally in 28-day 
cycles. You will receive a weekly dose of MLN9708 for 3 weeks and then rest for one week. 
That is considered one cycle. You may be able to receive up to 12 cycles of MLN9708 after your 
transplant.  


 
 
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Days –6, -5 
Fludarabine 30 mg/M2 IV qd 
 
Cyclophosphamide (CTX) 14.5 mg/kg IV qd* 
 
Mesna 11.6 mg/kg IVqd 
 
 
 
↓ 
 
Days –4 -2 
Fludarabine 30 mg/M2 IV qd 
 
 
↓ 
 
Day –1 
TBI (Total Body Irradiation) 200 cGy 
 
 
↓ 
 
Day 0 
Infuse unmanipulated PBSCs  
 
(peripheral blood stem cells) 
 
 
↓ 
 
Days 3, 4 
CTX 50 mg/kg IV q d 
 
 
 
↓ 
 
Day 5    
Begin Tacrolimus and  
               MLN9708 4mg weekly x 3doses every 28days, up to 12 monthly cycles 
 
 
↓ 
 
Day 30, 60, 90 
Assess Chimerism in peripheral blood 
 
 
↓ 
 
 
Day 180 
Discontinue Tacrolimus 


 
 
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During your treatment and follow-up, samples of blood, bone marrow, urine, and body fluids 
may be taken. Standard of care practice will require your blood to be drawn from your catheter 
almost everyday you come into the clinic and everyday when you are in the hospital. If your 
blood counts are low, you will be given red blood cells (cells that help your body carry oxygen to 
your organs) and platelets (cells that help the blood to clot) transfusions.  You will also be given 
antibiotics to prevent and treat any infections. 
 
You must agree to use a reliable form of birth control while on this study.  Some of these 
treatments may seriously harm or kill a fetus.  If you are a woman capable of having children, 
you will be given a pregnancy test before you begin the study.  You may not join this study if 
you are pregnant or breast-feeding.  If you become pregnant, you must notify the doctor listed on 
this form immediately. The treatment will be stopped and you will be taken off the study. 
 
You will need to come back to the BMTGA clinic for daily evaluations for at least 100 days after 
your transplant.  Usually around 100 days after your transplant you may be discharged back to 
the care of your referring physician.  All test results will be shared with you and your local 
physician. Periodically personnel from the BMTGA clinic will be contacting you to see how you 
are doing and will also request pertinent records from your referring physician related to your 
status.  You will need to have follow-up visits at BMTGA at 6, 12, 18, 24 and 36 months for 
purposes of this study. Additional, more frequent visits may be required if your physician feels it 
is necessary.  
 
WHAT ARE THE RISKS OF THE STUDY? 
POSSIBLE DISCOMFORTS AND RISKS OF MLN9708 
There are risks to taking part in any research study.  During the study, you may have problems or 
discomforts and risks from MLN9708, MLN9708 and other drug combinations, and/or study 
procedures.   The more commonly occurring discomforts and risks are listed below, as are the 
rare but serious discomforts and risks.  You should discuss these with your study doctor. There is 
always the possibility that unknown risks may occur, however your doctor will watch closely for 
problems or discomforts and risks.  Many discomforts and risks go away shortly after treatment 
is stopped or with treatment for the discomforts and risks, but in some cases discomforts and 
risks may be serious, long-lasting or permanent and may even result in hospitalizationor death.   
 
If any discomforts and risks occur, you must tell your study doctor or study staff, even if 
you do not think they are related to the study drug.  


 
 
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MLN9708 
Based on studies of MLN9708,  it is possible to predict some of the discomforts and risks.  
However, it is possible that MLN9708 may cause risks that have not yet been observed in 
patients.  The following risks might be seen based on previous experience: 
 
o Low platelet count which may increase the chance of bleeding (33%) 
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 (45%) 
o Feeling tired or weak (48%) 
o Nausea (41%) 
o Vomiting (30%) 
o Diarrhea (39%) 
o Numbness or tingling or pain feelings in hands and feet (21%) 
o Constipation (21%) 
o Lowered red cells or anemia which may make you feel tired (22%) 
o Lowered white blood cells called neutrophils that may increase your risk of 
infection (19%) and may be associated with fever (<1%) 
 
• Other discomforts and  risks reported in studies with MLN9708, which may have been 
due to the patient’s disease, MLN9708, other medications, or some combination of these 
include: 
o Not feeling like eating (13%) 
o Electrolyte imbalance [blood chemical imbalance] (18%) 
o Loss of water from the body (dehydration) because of vomiting and/or loose 
stools (11%) 
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] (3%) 
o Flu-like symptoms and other upper respiratory tract infections (17%) 
o Lung infections including pneumonia or pneumonitis (7%) 
o Cough (12%)Chills (6%) 


 
 
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o Pain in the abdomen (11%) or back (15%) 
o Swelling or fluid build-up in the arms or legs (20%) 
o Lowered blood pressure (12%) that can commonly cause you to feel light-headed, 
faint or pass out when you stand up (4%) 
o Lowered white blood cells called lymphocytes (10%) 
o Pain (muscular) in extremities (10%) 
 
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 MLN9708 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 MLN9708 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 MLN9708 
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.   
 
Transverse myelitis, also a rare condition (<1%), is an inflammatory disease causing injury to the 
spinal cord which has been reported in a patient receiving MLN9708. This condition may cause 
varying degrees of muscle weakness, reduced movement in legs, changes in the feelings of the 
toes and feet, unusual muscle tightness, feelings of pain, changes in bowel (constipation) or 
urinary (loss of control) function or  loss of leg movement.  In general, recovery may be partial, 
complete, or not at all but most patients experiencing transverse myelitis have good to fair 
recovery of symptoms. We do not know whether MLN9708 causes transverse myelitis, however, 
as it happened to a patient receiving MLN9708, we are not able to exclude the possibility that 
MLN9708 may have contributed to transverse myelitis. 
 
Progressive multifocal leukoencephalopathy (PML is a rare, serious infection of the brain that is 
caused by a virus.  Persons with a weakened immune system may develop PML. PML can result 
in death or severe disability.  PML has been observed rarely (<0.1%) in patients taking 
MLN9708.    It is not known whether MLN9708 may contribute to the development of PML.  
 
Additionally, it is worth noting that: 


 
 
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• MLN9708 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. 
• MLN9708, like Velcade, should not be taken if you have ever had an allergic reaction to 
boron or boron containing products.  Allergic reactions may be possible.   
 
•  The following side effects have been reported with VELCADE use and therefore may 
also be a risk with MLN9708: 
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 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 MLN9708 works.  Tell your doctor 
about all drugs and supplements you are taking while you are in this study. 
 
RISK TO THE UNBORN CHILD (MEN AND WOMEN)  
Female subjects: We do not know if the study drug MLN9708 will affect mother’s milk or an 
unborn child. Therefore, breast-feeding and pregnant women are not allowed to take part in the 
study.  Due to unknown risks and potential harm to the unborn child/ infant, you should not 
become pregnant or nurse a baby while on this study.   
 
You must have a negative pregnancy test prior to enrolling in the study. 
 
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), 


 
 
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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.  
 
You must use birth control methods as directed above, unless you completely avoid having 
heterosexual intercourse. 
 
Male subjects: We do not know if using MLN9708 will affect sperm.  Therefore, due to 
potential risk, you should not get your partner pregnant during the study drug treatment period 
(including interruptions in treatment).  Even if you are surgically sterilized (i.e. have had a 
vasectomy) you must agree to use an appropriate method of barrier contraception (latex or non-
latex condom with a spermicidal agent) during the entire study drug treatment period, and for 90 
days after completing study drug treatment.  Or, you should completely avoid having 
heterosexual intercourse. 
 
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.  


 
 
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All subjects (male or female):  If you or your partner becomes pregnant during this study, you 
must tell the study doctor immediately.  The doctor will advise you of the possible risks to your 
unborn child and discuss options for managing the pregnancy with you.  For female subjects who 
become pregnant while on this study, the study drug will be stopped immediately and the 
pregnancy will be followed until conclusion. 
 
If you do not understand what any of these discomforts and risks mean, please ask the study 
doctor or study staff to explain these terms to you. 
 
Graft Versus Host Disease (GVHD): A major risk of the allogeneic transplant is the risk of 
developing GVHD. GVHD occurs when cells of the donor’s immune system, which are present 
in the bone marrow, attack your normal tissues.  GVHD can cause rash, diarrhea, or liver 
damage, and can be severe enough to cause death.   
 
GVHD can be classified as either acute or chronic.  Acute GVHD, if it occurs, usually appears 
within the first 100 days after transplantation. It can affect the skin, liver and the intestinal tract. 
The chance of having all three areas affected is possible.  The affect on these areas can be at 
different stages of severity.  The possible signs/ symptoms for acute GVHD of the skin, liver and 
intestinal tracts are as follows: 
• GVHD of the skin: Elevated red rash, rash with blisters or dry, peeling skin 
• GVHD of the liver:  Liver function tests above normal range or liver failure 
• GVHD of the intestinal tract (gut):  Diarrhea greater than 500 ml/day or several liters of 
diarrhea a day with severe abdominal pain   
 
Chronic GVHD is a multi-system disease that can affect almost any organ in the body. The 
mostly commonly involved organs are the skin, mouth, liver and eyes.  This form of GVHD 
usually occurs more than 100 days after your transplant. The possible signs/symptoms of chronic 
GVHD include the following: 
• GVHD of the skin: Red rash or thick, dry skin over some or most of your body  
• GVHD of the mouth:  Dry and/or sore mouth 
• GVHD of the liver: Liver function tests above normal range or liver failure 
• GVHD of the eyes: Dry eyes or corneal erosion/ conjunctivitis (infection) 
 


 
 
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Graft rejection: Another risk of allogeneic transplant is that the donor’s stem cells will not 
grow.  If this happens, your own bone marrow is unlikely to come back given the intensity of 
pre-transplant therapy.  Graft rejection is life-threatening and usually fatal without performing a 
second transplant procedure.  You will have routine blood tests about day 30, day 60, day 180 
and yearly to see how many donor cells are in your bone marrow. 
 
Hemorrhagic cystitis: This complication is seen more frequently following mismatched 
allogeneic transplants.  About 1-2 months after transplant, patients may develop painful and 
often bloody urination that is usually related to a viral infection of the bladder.  Although not 
usually life-threatening, this complication may require patients to need additional hospitalization 
for pain control or bladder irrigation. 
 
Veno-Occlusive Disease (VOD): The pre-transplant treatment with drugs and/or radiation can 
damage the liver. This complication is called VOD.  VOD may develop within the first month 
after the stem cell transplant and causes pain and enlargement of the liver, a buildup of fluid in 
the abdomen and sometimes around the lungs, and jaundice (yellowing of the skin/eyes). There 
is no proven treatment for VOD.  VOD may get worse and cause fatal liver damage.  
 
Infections: Patients receiving allogeneic transplants have weakened immune systems for many 
months following the transplant and are at risk for multiple potentially life-threatening infections 
from viruses, bacteria, fungi, and parasites.  You will receive preventative antibiotics to help 
reduce the risk of infection, and will be monitored closely for signs of fever and infection.   
 
You will be given chemotherapy during your transplant process. Risks associated with these 
drugs include: 
 
Fludarabine: low white blood cells (which could lead to an increased risk of infection), low red 
blood cells (which can cause you to feel tired, short of breath or weak), low platelets (which can 
increase your risk of bleeding), weakness, agitation, confusion, numbness and/or tingling in the 
fingers and/or toes, changes in vision, nausea, vomiting, diarrhea, soreness in the mouth, 
decreased appetite, difficulty breathing, cough or bleeding in the urine. 
 
Cyclophosphamide: abdominal pain, diarrhea, painful sores on/in the mouth or stomach, loss of 
appetite, nausea and/or vomiting.  There may be temporary and total hair loss affecting not only 
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when drug treatment is stopped.  Cyclophosphamide will decrease the blood cells produced in 
bone marrow including low white blood cells (which could lead to an increased risk of 
infection), low red blood cells (which can cause you to feel tired, short of breath or weak) and 
low platelets (which can increase your risk of bleeding). Breakdown products of 
cyclophosphamide can cause bladder irritation and bleeding. This can cause pain and the 
appearance of blood in the urine and scarring of the bladder.  You will be given a medicine 
(Mesna) and extra fluid hydration in an effort to prevent this.  At very high doses, 
cyclophosphamide can cause severe heart muscle injury or death.   
 
Taking cyclophosphamide can damage the male (testes) or female (ovaries) sex glands.  Women, 
who are still menstruating may have irregular periods or stop having periods. The ability to have 
children will likely be permanently impaired. 
 
Very rarely after getting cyclophosphamide there can be scarring of the lungs which could cause 
you to experience coughing spells and shortness of breath. There is also a small chance after 
taking cyclophosphamide of getting a second cancer (i.e. leukemia or solid tumor). 
 
TBI Decrease in blood counts (white blood cell and platelet), fatigue, hair loss, skin changes 
included redness, irritation, swollen or blistered, “sunburned” or “tanned”, dry, flaky or peeling 
skin, itchiness. There may be an increased risk of secondary cancer from the use of radiation.  
 
Tacrolimus (FK-506): constipation, diarrhea, nausea, vomiting, headache, insomnia, tremor, 
localized skin burning, pruritus (itching), skin erythema (redness), and reduced kidney function. 
 
Other risks associated with stem cell transplant  
Drawing blood from your arm may cause pain, bruising, lightheadedness, and, on rare 
occasions, infections.  We will make every attempt to use your central venous catheter for 
drawing blood when possible. 
 
Central venous catheter placement risks include bleeding, infection and lung puncture causing 
collapse of the lung.  In rare cases, surgery is needed to correct these problems. After the catheter 
has been inserted, there may be problems with infection or blood clots.  The risk for these 
problems increases with the length of time that the catheter is in place.  Treatment may include 
antibiotics and “blood thinners” to dissolve the clot.  Sometimes, the catheter needs to be 
removed.  Very rarely, there is irreversible swelling of an arm or the neck.   


 
 
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Psychological risks: It is possible that in addition to the physical risks, there are also 
psychological and emotional risks to the relationship you may have with your donor if the donor 
changes his/her mind during the treatment and decides not to donate stem cells.  The Blood and 
Marrow Transplant Program at Northside Hospital has a Health Psychologist on staff to help you 
with any psychological or emotional needs that you may have during the transplant process.  
 
Unknown Risks: There is always the risk that unexpected side effects will occur. Your doctor 
will check you closely to see if any side effects are occurring and routine blood tests will be done 
to monitor the effects of treatment. For more information about risks and side effects, ask the 
researcher or study doctor at your institution. 
 
BENEFITS 
There is no guarantee that your condition will improve as a result of participation in this study.  
However, SCT does offer a potential cure of your blood disease.  In addition, MLN9708 may 
improve your outcome by decreasing the chance of relapse following transplant. There is also a 
possibility that the treatment will have no effect on your disease or that it may even be harmful to 
you. Future patients with similar blood diseases or disorders may benefit from what is learned 
from this study.   
 
ALTERNATIVE TREATMENT 
Other options may be available, including other research studies or standard of care therapy 
including transplant at BMTGA or other institutions. It is possible that if you choose not to 
participate in this study and still go on to transplant, you may receive any or all of the 
commercially available drugs being used in this study. If you do not go on study, you will not be 
able to receive MLN9708.  You may also choose not to receive treatment for your blood disease 
or disorder and receive comfort care only, where treatments are directed only at reducing 
symptoms, relieving suffering, and maximizing comfort. This type of care does not treat your 
disease directly, but instead tries to improve how you feel.  
Should you choose not to participate in this study, your ability to received medical care at 
BMTGA or Northside Hospital will not be affected. 
 
During your participation in this study, you will be informed in a timely manner of any 
significant new information that may affect your willingness to stay in this study. 
 


 
 
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COSTS 
You will not be compensated or receive payment for participating in this study.  MLN9708 will be 
provided to you free of charge.  The other drugs used in this study are commercially available and 
will be charged to you and your insurance provider.  You and your insurance company will be 
responsible for all costs related to the study treatment that are considered standard of care.  Taking 
part in this study may lead to added costs to you and your insurance company. In some cases, it is 
possible that your insurance company may not pay for routine costs of treatment because you are 
taking part in a research study. We will help you determine the extent of your insurance coverage 
before you are enrolled on this study.   
 
Your participation in this research study may contribute to the development of commercial 
products from which Millennium Pharmaceuticals, Inc. or others, may derive an economic 
benefit.  You will have no rights to any patents or discoveries arising from this research, and you 
will receive no economic benefit.  Millennium Pharmaceuticals, Inc. is providing MLN9708 for 
this study free of charge.  The company is also providing some financial support for the Blood 
and Marrow Transplant Program at Northside Hospital to conduct this study.  
 
COMPENSATION FOR INJURY 
If you suffer an injury directly related to your participation in this project, Northside Hospital 
will provide the medical and ancillary services ordered by the doctors at the established charges 
for these services. Neither Northside Hospital nor Blood and Marrow Transplant Group of 
Georgia will provide you with financial compensation or reimbursement for the cost of care 
provided to treat a research-related injury or for other expenses arising from a research-related 
injury. Northside Hospital and BMTGA will charge your insurance carrier, you, or any other 
party responsible for your treatment costs.  
STATEMENT OF NON-WAIVER 
By signing this consent form, you have not waived any of your legal rights or released any party 
from liability for negligence. 
 
WILL MY RECORDS BE CONFIDENTIAL? 
Efforts will be made to keep your personal information confidential. Absolute confidentiality 
cannot be guaranteed; however, confidentiality will be maintained to the extent permitted by 
local, state, and federal law. 
 
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decision to participate in this study means that you agree to the use and disclosure of your 
personal health information for the purposes explained in this consent form. 
 
During the course of this study the research team may use the following health information: 
Results of tests, exams or procedures conducted for this study, information in the research 
record, results of physical exams, blood tests, x-rays and other medical procedures, and other 
information in your medical record pertaining to your care. 
 
The following individuals or entities will have access to your personal health information as 
necessary to conduct this research study:  
• BMTGA clinical research team and clinical staff (involved in patient care) 
• The Northside Hospital Blood and Marrow Transplant Program research and clinical staff 
(involved in patient care) 
• Northside Hospital healthcare professional team (e.g., nurses or radiologists involved in 
patient care) 
 
Your personal health information may also be disclosed to:  
• The Food and Drug Administration (FDA), a group that regulates research 
•   Center for International Blood and Marrow Transplant Research (CIBMTR) and the National 
Marrow Donor Program (NMDP), groups that maintain Registry databases that include all 
patients who receive blood and marrow transplants 
• The Northside Hospital Institutional Review Board (a board that oversees research done by 
the Blood and Marrow Transplant Program at Northside Hospital to ensure that the rights of 
human subjects are protected.) 
• Millennium Pharmaceuticals, the company who is responsible for supplying the study drug, 
its collaborators and designees  
 
There is the potential of further disclosure of your personal health information by these 
individuals or entities such that your information is no longer subject to protection under federal 
regulations governing the privacy of health information. Information connected to research and 
treatment offered may result in scientific presentations and publications, but precautions will be 
taken to make sure you cannot be identified in any way. 
 
By signing this consent form, you authorize the use of your personal health information.  This 
authorization has no expiration date.  You have the right to revoke your authorization to use your 


 
 
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personal health information.  
 
The revocation must be in writing and sent to the Director of the Central Research Office at 
Northside Hospital at 1000 Johnson Ferry Rd. NE, Atlanta, Georgia 30342. If you revoke your 
authorization it will not apply to prior uses or disclosures of your personal health information 
made in accordance with the purposes explained in this consent form. 
 
If you refuse to provide authorization to use and disclose your personal health information for 
this study, the investigator may refuse to include you as a participant in this study. 
 
If you are treated as part of a research study your right to access the health information used and 
disclosed for the study may be restricted during the course of the research study; however, your 
right to access will be reinstated, upon completion of the research study.  You have the right to 
review the results of any testing done on you during the course of evaluation and treatment. 
 
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.  
 
VOLUNTARY PARTICIPATION AND WITHDRAWAL 
Your participation in this study is voluntary.  You may decide not to participate in this study.  If you 
do participate, you may freely withdraw from the study at any time.  Your decision will not result in 
any penalty or loss of benefits to which you are entitled.  Your decision will not change your ability 
to receive medical care at Northside Hospital and BMTGA.  
 
Your participation in this study may be stopped at any time by the study doctor without your 
consent due to: 
• Unacceptable toxicity (side effects) from study treatment; 
• Inability to follow study procedures as outlined in the protocol as described in this 
consent form; 
• Unforeseen events which make continuing on treatment against medical judgment; 
• Serious adverse event that requires you to end your study participation; 
• The study is closed early for safety or efficacy (effectiveness) reasons; 
• You withdraw your consent to participate; 
• For any other reason that your physician feels is necessary. 


 
 
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WHAT IF I HAVE QUESTIONS OR PROBLEMS? 
If at any time you would like to ask questions about this research study, please call Dr. Lawrence 
Morris, Dr. Scott Solomon, Dr. Asad Bashey, Dr. Melhem Solh or Dr. Kent Holland at (404) 
255-1930. 
 
The Institutional Review Board at Northside Hospital has reviewed this study in the context of 
certain federal regulations relating to experimentation involving human subjects. Approval of 
this study by the Northside Hospital Institutional Review Board is not an endorsement of this 
study or its outcome. If you have any questions or concerns about this study or your rights as a 
research subject, you should contact the Chairman of the Northside Hospital Institutional Review 
Board at (404) 851-6848. 
 
WHERE CAN I GET MORE INFORMATION? 
There are many places to obtain additional information about cancer treatment and cancer 
research.  Some suggested sources of information are detailed below: 
 
You may call the National Cancer Institute’s (NCI) Cancer Information Service at 1-800-4-
CANCER (1-800-422-6237).  
 Visit the NCI’s Web site at: http://www.nci.nih.gov/cancerinfo/ 
 
You will be given a signed copy of this consent form. 
 
OPTIONAL RESEARCH SAMPLES
This study is collecting additional research samples to determine how the investigational drug, 
MLN9708, affects the recovery of your immune system following transplant.  You are able to 
decline these research samples and still participate in this study. 
 
_________ 
I AGREE to allow additional blood to be collected for research purposes only. 
 
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_________ 
I DO NOT AGREE to allow additional blood to be collected for research 
purposes only. 
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STATEMENT OF CONSENT 
My signature on this informed consent form means that I understand the explanation and freely 
consent to participate.  I will be given a signed copy of this consent form.  I also certify that I 
have been allowed to ask questions and that I have received answers to these questions. 
 
I understand that by consenting to participate in this study, I am responsible for carrying out 
instructions and that I must report to my doctors, nurses, or other personnel any information that 
might be pertinent to this study such as any side effects of the treatment.  Any reluctance that I 
might have to continue must also be reported.  I have been informed that any new information 
that might affect my willingness to continue my participation in this study will be told to me in 
an appropriate way. I further authorize the use and disclosure of my personal health information 
for the purposes described in this consent form.  
 
Printed Name/Signature of Recipient or Legal Representative 
Date 
 
Time 
___________________________________________________ 
Representative’s Authority to Sign 
 
 
 
 
 
______________________________________________________________________________ 
Printed Name/Signature of Person Obtaining Consent 
 
Date 
 
Time 
 
INVESTIGATOR STATEMENT 
It has been explained to the person named above the nature of the treatment plan described 
above. To the best of my knowledge the person signing this consent form understands the nature, 
demands, benefits and risks involved in participating in this treatment plan. 
__________________________________________________________________________ 
Signature of Physician  
 
 
 
 
 
Date 
 
Time