Clinical trial NCT02250300
Conditions: Allogeneic Hematopoietic Stem Cell Transplantation
Keywords: Stem cell transplantation Hematopoietic transplantation Hematopoietic stem cell
Sponsor: Mehdi Hamadani
Start date: 2014-11-19; Completion date: 2020-10-06
Enrollment: 68 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase I/II study of MLN9708 for the prophylaxis of chronic graft-versus-host-disease (GVHD) in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT).

During the phase I portion, patients undergoing both sibling and unrelated donor transplantation will be enrolled on the same arm to determine the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD).

During the phase II portion of the trial, patients will be enrolled into two separate and independent cohorts: a) Matched sibling transplants and b) Unrelated donors transplants. Both cohorts will be enrolled and analyzed separately.

Detailed description:
* For potential candidates for this trial, the recommended acute GVHD prophylaxis is a tacrolimus, methotrexate and atorvastatin combination. However, any acute GVHD prophylaxis regimen at the discretion of treating physician (not involving in vivo or ex vivo T-cell depletion, cluster of differentiation 34 (CD34) + cell selection, or post-HCT cyclophosphamide) will be permitted.
* During the phase I portion for chronic GVHD prophylaxis, four doses of MLN9708 will be administered orally (to patients undergoing either matched sibling or unrelated donor transplantation) on days 1, 8, 15 and 22, starting on day +60 to +74 post allogeneic HCT.

If zero of three patients experienced DLT at dose level 2, then it would be considered a MTD. If two or more patients experienced a DLT, dose escalation would halt and the dose level would be expanded to six patients to determine the MTD. If the dose level below already has six patients, enrolled, then it will be considered the MTD. If two or more patients experience DLT on first dose level (i.e., dose level 1), then, patients will be enrolled on dose level -1. No intrapatient dose escalation will be permitted.

* MTD is defined at maximum dose level with fewer than two of six patients experiencing DLT.
* The phase II portion will utilize the MTD for MLN9708, determined from phase I portion of the study. In phase II, patients will be enrolled in two independent cohorts of matched sibling and matched unrelated donor transplants.
* During the phase II portion, for chronic GVHD prophylaxis, four doses of MLN9708 will be administered orally on days 1, 8, 15 and 22, starting on day +60 to +90 post allogeneic HCT.

Arms: arm 1: Phase II Patients will be enrolled in two independent cohorts of matched sibling and matched unrelated donor transplants. Four doses of MLN9708 will be administered on days 1, 8, 15, \& 22 starting on day +60 to +90 post allogeneic HCT. arm 2: Phase II Patients will be enrolled in two independent cohorts of matched sibling and matched unrelated donor transplants. Four doses of MLN9708 will be administered on days 1, 8, 15, \& 22 starting on day +60 to +90 post allogeneic HCT. arm 3: Phase I Four doses of MLN9708 will be administered on days 1, 8, 15, \& 22 orally based on a dose escalation schema. arm 4: Phase I Four doses of MLN9708 will be administered on days 1, 8, 15, \& 22 orally based on a dose escalation schema. arm 5: Phase I Four doses of MLN9708 will be administered on days 1, 8, 15, \& 22 orally based on a dose escalation schema.
Interventions: intervention 1: MLN9708 (2.3 mg) intervention 2: MLN9708 (4.0 mg) intervention 3: MLN9708 (3.0 mg)
Intervention descriptions: intervention 1: 2.3 mg intervention 2: 4.0 mg intervention 3: 3.0 mg

Protocol documents:
Prot_SAP_000.pdf: 
Protocol title:  The MLN9708 for the prophylaxis of chronic graft-versus-host disease in 
patient undergoing allogeneic transplantation. 
 
Document date:  03-13-18 
 
NCT number:  NCT02250300 


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The MLN9708 for the prophylaxis of chronic graft-versus-host 
disease in patient undergoing allogeneic transplantation. 
 
Principal Investigator: 
Mehdi Hamadani, MD 
 
Associate Professor of Medicine,  
 
 
Division of Hematology and Oncology 
 
Froedtert Hospital and the Medical College of Wisconsin 
 
9200 W. Wisconsin Ave. 
 
Milwaukee, WI 53226 
 
Protocol Team: 
Parameswaran Hari, MD, MRCP, MS 
 
William R Drobyski, MD 
 
Timothy S. Fenske, MD 
 
Douglas Rizzo, MD 
 
Marcelo Pasquini, MD 
 
Mary Eapen, MD 
 
Wael Saber, MD 
 
Anita D’Souza, MD 
 
Bronwen Shaw, MD 
 
Nirav Shah, MD 
 
Sameem Abedin, MD 
 
Lyndsey Runaas, MD 
 
James Jerkins, MD 
 
 
 
Statistician: 
Alexis Visotcky, MS 
 
Biostatistician II 
 
Division of Biostatistics 
 
Institute for Health and Society 
 
avisotcky@mcw.edu  
 
Study Coordinator: 
For Medical College of Wisconsin:  
Kassandra Cantrall 
Froedtert Hospital and the Medical College of Wisconsin 
Cancer Center Clinical Trials Office 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
Phone: 414-805-8755 
Fax: 414-805-0596 
Email: kcantrall@mcw.edu   
 
 


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Pharmacist 
For Medical College of Wisconsin: 
Angela Urmanski, Pharm D.  
Froedtert Hospital  
Inpatient Pharmacy  
Attn: Senad Novic  
9200 W Wisconsin Ave  
Milwaukee, WI 53226 
 


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CLINICAL STUDY PROTOCOL  
Protocol Number = IISR-2013-M100104; Grant Number: X16034 
MLN9708 for the prophylaxis of chronic graft-versus-host disease in patient undergoing 
allogeneic transplantation. 
 
 
 
Indication: 
Chronic graft-versus-host disease prophylaxis  
Phase: 
Phase I/II  
 
 
 
Protocol History 
Original 
Amendment 1 
Amendment 2 
Amendment 3 
 
23 August 2013 
04 November 2014 
25 June 2015 
15 March 2017 
Amendment 4 
 
14 September 2017 
Amendment 5 
 
13 March 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This is an investigator-initiated study.  The principal investigator Mehdi Hamadani, 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. 


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PROTOCOL SUMMARY  
Study Title:  MLN9708 for the prophylaxis of chronic graft-versus-host disease. 
Phase:  Phase I/II 
Number of Patients:  6 patients were enrolled in phase I portion. No DLTs were seen. In the phase 
II portion a total of 52 patients (25 sibling and 27 unrelated donor transplantation) will be enrolled. 
Total accrual = 58 patients. 
Study Objectives  
Primary Objectives: 
Phase I Primary Objectives: 
1. To determine the maximum tolerated dose (MTD), dose limiting toxicity (DLT) and 
recommended phase II dose (RDP) of MLN9708 for the prophylaxis of chronic GVHD in 
patients undergoing allogeneic hematopoietic cell transplantation (HCT). 
Phase II Primary Objectives: 
2. Determine the 1-year (from the date of HCT) cumulative incidence of chronic GVHD 
following MLN9708 administration as prophylaxis, in patients undergoing matched sibling 
allogeneic HCT.  
3. Determine the 1-year (from the date of HCT) cumulative incidence of chronic GVHD 
following MLN9708 administration as prophylaxis, in patients undergoing unrelated donor 
allogeneic HCT.  
Phase I/II Primary Objectives: 
4. Assess the safety of chronic GVHD prophylaxis with MLN9708 in patients undergoing 
allogeneic HCT. 
Secondary Objectives: 
1. To assess the 1-year and 2-year (from the date of HCT) cumulative incidence of 
corticosteroid requiring chronic GVHD, in the matched sibling and unrelated donor cohorts 
separately. 
2. Determine the 2-year (from the date of HCT) cumulative incidence of chronic GVHD 
following MLN9708 administration as prophylaxis, in the matched sibling and unrelated 
donor cohorts separately.  
3. To assess the 1-year and 2-year (from the date of HCT) cumulative incidence of mild, 
moderate and severe chronic GVHD (by NIH criteria) and limited or extensive chronic 
GVHD (by conventional criteria), in the matched sibling and unrelated donor cohorts 
separately. 
4. To assess cumulative incidence of grade II-IV acute GVHD at days +100, +180 and +365, in 


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the matched sibling and unrelated donor cohorts separately. 
5. To assess cumulative incidence of grade III-IV acute GVHD at days +100, +180 and +365, 
in the matched sibling and unrelated donor cohorts separately. 
6. To assess non-relapse mortality rate at 100 days, 1-year post-HCT. 
7. To assess the incidence of motor and sensory neuropathy associated with MLN9708 
8. To assess incidence of secondary graft failure. 
9. To assess incidence of secondary immunologic graft rejection. 
10. To assess relapse rate of the primary hematological malignancy.  
11. To assess lineage specific chimerism kinetics in patients at baseline (approximately day 
+30), day +100, day +180 and day +365. 
12. To assess immune reconstitution following transplantation at baseline (approximately day 
+30), day +100, day +180, day +365 and day +730. 
13. To assess absolute neutrophil count on day +100, day +180 and day +365. 
14. Response of acute GVHD to MLN9708 at day +100, in those patients with controlled grade 
I-II acute GVHD at the time of enrollment.  
15. To assess 1-year and 2-years progression free survival (PFS) and overall survival (OS) 
following transplantation.  
16. To evaluate biologic markers potentially associated with GVHD and/or MLN9708. 


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Overview of Study Design:   
This is a phase I/II study of MLN9708 for the prophylaxis of chronic GVHD in patients undergoing 
allogeneic HSCT. During the phase I portion patients undergoing both sibling and unrelated donor 
transplantation will be enrolled on the same arm to determine the DLT and MTD. During the phase 
II portion of the trial, patients will be enrolled into two separate and independent cohorts: a) Matched 
sibling transplants and b) Unrelated donors transplants. Both cohorts will be enrolled and analyzed 
separately. 
Study Population:   
Inclusion criteria: 
1. Patients with a history of a hematological malignancy or bone marrow failure syndrome 
undergoing (or status post) a peripheral blood allogeneic HCT. 
2. Patients aged ≥18 are eligible. 
3. All patients must have received or plan to receive an allograft from a suitable HLA-
matched sibling or unrelated donor according to transplant center’s guidelines (for selection 
of appropriate donor). 
4. Voluntary written consent must be given before patient registration and 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. Bilirubin ≤ 2 x the ULN. For patients with Gilbert’s syndrome or suspected mild veno-
occlusive disease, bilirubin ≤ 3 x ULN is permitted.  
6. Creatinine clearance of > 30 mL/min calculated by Cockcroft-Gault equation. 
7. Karnofsky performance status > 60.  
8. A negative pregnancy test will be required for all women of child bearing potential. 
Females of child bearing potential should 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 must also adhere to the guidelines of 
any treatment-specific pregnancy prevention program, if applicable, or agree to practice 
true abstinence when this is in line with the preferred and usual lifestyle of the subject.  
(Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and 
withdrawal are not acceptable methods of contraception.). Breast feeding is not permitted.  
9. Male patients, even if surgically sterilized (ie, status post-vasectomy), must agree to one of 
the following: practice effective barrier contraception during the entire study treatment 
period and through 90 days after the last dose of study drug, or must also adhere to the 
guidelines of any treatment-specific pregnancy prevention program, if applicable, or agree 
to practice true abstinence when this is in line with the preferred and usual lifestyle of the 
subject.  (Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation 
methods] and withdrawal are not acceptable methods of contraception.) 
10. No evidence of uncontrolled bacterial, viral or fungal infections at the time of enrollment. 
11. No known active hepatitis B or C virus infection, or known human immunodeficiency virus 
(HIV) positive. 
 


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Exclusion Criteria: 
1. Patients with active ≥ grade 3 peripheral neuropathy or grade 2 with pain on clinical 
examination during the screening period will be excluded. 
2. Patients with history of allergy and/or intolerance to MLN9708 are not eligible. 
3. Known GI disease or GI procedure that could interfere with the oral absorption or tolerance 
of MLN9708 including difficulty swallowing is not permitted. 
4. Patients receiving (or status post) a cord blood or a haplo-identical allograft will not be 
eligible.  
5. Patients undergoing (or status post) a T-cell depleted allogeneic transplantation will not be 
eligible. 
6. Patients receiving (or status post) conditioning regimens containing antithymocyte 
globulin, and/or campath, one receiving post-HCT planned cyclophosphamide will not be 
eligible.  
7. Method of stem-cell collection from the donor will be at the discretion of the treating 
physician. Although it is anticipated that majority of patients will receive allograft 
mobilized with G-CSF alone; however donors receiving allografts mobilized with 
experimental agents (e.g. plerixafor) will remain eligible for the study. 
8. Patients experiencing disease relapse (for those in complete remission at the time of HCT) 
or progression (for those in partial remission, stable or refractory disease at the time of 
HCT) will be excluded.  
9. Donor lymphocyte infusions between day zero of HCT and first dose of MLN9708 are not 
permitted.  
10. Rituximab (or other B-cell depleting monoclonal antibodies) or bortezomib administration 
between day zero of HCT and before the first day of MLN9708 is not permitted.  
11. Patients with steroid refractory (defined as no improvement of symptoms after 7 days of 
systemic corticosteroids at a dose of ≥1mg/kg/day) grade II-IV acute GVHD, that is active 
at the time of enrollment will be excluded.  
12. Patients with grade III-IV acute GVHD (even if it is not meeting criteria for steroid 
refractory acute GVHD), that is active at the time of enrollment will be excluded. Patients 
with controlled grade I-II acute GVHD can be enrolled after discussing with study PI. 
Topical or systemic corticosteroids therapy, as per standard of care for such grade I-II acute 
GVHD patients is permitted.   
13. Patients with active chronic GVHD (although unlikely before day +100) will be excluded. 
14. No major surgery within 14 days before enrollment. 
15. No radiotherapy within 14 days before enrollment. If the involved field is small, 7 days will 
be considered a sufficient interval between treatment and administration of the MLN9708. 
16. No 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. Cardiac enzyme 
elevations for reasons other than document myocardial infarction is not an exclusion.  
17. No systemic treatment, within 14 days before the first dose of MLN9708, with strong 
inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of CYP3A 
(clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, 


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posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, 
phenytoin, phenobarbital), or use of Ginkgo biloba or St. John’s wort. 
18. No serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with the completion of treatment according to this protocol. 
19.  No participation in clinical trials with other investigational agents, within 21days of the 
start of this trial and for two weeks after the last dose of MLN9708 or resolution of 
MLN9708 related adverse events to grade 1 or less (whichever occurs later). However, co-
enrollment on trials evaluating conditioning regimens, institutional protocols evaluating 
atorvastatin for acute GVHD prophylaxis, and stem cell collection protocols in transplant 
donors will be permitted. In addition, patients randomized to standard-of-care (non-
experimental) arms of available phase II/III trials will be eligible for this study.  
Duration of Study:  Accrual period: Approximately 24-30 months. 
 


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ABBREVIATIONS USED: 
AE: ADVERSE EVENT 
AESIS: ADVERSE EVENTS OF SPECIAL INTEREST  
APC: ANTIGEN PRESENTING CELLS 
BAFF: B CELL ACTIVATING FACTOR  
BCRP: BREAST CANCER RESISTANCE PROTEIN 
CL: CLEARANCE  
CYP: CYTOCHROME P450 
DLT: DOSE LIMITING TOXICITY  
FDA: FOOD AND DRUG ADMINISTRATION 
FOXP3: FORKHEAD BOX P3 
GVHD: GRAFT-VERSUS-HOST DISEASE 
GVL: GRAFT-VERSUS-LEUKEMIA 
HSCT: ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION  
IL-1: INTERLEUKIN 1  
IFN: INTERFERON  
MHC: MAJOR HISTOCOMPATIBILITY COMPLEX CLASS 
MRP2: MULTIDRUG RESISTANCE ASSOCIATED PROTEIN  
MTD: MAXIMUM TOLERATED DOSE NDMM: NEWLY DIAGNOSED MULTIPLE 
MYELOMA 
P-GP: P GLYCOPROTEIN 
PK: PHARMACOKINETIC 
RDP: RECOMMENDED PHASE II DOSE  
SAE: SERIOUS ADVERSE EVENT 
STATINS: HMG-COA REDUCTASE INHIBITORS  


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TH-1: T HELPER TYPE 1 
TH-2: T HELPER TYPE 2  
TMAX: MAXIMUM PLASMA CONCENTRATION 
TNF: TUMOR NECROSIS FACTOR  
TREG: REGULATORY T  
TW: TWICE WEEKLY 
W: WEEKLY 


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 Table of Contents 
 
1. 
INTRODUCTION: .......................................................................................................................................... 13 
Statins as Potential Modulators of GVHD: ............................................................................................................. 14 
Statins and Murine Acute GVHD: .......................................................................................................................... 14 
Clinical Trial Data for Statin use for Preventing GVHD: ....................................................................................... 15 
Role of B-cells in Pathogenesis of Chronic GVHD: ............................................................................................... 16 
Rituximab for Chronic GVHD Prophylaxis:........................................................................................................... 17 
Proteasome Inhibitors and GVHD: ......................................................................................................................... 18 
MLN9708: .............................................................................................................................................................. 19 
Study Rationale: ...................................................................................................................................................... 30 
Potential Risks and Benefits: .................................................................................................................................. 31 
2. 
OBJECTIVES: ................................................................................................................................................. 31 
Primary Objectives: ................................................................................................................................................ 31 
Secondary Objectives: ............................................................................................................................................ 32 
3. 
ELIGIBILITY CRITERIA: ............................................................................................................................ 33 
4. 
REGISTRATION PROCEDURE: ................................................................................................................. 36 
Registration ............................................................................................................................................................. 36 
5. 
TREATMENT PLAN: ..................................................................................................................................... 36 
Administration schedule to Transplant recipients ................................................................................................... 37 
Dose modification ................................................................................................................................................... 41 
Duration of therapy ................................................................................................................................................. 41 
Data Safety Monitoring Plan .................................................................................................................................. 41 
6. 
MEASUREMENT OF EFFECT: ................................................................................................................... 42 
Follow up schedule: ................................................................................................................................................ 42 
Patients will be followed for survival, relapse and cause of death for 5 years post transplantation. ...................... 42 
Phase I patients will be seen weekly for toxicity assessment during the DLT period. ........................................... 42 
GVHD Assessment: ................................................................................................................................................ 42 
Chimerism Assessment and Immune Reconstitution: ............................................................................................. 43 
7. 
STUDY PARAMETERS (STUDY CALENDAR): ....................................................................................... 43 
PATIENT STUDY CALENDAR: ............................................................................................................................ 43 
8. 
DRUG FORMULATION AND PROCUREMENT ...................................................................................... 47 
MLN9708 (Ixazomib® Millennium Pharmaceuticals, Inc.) .................................................................................... 47 
Drug description ..................................................................................................................................................... 47 
Pharmacodynamics ................................................................................................................................................. 47 
Pharmacokinetics .................................................................................................................................................... 48 
Contraindications .................................................................................................................................................... 49 
Concomitant Medications ....................................................................................................................................... 49 
Safety: ..................................................................................................................................................................... 50 
Preparation, Reconstitution, and Dispensing .......................................................................................................... 51 
Packaging and Labeling .......................................................................................................................................... 52 
Storage, Handling, and Accountability ................................................................................................................... 52 
9. 
STATISTICAL CONSIDERATIONS: .......................................................................................................... 53 
10. 
ADVERSE EVENT REPORTING REQUIREMENTS ............................................................................... 56 
11. 
DEFINITIONS ................................................................................................................................................. 56 


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12. 
ADMINISTRATIVE REQUIREMENTS ...................................................................................................... 63 
Ethical Considerations ............................................................................................................................................ 64 
Subject Information and Informed Consent ............................................................................................................ 64 
Patient Confidentiality ............................................................................................................................................ 65 
Investigator Compliance ......................................................................................................................................... 65 
On-site Audits ......................................................................................................................................................... 66 
Investigator and Site Responsibility for Drug Accountability ................................................................................ 66 
Product Complaints ................................................................................................................................................. 66 
Closure of the Study ............................................................................................................................................... 67 
Record Retention .................................................................................................................................................... 67 
Use of Information .................................................................................................................................................. 68 
13. 
REFERENCES ................................................................................................................................................. 69 
14. 
APPENDIX A ASSESSMENT OF ACUTE GVHD...................................................................................... 75 
15. 
APPENDIX B GRADING OF CHRONIC GVHD (NIH CRITERIA) ........................................................ 77 
16. 
APPENDIX C. SAMPLE SAE FORM ........................................................................................................... 79 
17. 
APPENDIX D. MILLENNIUM PREGNANCY REPORTING FORM ..................................................... 83 
 
 
 


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1. Introduction:   
 
Graft-versus-host disease (GVHD) is one of the most frequent complications after 
allogeneic hematopoietic stem cell transplantation (HSCT) 1. Acute and chronic forms of 
GVHD develops in 30-75% of recipients of allogeneic HSCT depending on the degree of 
histocompatibility between the donor and the recipient, number of T-cells in the graft, 
recipient’s age and GVHD prophylactic regimen used 2-4. Novel strategies designed to 
effectively prevent the development of this life threatening complication of allogeneic 
transplantation are urgently needed. Immune modulation with atorvastatin in matched sibling 
transplantation, in our experience has shown promise in preventing acute GVHD; however 
rates of chronic GVHD remain high. No pharmacological agents are currently approved or 
considered standard treatment for preventing chronic GVHD, following allogeneic HSCT. 
Extensive preclinical and clinical data (discussed in subsequent sections) suggest efficacy of 
proteasome inhibitors as novel agents, with potential to prevent chronic GVHD. MLN9708 is 
an oral proteasome inhibitor, associated with reduced risk of peripheral neuropathy. The 
current phase I/II study aims to investigate the role of MLN9708, as a novel, oral 
pharmacological prophylaxis for chronic GVHD in patients receiving standard acute GVHD 
prophylaxis post allogeneic HSCT.   
 
Pathophysiology of Acute GVHD: 
Acute GVHD is initiated when donor T cells encounter host APCs in lymphoid tissues 
and become activated 5. This T-cell activation process requires co-stimulation via CD80 and 
CD86, which are up-regulated on APCs during the early phase of acute GVHD. Activation is 
enhanced by local tissue damage due to the conditioning regimen. Local proinflammatory 
cytokines such as tumor necrosis factor (TNF), interleukin 1 (IL-1), and interferon (IFN)-
gamma, promote Th-1 differentiation of donor-derived T cells and enhance their proliferation 
and reactivity against host tissues 6. Massive cytokine release related to the Th-1 phenotype 
predicts the incidence and severity of acute GVHD in both murine models and humans, 
whereas patients with high IL-10 production are less at risk for GVHD development 7-9. 
 
 
 


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Statins as Potential Modulators of GVHD: 
HMG-CoA reductase inhibitors (statins), the cholesterol-lowering drugs that are 
prescribed worldwide to prevent and treat atherosclerosis, are increasingly being recognized 
to exhibit a variety of immunomodulatory properties 10. Reduced mevalonate production by 
statins, not only inhibits the synthesis of cholesterol but also that of key isoprenoid 
intermediate molecules required for the isoprenylation of GTP-binding cell signaling proteins 
such as Ras, Rho and Rac 11. By inhibiting this posttranslational modification, statins affect 
intracellular signaling pathways and cellular functions such as differentiation, motility, 
secretion and proliferation 12, 13. Inhibiting Ras leads to a bias towards T helper type 2 (Th-2) 
cell development, and inhibition of pro-inflammatory Th-1 driven responses 12, 14. This 
change in intracellular signaling can also affect the development of regulatory T (Treg) cells, 
as exposure of human CD4+ T cells to atorvastatin in vitro increases expression of forkhead 
box P3 (FOXP3) 15. In fact. increased numbers of circulating FOXP3+ Treg cells are present 
in dyslipidemic patients taking statins for 4-6 weeks 15. In addition to direct effects on T 
cells, statins can also indirectly decrease T-cell activation by inhibiting interferon-γ–induced 
expression of major histocompatibility complex class (MHC) II and by blocking up-
regulation of a variety of co-stimulatory molecules and cytokines in antigen presenting cells 
(APCs) 12. Hence statins appear to suppress T cell–dependent immune responses at many 
levels and hold promise as a new class of immunomodulatory drugs, with potential role in 
preventing acute GVHD. 
 
Statins and Murine Acute GVHD: 
Zeiser and colleagues 16 reported protective effects of atorvastatin against acute GVHD in 
a MHC mismatched mouse model. In a series of elegant experiments, the authors 
demonstrated reduced risk of lethal acute GVHD by pre-treating the donor mice with 
atorvastatin. T-cells derived from these atorvastatin pre-treated mice not only showed 
reduced proliferation potential, but also displayed (both in-vivo and in-vitro) reduced Th-1 
cytokine (TNF, IFN-gamma) and increased Th-2 cytokine (IL-10, IL-4) production. Zeiser 
and colleagues also investigated the impact of atorvastatin administration to recipient mice. 
Atorvastatin when given to recipient mice only translated into acute GVHD protection with a 
long-term survival of 50%, compared with 0% survival in control animals. Recipient APCs 
derived from liver, spleen, and lymph nodes of recipient mice getting atorvastatin or PBS 


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were analyzed at different time points after transplantation. Surface expression of CD80, 
CD86, CD40, and MHC class II was decreased in animals treated with the atorvastatin as 
compared with PBS-treated recipients. Interestingly pre-treating both donor and recipient 
mice with atorvastatin produced synergistic protective effects, when compare with survival 
of only donor or recipient pre-treated groups. Perhaps the most significant finding was that 
atorvastatin pretreatment did not interfere with perforin-mediated cytolysis or Fas–Fas-ligand 
interaction–mediated killing. In summary, these key experiments highlight the potential of 
atorvastatin in protecting against acute GVHD, while preserving the graft-versus-leukemia 
(GVL) effects.  
 
Clinical Trial Data for Statin use for Preventing GVHD: 
A number of retrospective studies suggest projective role of statins against acute and 
chronic GVHD 17-19. Based on this data, our group conducted a single-arm phase-II study 
evaluating the safety and efficacy of atorvastatin for the prophylaxis of acute graft-versus-
host disease in patients with hematological malignancies undergoing HLA-matched sibling 
donor hematopoietic SCT (www.clinicaltrials.gov NCT01175148). Atorvastatin 
administration in healthy donors and recipients was not associated with any grade 3-4 
adverse events. The cumulative incidence rates of grade II-IV acute GVHD at days +100 and 
+180 were 3.3% (95%CI=0.2 - 14.8%) and 11.1% (95%CI=2.7-26.4%), respectively. The 1-
year cumulative incidence of chronic GVHD was 52.3% (95%CI=27.6-72.1%). One-year 
cumulative incidences of non-relapse mortality and relapse were 9.8% (95%CI=1.4-28%) 
and 25.4% (95%CI=10.9-42.9%), respectively. The 1-year overall survival and progression-
free survival were 74% (95%CI=58-96%) and 65% (95%CI=48-87%), respectively. 
Compared to baseline, atorvastatin administration in sibling donors was associated with a 
trend towards increased mean plasma interleukin-10 concentrations (5.6pg/ml vs. 7.1 pg/ml; 
p=0.06). This study showed that a novel two-pronged strategy of atorvastatin administration 
to both donors and recipients of matched sibling allogeneic HCT appears to be a feasible, 
safe and potentially effective strategy to prevent acute GVHD (manuscript submitted for 
publication). In an ongoing protocol, we are evaluating the role of atorvastatin for the 
prophylaxis of acute GVHD when administered to recipients of matched sibling and 
unrelated donor transplants alone, to assess if routine administration of atorvastatin to healthy 
sibling donors is warranted (www.clinicaltrials.gov NCT01665677). The results of 


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NCT01175148 and the preliminary observations from NCT01665677 suggest that while an 
atorvastatin-based GVHD prophylaxis provides protection against acute GVHD; compared 
to historical controls 3, 4 the incidence of chronic GVHD remains high and represents a 
significant clinical challenge. This preliminary data underscores the need to develop 
prophylactic strategies for chronic GVHD in allogeneic transplant patients getting 
atorvastatin based acute GVHD prophylaxis in particular, and for patients undergoing 
allografting in general.  
 
Role of B-cells in Pathogenesis of Chronic GVHD: 
Although the exact causes of chronic GVHD remain unknown, higher antibody levels 
have been associated with autoimmunity and implicated in chronic GVHD 20. Newly 
diagnosed patients with extensive chronic GVHD have elevated soluble B cell activating 
factor (BAFF) levels and anti-double-strand DNA antibodies 21, 22, suggesting that B-cells 
play a role in chronic GVHD pathogenesis. Peripheral B cells in post allogeneic transplant 
patients with chronic GVHD have significantly higher BAFF/B-cell ratios compared with 
patients without chronic GVHD 23. In chronic GVHD, increasing BAFF concentrations 
correlate with increased numbers of circulating pre-germinal center (GC) B-cells and post-
GC "plasmablast-like" cells, suggesting in vivo BAFF dependence of these two CD27+ B-
cell subsets 23. The patients who develop chronic GVHD have delayed reconstitution of naive 
B-cells despite persistent BAFF elevation as well as proportional increase in CD27+ B cells 
in the first year after transplantation 23. B cells from chronic GVHD patients are 
hyperresponsive to Toll-like receptor-9 signaling and have up-regulated CD86 levels 24, 
suggesting an important participatory role for B cells in establishing chronic GVHD. Recent 
studies also reveal that B-cells from patients with active chronic GVHD are in a heightened 
metabolic state and are resistant to apoptosis 25. These B-cells have significantly increased 
signaling through ERK and AKT that is associated with decreased levels of proapoptotic 
Bim, suggesting a mechanistic link between elevated BAFF levels and aberrant B-cell 
survival 25. Altered B cell homeostasis in chronic GVHD is associated with persistence of 
circulating, potentially autoreactive, B-cells 23. A murine study demonstrated that allogeneic 
antibody deposit in chronic GVHD-affected tissues, and chronic GVHD was prevented when 
the donor graft was genetically prevented from secreting IgG 26. Moreover, during GVHD 
onset, donor B-cells are activated by donor CD4+ T cells to upregulate MHC II and 


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costimulatory molecules. Acting as efficient APCs, donor B-cells augment donor CD4+ 
clonal T-cell expansion, autoreactivity, IL-7Rα expression, and survival. These qualitative 
changes markedly augment donor CD4+ T cells' capacity in mediating autoimmune-like 
chronic GVHD 27. Collectively these data support an integral role of B-cell in the 
pathogenesis of chronic GVHD. 
  
Rituximab for Chronic GVHD Prophylaxis: 
Treatment of steroid refractory chronic GVHD patients with rituximab, a B cell–depleting 
anti-CD20 monoclonal antibody, has shown encouraging activity 28, 29, with overall response 
rates of 29% to 36% for oral, hepatic, gastrointestinal, and lung chronic GVHD, and 60% for 
cutaneous chronic GVHD 30 in aggregate data from multiple trials. Based on rituximab’s 
activity in the steroid refractory setting, recent studies have evaluated its role as chronic 
GVHD prophylactic agent. Rituximab added to fludarabine and cyclophosphamide 
conditioning resulted in a low rate of chronic GVHD in 10 chronic lymphocytic leukemia 
patients 31. Arai S et al. used prophylactic rituximab 2 months after transplantation to 
decrease the incidence of chronic GVHD 32. The study included 35 patients undergoing total 
lymphoid irradiation/antithymocyte globulin conditioning. Rituximab (375 mg/m2) was 
infused weekly on days 56, 63, 70, and 77 after transplantation. The incidence of acute 
GVHD was 6%. The cumulative incidence of chronic GVHD was 20%. Non-relapse 
mortality was 3%. Rituximab treatment after allogeneic transplantation significantly reduced 
B-cell allogeneic immunity, with complete prevention of alloreactive H-Y Ab development 
in male patients with female donors (P = .01) 32. Similarly Cutler and colleagues using an 
alternative rituximab prophylaxis schedule reported chronic GVHD and systemic 
corticosteroid-requiring chronic GVHD cumulative incidence at 2 years from transplantation 
of 48% and 31% respectively, both lower than the corresponding rates in a concurrent control 
cohort (60%, p=0.1 and 48.5%, p=0.015) 28. 
In addition to infusion reactions, cost and requirements for parenteral administration, 
rituximab used post AHCT can also potentially lead to life threatening neutropenia and 
infections. McIver et al reported the rituximab administration within six months of an 
allogeneic transplant was associated with prolonged, profound and life-threatening 
cytopenias 33. In experience by Arai et al neutropenia after rituximab infusion was observed 
in 40% of the patients and should be a caution when using rituximab after transplantation 32. 


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Proteasome Inhibitors and GVHD: 
Bortezomib is the prototype proteasome inhibitor. Bortezomib is effective against multiple 
myeloma via inhibition of nuclear factor–κB, attenuation of interleukin (IL)-6 mediated cell 
growth, a direct apoptotic effect, and possibly antiangiogenic and other mechanisms. Nuclear 
factor–κB plays an important role in cytokine signaling and T-cell activation, proliferation, 
and apoptosis 34, 35. Bortezomib inhibits APCs by attenuating Toll-like-receptor 4–mediated 
activation, with reduced cytokine production and immunostimulatory activity 36. In addition, 
treatment of CD4+ T cells with bortezomib was found to preserve natural regulatory T-cells 
while allowing the emergence of a distinct suppressor T cell population that inhibited the 
proliferation, IFN-γ production, and CD40L expression in stimulated effector T cells 37. In 
the preclinical setting, bortezomib preferentially and specifically depletes alloreactive T 
lymphocytes 38. In mouse models of HLA-mismatched allografting, administration of 
bortezomib protects against GVHD without impairing engraftment 39, 40. In summary 
proteasome inhibition eliminates alloreactive plasma cells and alloreactive T cells. 
Furthermore, it interferes with APC function and reduces inflammatory cytokine production 
either by eliminating the cytokine-secreting cell or by inhibiting its production through the 
downmodulation of NF-κB-dependent transcription, supporting the role of proteasome 
inhibitors as GVHD prophylactic agents. 
Mateos-Mazon et al. 41found that bortezomib may be useful in the management of chronic 
GVHD. The investigators administered bortezomib to 8 patients who relapsed after reduced-
intensity conditioning allogeneic transplantation. At the time of bortezomib administration, 4 
patients had chronic GVHD, including severe punctate keratopathy in 3 patients. 
Interestingly, in all 4 patients, chronic GVHD significantly improved; especially in the 3 
patients with ocular involvement, in whom both symptoms and conjunctival ulcerations 
responded. As previously shown and noted by the investigators, NF-κB activation plays a 
crucial function in inflammatory eye disease; therefore, NF-κB blockade may have an 
important role in the management of ocular GVHD 42. In another study by El-Cheikh et al. 43, 
bortezomib was administered as salvage treatment after multiple myeloma relapse or 
progression after allogeneic stem cell transplantation in 37 patients. Before the start of 
treatment, 8 patients were suffering limited chronic GVHD, whereas 3 patients had extensive 
signs. Two of the 3 patients with extensive chronic GVHD signs before the start of treatment 


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showed a significant improvement in GVHD.  Koreth et al 44 used bortezomib for acute 
GVHD prophylaxis in a phase I/ trial. They found that 180-day cumulative incidence of 
grades II to IV acute GVHD was 22%. One-year cumulative incidence of chronic GVHD 
was only 29%. Disease relapse were comparable to historical controls, underscoring the fact 
that proteasome inhibitors do not interfere with GVL effects.  Taken together, the above 
results demonstrate the potential of proteasome inhibitors in the prevention of chronic 
GVHD due to marked immunomodulatory activity. However, administration of bortezomib 
requires parenteral or subcutaneous administration and is often complicated by severe painful 
peripheral neuropathy. To circumvent these limitations, MLN9708, a novel oral proteasome 
inhibitor with reduced risk of peripheral neuropathy warrants investigation for chronic 
GVHD prophylaxis, in patients undergoing allogeneic transplantation. 
  
MLN9708: 
 
Preclinical Experience 
 
Please refer to the current MLN9708 Investigator’s Brochure (IB) and Safety 
Management Attachment (SMA). 
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 systemic light chain 
amyloidosis. A clinical pharmacology study looking at drug-drug interactions, the effect of 
food, and bioavailability also uses the oral formulation. Details of these trials can be found in 
Pharmacokinetics and Drug Metabolism ClinicalTrials.gov and the MLN9708 IB.  
 


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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 in 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 days 45.  Results of a population PK analysis (N = 137) show that there is no relationship 
between body surface area (BSA) or body weight and clearance (CL).  Also, based on 
stochastic simulations for fixed dose, exposures are independent of the individual patient’s 
BSA.[2] Based on this data, a recommendation was made for fixed dosing (4mg on days 1, 8, 
and 15 of a 28-day cycle) in the clinical trial. Hence, the 4mg dose will be the highest dose 
level tested, in the phase 1 portion of current clinical trial. An absolute bioavailability of 67% 
was determined for MLN9708 using the population PK analysis. 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 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. 
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 


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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 
RR-AL 
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 
DLT: 
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; RPh2D = 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 4 clinical 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 is shown in Table 1. 
 
Table 1 
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=146n (%) 
Subjects with at Least One Adverse Event 135 (92) 
 
Gastrointestinal disorders 102 (70) 
Nausea 68 (47); Diarrhea 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); Anemia 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 


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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 
 
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) 
Diarrhea 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); Anemia 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) 
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 
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 tumors 46, non-Hodgkin’s disease, Hodgkin’s disease 47, relapsed and/or 


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refractory multiple myeloma [RRMM; 48, 49], relapsed or refractory systemic light chain 
amyloidosis [RRAL; 50], and newly diagnosed multiple myeloma [NDMM; 51-53]) 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. 
 
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 
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 tolerated.54, 55 


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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 
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.  


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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 exposed.56 
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.  
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. 


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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. 
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.   
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, diarrhea, 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 


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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%) 
Diarrhea (26%) 
Thrombocytopenia (23%) 
Upper respiratory tract infection (22%) 
Anemia 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, localized infection, gastrointestinal hemorrhage, respiratory 


Version Date 03-13-18 Amendment 5 
30 
 
syncytial virus (RSV) pneumonia faecaloma, pyrexia, pneumonia respiratory syncytial viral, 
non-cardiac chest pain, peripheral oedma, asthenia, hyponatraemia vomiting, diarrhea, 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.   
Clinical Trial Experience Using the Intravenous Formulation of 
MLN9708 
See the IB for descriptions of the 2 ongoing studies investigating IV MLN9708 in advanced solid 
tumors and advanced lymphoma (Studies C16001 and C16002, respectively). 
Study Rationale: 
Proteasome inhibition eliminates alloreactive T cells, interferes with APC function and 
reduces inflammatory cytokine production either by eliminating the cytokine-secreting cell or 
by inhibiting its production through the downmodulation of NF-κB-dependent transcription, 
supporting the role of proteasome inhibitors as GVHD prophylactic agents. Based on the 
previously discussed preclinical and limited clinical data, we now propose a phase I/II study 
of chronic GVHD prophylaxis with oral proteasome inhibitor MLN9708 in patients 
undergoing matched related or unrelated donor allogeneic transplantation. Phase I will be 
conducted as a single site study and Phase II as a multi-site study.  The additional site, the 
University of West Virginia, will be added when the Phase II portion of the study is opened.  
Building on our prior experience showing reduced rates of acute GVHD with an atorvastatin-
containing acute GVHD prophylaxis, the preferred acute GVHD prophylactic regimen on the 
current study will be atorvastatin, mini-dose methotrexate and tacrolimus; however the acute 
GVHD prophylaxis used will remain at the discretion of the treating physician since rate of 
acute GVHD is not the primary outcome of the current protocol. Furthermore flexibility in 
type of acute GVHD prophylaxis permitted, will support robust accrual on the current 
protocol.  
 


Version Date 03-13-18 Amendment 5 
31 
 
Potential Risks and Benefits: 
Please refer to the current MLN9708 Investigator’s Brochure (IB). 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 trials.46, 47, 49-56 
 
This study will be conducted in compliance with the protocol, good clinical practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonization (ICH) 
guidelines. 
 
2. Objectives:  
 
Primary Objectives: 
Phase I Primary Objectives: 
• To determine the maximum tolerated dose (MTD), dose limiting toxicity (DLT) and 
recommended phase II dose (RDP) of MLN9708 for the prophylaxis of chronic GVHD in 
patients undergoing allogeneic hematopoietic cell transplantation (HCT). 
Phase II Primary Objectives: 
• Determine the 1-year (from the date of HCT) cumulative incidence of chronic GVHD 
following MLN9708 administration as prophylaxis, in patients undergoing matched 
sibling allogeneic HCT.  
• Determine the 1-year (from the date of HCT) cumulative incidence of chronic GVHD 
following MLN9708 administration as prophylaxis, in patients undergoing unrelated 
donor allogeneic HCT.  


Version Date 03-13-18 Amendment 5 
32 
 
Phase I/II Primary Objectives: 
 
• Assess the safety of chronic GVHD prophylaxis with MLN9708 in patients undergoing 
allogeneic HCT. 
 
Secondary Objectives: 
 
• To assess the 1-year and 2-year (from the date of HCT) cumulative incidence of 
corticosteroid requiring chronic GVHD, in the matched sibling and unrelated donor 
cohorts separately. 
• Determine the 2-year (from the date of HCT) cumulative incidence of chronic GVHD 
following MLN9708 administration as prophylaxis, in the matched sibling and unrelated 
donor cohorts separately.  
• To assess the 1-year and 2-year (from the date of HCT) cumulative incidence of mild, 
moderate and severe chronic GVHD (by NIH criteria) and limited or extensive chronic 
GVHD (by conventional criteria), in the matched sibling and unrelated donor cohorts 
separately. 
• To assess cumulative incidence of grade II-IV acute GVHD at days +100, +180 and 
+365, in the matched sibling and unrelated donor cohorts separately. 
• To assess cumulative incidence of grade III-IV acute GVHD at days +100, +180 and 
+365, in the matched sibling and unrelated donor cohorts separately. 
• To assess non-relapse mortality rate at 100 days, 1-year post-HCT. 
• To assess the incidence of motor and sensory neuropathy associated with MLN9708 
• To assess incidence of secondary graft failure. 
• To assess incidence of secondary immunologic graft rejection. 
• To assess relapse rate of the primary hematological malignancy.  
• To assess lineage specific chimerism kinetics in patients at baseline (approximately day 
+30), day +100, day +180 and day +365. 
• To assess immune reconstitution following transplantation at baseline (approximately day 
+30), day +100, day +180, day +365 and day +730. 
• To assess absolute neutrophil count on day +100, day +180 and day +365. 


Version Date 03-13-18 Amendment 5 
33 
 
• Response of acute GVHD to MLN9708 at day +100, in those patients with controlled 
grade I-II acute GVHD at the time of enrollment.  
• To assess 1-year and 2-years progression free survival (PFS) and overall survival (OS) 
following transplantation.  
• To evaluate biologic [BRAF levels] markers potentially associated with GVHD and/or 
MLN9708. 
 
3. Eligibility Criteria: 
Inclusion criteria: 
• Patients with a history of a hematological malignancy or bone marrow failure syndrome 
undergoing (or status post) a peripheral blood allogeneic HCT. 
• Patients aged ≥18 are eligible. 
• All patients must have received or plan to receive an allograft from a suitable HLA-
matched sibling or unrelated donor according to transplant center’s guidelines (for 
selection of appropriate donor). 
• Voluntary written consent must be given before patient registration and 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. 
• Bilirubin ≤ 2 x the ULN. For patients with Gilbert’s syndrome or suspected mild 
veno-occlusive disease, bilirubin ≤ 3 x ULN is permitted.  
• Creatinine clearance of  30 mL/min calculated by Cockcroft-Gault equation. 
• Karnofsky performance status > 60.  
• A negative pregnancy test will be required for all women of child bearing potential. 
Females of child bearing potential should 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 must also adhere to the guidelines 
of any treatment-specific pregnancy prevention program, if applicable, or agree to 
practice true abstinence when this is in line with the preferred and usual lifestyle of the 
subject.  (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation 


Version Date 03-13-18 Amendment 5 
34 
 
methods] and withdrawal are not acceptable methods of contraception.). Breast feeding 
is not permitted.  
• Male patients, even if surgically sterilized (ie, status post-vasectomy), must agree to one 
of the following: practice effective barrier contraception during the entire study 
treatment period and through 90 days after the last dose of study drug, or must also 
adhere to the guidelines of any treatment-specific pregnancy prevention program, if 
applicable, or agree to practice true abstinence when this is in line with the preferred and 
usual lifestyle of the subject.  (Periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of 
contraception.) 
• No evidence of uncontrolled bacterial, viral or fungal infections at the time of 
enrollment. 
• No known active hepatitis B or C virus infection, or known human immunodeficiency 
virus (HIV) positive. 
Exclusion Criteria: 
• Patients with active ≥ grade 3 peripheral neuropathy or grade 2 with pain on clinical 
examination during the screening period will be excluded. 
• Patients with history of allergy and/or intolerance to MLN9708 are not eligible. 
• Known GI disease or GI procedure that could interfere with the oral absorption or 
tolerance of MLN9708 including difficulty swallowing is not permitted. 
• Patients receiving (or status post) a cord blood or a haplo-identical allograft will not be 
eligible.  
• Patients undergoing (or status post) a T-cell depleted allogeneic transplantation will not 
be eligible. 
• Patients receiving (or status post) conditioning regimens containing antithymocyte 
globulin, and/or campath, one receiving post-HCT planned cyclophosphamide will not 
be eligible.  
• Method of stem-cell collection from the donor will be at the discretion of the treating 
physician. Although it is anticipated that majority of patients will receive allograft 


Version Date 03-13-18 Amendment 5 
35 
 
mobilized with G-CSF alone; however donors receiving allografts mobilized with 
experimental agents (e.g. plerixafor) will remain eligible for the study. 
• Patients experiencing disease relapse (for those in complete remission at the time of 
HCT) or progression (for those in partial remission, stable or refractory disease at the 
time of HCT) will be excluded.  
• Donor lymphocyte infusions between day zero of HCT and first dose of MLN9708 are 
not permitted.  
• Rituximab (or other B-cell depleting monoclonal antibodies) or bortezomib 
administration between day zero of HCT and before the first day of MLN9708 is not 
permitted.  
• Patients with steroid refractory (defined as no improvement of symptoms after 7 days of 
systemic corticosteroids at a dose of ≥1mg/kg/day) grade II-IV acute GVHD, that is 
active at the time of enrollment will be excluded.  
• Patients with grade III-IV acute GVHD (even if it is not meeting criteria for steroid 
refractory acute GVHD), that is active at the time of enrollment will be excluded. 
Patients with controlled grade I-II acute GVHD can be enrolled after discussing with 
study PI. Topical or systemic corticosteroids therapy, as per standard of care for such 
grade I-II acute GVHD patients is permitted.   
• Patients with active chronic GVHD (although unlikely before day +100) will be 
excluded. 
• No major surgery within 14 days before enrollment. 
• No radiotherapy within 14 days before enrollment. If the involved field is small, 7 days 
will be considered a sufficient interval between treatment and administration of the 
MLN9708. 
• No 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. Cardiac enzyme 
elevations for reasons other than document myocardial infarction is not an exclusion.  
• No systemic treatment, within 14 days before the first dose of MLN9708, with strong 
inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of 


Version Date 03-13-18 Amendment 5 
36 
 
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. 
• No serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with the completion of treatment according to this protocol.  
• No participation in clinical trials with other investigational agents, within 21days of the 
start of this trial and for two weeks after the last dose of MLN9708 or resolution of 
MLN9708 related adverse events to grade 1 or less (whichever occurs later). However, 
co-enrollment on trials evaluating conditioning regimens, institutional protocols 
evaluating atorvastatin for acute GVHD prophylaxis, and stem cell collection protocols 
in transplant donors will be permitted. In addition, patients randomized to standard-of-
care (non-experimental) arms of available phase II/III trials will be eligible for this 
study. 
4. Registration Procedure: 
 
Registration 
• 
All source documents that support eligibility include a signed informed consent/HIPAA 
and signed eligibility checklist.  These must be available for review and verification. 
• 
At the point of registration, the study staff will register the patient in the electronic 
database (where applicable), including demographic, consent and on-study information.  
The patient will be assigned a unique sequence number for the study. 
• 
 Patients will be enrolled on this trial after day zero of HCT (ideally between days +60 - 
90).  
5. Treatment Plan: 
 
This is a phase I/II study of MLN9708 for the prophylaxis of chronic GVHD in patients 
undergoing allogeneic HSCT. During the phase I portion patients undergoing both sibling and 
unrelated donor transplantation will be enrolled on the same arm to determine the DLT and 
MTD. During the phase II portion of the trial, patients will be enrolled into two separate and 


Version Date 03-13-18 Amendment 5 
37 
 
independent cohorts: a) Matched sibling transplants and b) Unrelated donors transplants. Both 
cohorts will be enrolled and analyzed separately. 
 
Administration schedule to Transplant recipients 
• For potential candidates for this trial, the recommended acute GVHD prophylaxis is 
tacrolimus, methotrexate and atorvastatin combination. However, any acute GVHD 
prophylaxis regimen at the discretion of treating physician (not involving in-vivo or ex-
vivo T-cell depletion, CD34+ cell selection, or post-HCT cyclophosphamide) will be 
permitted.  
• During the phase I portion, for chronic GVHD prophylaxis, four doses of MLN9708 will 
be administered orally (to patients undergoing either matched sibling or unrelated donor 
transplantation) on days 1, 8, 15 and 22, starting on day +60 to +74 post allogeneic HCT. 
Dose escalation will be conducted as shown in Table 2 to determine the MTD and DLT. 
 
Table 2. Phase I dose escalation schema.  
MLN 9708 Phase I dose Levels 
Oral Dose 
(given on days 1, 8, 15 and 22) 
-1 
2.3 mg 
1 
3.0 mg 
2 
4.0 mg 
 
• Dose escalation will start at dose level 1 and will be carried out according to standard 3+3 
design. If 0 of 3 patients experiences DLT, dose escalation will proceed to the next higher 
dose level, at which 3 patients will be enrolled. On observing a DLT, the cohort will be 
expanded to 6 patients. Dose escalation will continue if no greater than 1 of 6 patients 
experience DLT, up to a maximum dose of 4mg. If 0 of 3 patients experiences DLT at 
dose level 2, then it will be considered MTD. If 2 or more patients experience a DLT, 
dose escalation will halt and the dose level below will be expanded to 6 patients to 
determine the MTD. If the dose level below already has 6 patients, enrolled, then it will 
be considered the MTD. If 2 or more patients experience DLT on first dose level (i.e. 


Version Date 03-13-18 Amendment 5 
38 
 
dose level 1), then patients will be enrolled on dose level -1. No intrapatient dose 
escalation will be permitted.  
• MTD is defined at maximum dose level with fewer than 2 of 6 patients experiencing 
DLT. 
• Toxicity will be evaluated according to CTCAE v4.0. DLT will be defined as shown in 
Table 3. DLT observation period will be from first dose of MLN9708 to 28 days after the 
last dose. Dose escalation to higher dose level will require the last patient on the previous 
dose level to be out of DLT observation period.  
Table 3. Definition of DLT for patients receiving MLN9708 
Non-hematologic toxicities 
• Grade 2 peripheral neuropathy with pain or Grade 3 or greater peripheral 
neuropathy, (definitely or probably) related to MLN9708 
• Any grade 3-4 non-hematologic toxicity (definitely or probably) related to 
MLN9708, with the exception of alopecia, transient electrolyte or LFT 
abnormalities which resolve to ≤ grade 1 within 72hours, Grade 3 
arthralgia/myalgia, and brief (<1 week) Grade 3 fatigue 
• Grade 3 or greater nausea and/or emesis (not due to GVHD) despite the use of 
optimal anti-emetic prophylaxis. Optimal anti-emetic prophylaxis is defined as an 
anti-emetic regimen that employs a 5-HT3 antagonist given in standard doses and 
according to standard schedules. 
• Grade 3 or greater diarrhea (definitely or probably) related to MLN9708 that 
occurs despite maximal supportive therapy. 
Hematologic and infectious toxicity 
• Drop in donor myeloid-cell chimerism by more than 50% at day +90 (±7days) (in 
the absence of relapsed disease) 
• Unexplained immunologic graft rejection at day +90 (±7days) (define as donor 
myeloid-cell chimerism of <5%) 
• Grade 4 neutropenia (ANC <500/mm3) lasting ≥14 consecutive days, (definitely 
or probably) related to MLN9708 
• Grade 3 neutropenia with fever and/or infection, where fever is defined as a 
temperature ≥ 38.5°C, (definitely or probably) related to MLN9708 
• Grade 4 thrombocytopenia (platelets <25,000/mm3) lasting at least 7 consecutive 
days, (definitely or probably) related to MLN9708 
 
• The phase II portion will utilize the MTD for MLN9708, determined from phase I portion 
of the study. In phase II, patients will be enrolled in two independent cohorts of matched 
sibling and matched unrelated donor transplants.  


Version Date 03-13-18 Amendment 5 
39 
 
• During the phase II portion, for chronic GVHD prophylaxis, four doses of MLN9708 will 
be administered orally on days 1, 8, 15 and 22, starting on day +60 to +90 post allogeneic 
HCT. 
• 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. 
• 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. 
• 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.   
• All MLN9708 doses will be administered by authorized study personnel during patients’ 
inpatient or outpatient visits, to ensure compliance. If the patient vomits after taking the 
study drug, the dose should not be repeated but should resume dosing at the time of the 
next scheduled dose. Missed doses can be taken as soon as the patient remembers if the 
next scheduled dose is 72 hours or more away. A double dose should not be taken to 
make up for a missed dose.   
• Acute GVHD medications expected to be ongoing at the time of MLN9708 
administration include calineurine inhibitors (e.g. tacrolimus or cyclosporine) OR 
mycophenolate mofetil OR sirolimus OR atorvastatin.  
• Tapering of any concomitant acute GVHD prophylaxis will be per institutional 
guidelines, however in absence of acute GVHD, renal insufficiency and disease 
relapse/progression it is recommended that taper SHOULD NOT commence before day 
+100. The recommended goal of tapering is the complete discontinuation of 
immunosuppressive medications by day +180.  
 
Excluded Concomitant Medications and Procedures 
The following medications and procedures are prohibited during the study:  


Version Date 03-13-18 Amendment 5 
40 
 
 
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. 
  
• Concomitant administration of strong inhibitors of CYP1A2 (fluvoxamine, 
enoxacin, ciprofloxacin) and 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. 
  
• Strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, 
phenytoin and phenobarbital). 
• The dietary supplements St. John’s wort and Ginkgo biloba are not permitted. 
 
• Antibiotic prophylaxis will be given according to institutional guidelines. Herpes zoster 
prophylaxis per institutional guidelines will be required during prophylaxis with 
MLN9708. 
• Patients missing a single dose of MLN9708 (due to decreased oral intake secondary to 
severe nausea, vomiting, mucositis etc.) should be discussed with study PI. Patients 
missing >1 dose will need to be replaced. In case MLN9708 therapy is interrupted, the 
time interval should be recorded.  
• Toxicity will be evaluated according to CTCAE v4.0. 
• Progression free survival (PFS) and overall survival (OS) following transplantation will 
be recorded. 
 
 
 


Version Date 03-13-18 Amendment 5 
41 
 
 
Dose modification 
• Patients experiencing a grade 3-4 hematological or non-hematological toxicity (as 
specified in CTCAE v4.0) thought to be related to MLN9708 will be removed from the 
study permanently (except the exceptions allowed in Table 3). No dose modifications are 
permitted. 
• If a patient experiences a Grade 3 or 4 non-drug-related renal function impairment or 
hepatic function impairment, MLN9708, can be held until recovery to Grade 1 or 
baseline (up to a maximum of 14 days). Upon recovery of the toxicity to a level allowing 
continuation of therapy, a dose reduction is not necessary. 
 
Duration of therapy 
        MLN9708 will be continued until any one of the following criteria is met: 
- 
Patient finishes four doses of MLN9708. 
- 
Patient develops grade III-IV acute GVHD.  
- 
Patient develops severe chronic GVHD. 
- 
Patient develops any grade 3-4 toxicity related to MLN9708 use. 
 
Data Safety Monitoring Plan 
The Medical College of Wisconsin (MCW) Cancer Center (CC) Data Safety Monitoring 
Committee (DSMC) is responsible for monitoring data quality and subject safety for all cancer 
center investigator initiated clinical trials.  A six to eight member Data and Safety Monitoring 
Committee will complete a review of protocol-specific data safety monitoring reports, to provide 
recommendations on trial continuation, suspension or termination.   
 
A summary of the MCW CC DSMC activities are as follows:  
• Review the clinical trial for data integrity and safety  
• Review all unexpected grade 3, and all grade 4, and 5 adverse events, as well as any 
others requiring expedited reporting as defined in this protocol. (Grades 4 & 5 events 
must be reported to the DSMC within 5 calendar days of study staff’s knowledge.)  
• Review all DSMC reports  
• Submit a summary of any recommendations related to study conduct  
• Terminate the study if deemed unsafe for patients  
 
A copy of the MCW CC Data and Safety Monitoring Plan and membership roster will be 
maintained in the study research file and updated as membership changes. The committee will 


Version Date 03-13-18 Amendment 5 
42 
 
review reports from the study PI twice annually (or more frequently if needed) and provide 
recommendations on trial continuation, suspension or termination as necessary.  
 
Any available DSMC letters will be submitted to the IRB of record as required. 
6. Measurement of Effect: 
Follow up schedule: 
The schedule for follow up on the study is shown in the table below. 
Study Visit  
Approximate target 
Day Post-Transplant  
1  
60 days  
2  
67 days  
3  
74 days  
4  
81 days  
5  
90-100 days  
6 
180 days  
7 
365 days 
8 
2 years 
Patients will be followed for survival, relapse and cause of death for 5 years post 
transplantation.  
Phase I patients will be seen weekly for toxicity assessment during the DLT period. 
 
GVHD Assessment: 
At the time of enrollment and/or first dose of MLN9708 patients will be graded for acute 
and chronic GVHD. Subsequently patients will be monitored for development of acute and 
chronic GVHD approximately once a week until day +100. After Day 100, patients will be 
assessed at each study visit for the presence of GVHD. Diagnosis of acute GVHD will 
ideally require biopsy confirmation in at least one involved organ. When more than one 
organ is involved, biopsy confirmation of all involved organs is recommended but not 
necessary. Liver-only GVHD must be confirmed by biopsy. Acute GVHD will be assessed 
by consensus criteria (Appendix A) 57 and graded on BMT CTN MOP suggested grading 
sheets (Appendix A). Acute GVHD assessment and grading will be performed by treating 
physicians. Chronic GVHD diagnosis and grading will be according to NIH Criteria. Please 
see Appendix B 58, 59. 
 
Clinical Grading of Chronic GVHD (According to Appendix B) 
None 


Version Date 03-13-18 Amendment 5 
43 
 
Mild chronic GVHD involves only 1 or 2 organs or sites (except the lung: see below ‡), 
with no clinically significant functional impairment (maximum of score 1 in all affected 
organs or sites) 
Moderate chronic GVHD involves: (1) at least 1 organ or site with clinically significant 
but no major disability (maximum score of 2 in any affected organ or site) or (2) 3 or more 
organs or sites with no clinically significant functional impairment (maximum score of 1 in 
all affected organs or sites). ‡A lung score of 1 will also be considered moderate chronic 
GVHD. 
Severe chronic GVHD indicates major disability caused by chronic GVHD (score of 3 in 
any organ or site). ‡A lung score of 2 or greater will also be considered severe chronic 
GVHD. 
Presence of limited or extensive chronic GVHD will be also be recorded. 
 
Chimerism Assessment and Immune Reconstitution: 
Chimerism will be evaluated using sorted whole blood in CD3 and CD33 fractions. For the purpose 
of this protocol, mixed chimerism is defined as the presence of donor cells, as a proportion of total 
cells to be < 95% but > 5% in the bone marrow or peripheral blood. Full donor chimerism is defined 
as ≥ 95% of donor cells. Mixed and full chimerism will be evidence of donor cell engraftment. Donor 
cells of ≤ 5% will be considered as graft rejection.  Similarly, platelet recovery is defined as first 
day of platelet count  20,000 x 109/L, without transfusion for 7 consecutive days. Lineage 
specific chimerism analysis (myeloid, T-cell [B-cell if available] subsets), quantitative 
immunoglobulins and immune reconstitution will be performed at baseline (if not performed as 
standard of care at or around day +30) and then on approximately days +90, +180 and +365. 
 
Secondary graft failure is defined as, ANC <500 x 109/L after post-transplant neutrophil 
recovery in the absence of disease relapse/progression. Immunological graft rejection is 
defined as detecting <5% donor myeloid cells on chimerism analysis.  
 
7. Study Parameters (Study Calendar): 
 
Patient Study Calendar: 
 
The table below summarizes the patient clinical assessments over the course of the study. 


Version Date 03-13-18 Amendment 5 
44 
 
Study Assessment 
Screening1 
MLN Dosing days 
(starting on day +60 to +90 post 
HCT) 
Days Post Transplant (~ ±10 days up to day 365 and then ±28 days) 
 
 
1 
8±1 
15±1 
22±1 
90-100 
180 
365 
730 
3 year 
4 year 
5 year 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
H & PE2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Karnofsky performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC/differential & platelet count 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Serum chemistries panel4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
CMV quantitative PCR12 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Β-HCG serum pregnancy test 5 
X 
 
 
 
 
 
 
 
 
 
 
 
Quantitative immunoglobulins6 
X 
 
 
 
 
X 
X 
X 
X 
 
 
 
Peripheral blood for chimerism 
X7 
 
 
 
 
X 
X 
X 
 
 
 
 
Immune reconstitution panel8 
X 
 
 
 
 
X 
X 
X 
X 
 
 
 
CD34/CD3 cell dose infused 
X 
 
 
 
 
 
 
 
 
 
 
 
Acute GVHD assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Chronic GVHD assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity assessment9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Research specimens (optional)10 
X 
 
 
 
 
X 
X 
X 
X 
 
 
 
ANC and platelet recovery11 
X 
 
 
 
 
 
 
 
 
 
 
 
Specify (if any) co-enrollment 
X 
 
 
 
 
 
 
 
 
 
 
 


Version Date 03-13-18 Amendment 5 
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with other clinical trials 
Notes 
H & PE= history and physical examination 
1Baseline refers to the period prior to enrolling on trial. Assessments should be made within 6 weeks prior to first planned dose of MLN9708, 
unless a longer window is allowed. 
2History is only required at baseline. 
3Vital signs: blood pressure, pulse rate, respiratory rate and temperature. 
4Serum chemistries panel: electrolytes, BUN, ALT, AST, creatinine, bilirubin. Electrolytes to include sodium, potassium. 
5Females of reproductive potential only. 
6IgG, IgM and IgA. 
7Baseline assessment of chimerism can be done any day between day 28 posttransplant and first dose of MLN9708. Chimerism testing should 
be sorted (lineage specific) to assess myeloid and lymphoid cell chimerism. 
8Peripheral blood flow cytometry to assess recipient immune reconstitution. The Immune reconstitution panel at the minimum should include 
determination of CD4+ T-cells, CD8+ T-cell, natural killer -cells (defined as CD3-CD56+CD16+) and CD19+ B cells. It is recommended (but 
not required) that this panel should include the following: 
a. CD4+ Memory T-cells defined as CD3+CD27+CD45RO+CD4+ 
b. CD8+ Memory T-cells defined as CD3+CD27+CD45RO+CD8+  
c. CD4+ naïve T-cells defined as CD3+CD45RA+CD45RO-CD4+ 
d. CD8+ naïve T-cells defined as CD3+CD45RA+CD45RO-CD8+ 
e. Regulatory T-cells defined as either CD3+CD4+CD25med-highCD127low OR CD4+CD25+FOXP3+ 
9Phase I patients will be seen weekly for toxicity assessment (along with CBC/differential & platelet count and serum chemistries panel4), 
during the DLT period. 


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10Peripheral whole blood specimens: draw in two 15 mL purple top  (EDTA containing) tubes. Plasma will be separated from one whole blood 
tube by centrifugation at 600 × g. Plasma will be stored in aliquots at −80°C. The second whole blood tube will be used for separation and 
cryopreservation of mononuclear cells.  
11Record time to neutrophil engraftment defined as first of three consecutive days with ANC  500 x 109/L, and platelet engraftment defined 
as first day of platelet count  20,000 x 109/L, without transfusion for 7 consecutive days 
12 CMV quantitative PCR may be drawn within the window of plus/minus 7 days 
.


Version Date 03-13-18 Amendment 5 
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8. Drug Formulation and Procurement 
 
MLN9708 (Ixazomib® Millennium Pharmaceuticals, Inc.)  
Drug description 
MLN9708 is Millennium’s next generation small molecule inhibitor of the 20S 
proteasome that is under development for the treatment of nonhematologic 
malignancies, lymphoma, multiple myeloma (MM), and plasma cell dyscrasias. 
Inhibition of the 20S proteasome has been validated as a therapeutic target for the 
treatment of malignancies using VELCADE (bortezomib) for Injection, Millennium 
Pharmaceuticals, Inc.’s first-in-class proteasome inhibitor. MLN2238 refers to the 
biologically active, boronic acid form of the drug substance, MLN9708. 
(Conversely, MLN9708 refers to the citrate ester of MLN2238.) In water or aqueous 
systems, the equilibrium shifts from MLN9708 to the biologically active boronic 
acid form MLN2238. 
 
 
 
Pharmacodynamics 
The pharmacodynamic effect being evaluated in the development of MLN9708 is 
proteasome inhibition as measured by whole blood 20S proteasome activity, as well 
as elevation of the transcription factor ATF-3 in solid tumors (Study C16001) to 
explore target engagement. Following a single dose of MLN9708, maximal 20S 
proteasome inhibition occurs at the first sampling time postdose (0.08 hr) with 
substantial return towards baseline by 4 hours for all dose groups except 2.34 mg/m2. 
Maximal 20S proteasome inhibition also occurs at the first sampling time postdose 
(0.08 hr) following the Day 11 dose of MLN9708. There is substantial return 


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towards baseline by 2 hours for doses of 0.125 to 1.0 mg/m2 and by 96 hours for 
doses 1.33 to 2.34 mg/m2. 
 
Pharmacokinetics 
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 
days. Results of a population PK analysis (N = 137) show that there is no relationship 
between body surface area (BSA) or body weight and clearance (CL).  Also, based on 
stochastic simulations for fixed dose, exposures are independent of the individual patient’s 
BSA.  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. 
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 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. 
 


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 Contraindications  
Hypersensitivity to any Component of this Medication 
Pregnancy 
Nursing Mothers 
 
 Concomitant Medications 
Systemic treatment with any of the following metabolizing enzyme inhibitors is 
discouraged during this study.  A drug-drug interaction (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. 
• Strong CYP3A inducers:  rifampin, rifapentine, rifabutin, carbamazepine, 
phenytoin, and phenobarbital 
• The dietary supplements St John’s wort and Ginkgo biloba are not permitted. 
The following medications and procedures are permitted during the study: 
• Antiemetics, including 5-HT3 serotonin receptor antagonists, may be used at 
the discretion of the investigator. 
• Loperamide or other antidiarrheal should be used for symptomatic diarrhea at 
discretion of the investigator. The dose and regimen will be according to 
institutional guidelines. IVF should be given to prevent volume depletion. 
• Growth factors (eg, granulocyte colony stimulating factor [G-CSF], 
granulocyte macrophage-colony stimulating factor [GM-CSF], recombinant 
erythropoietin) are permitted. Their use should follow published guidelines 
and/or institutional practice. Erythropoietin will be allowed in this study. 
Their use should follow published guidelines and/or institutional practice. 


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• Antiviral therapy such as acyclovir may be administered if medically 
appropriate. 
• Supportive measures consistent with optimal patient care may be given 
throughout the study. 
 Safety: 
As of the clinical data cutoff of 30 April 2012, a total of 382 patients have received 
at least 1 dose of MLN9708 in Studies C16001 (advanced solid tumors), C16002 
(advanced lymphoma), C16003 (relapsed and/or refractory multiple myeloma 
[RRMM]), C16004 (RRMM), C16005 (newly diagnosed multiple myeloma 
[NDMM]), C16006 (NDMM), C16007 (AL amyloidosis), C16008 (NDMM), and 
C16009 (clinical pharmacology stud in nonhematologic malignancy or lymphoma). 
 
The most frequent (at least 10% of the total safety population) AEs occurring in the 
pooled safety population from all ongoing studies irrespective of MLN9708 
causality, are shown below: 


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Side effects not listed above but mentioned in informed consent form include: skin 
rash, distortion of the sense of taste, trouble falling asleep, staying asleep, or both, 
electrolyte imbalance, elevated blood creatinine (including renal failure and possible 
need for dialysis), headache, flu-like symptoms and other upper respiratory tract 
infections, hypotension, light headedness, or dizziness on standing, lymphopenia, 
and pain (muscular) in extremities.  
 
Preparation, Reconstitution, and Dispensing  
MLN9708 is an anticancer drug and as with other potentially toxic compounds 
caution should be exercised when handling MLN9708 capsules. Investigational 


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MLN9708 (expired or end of study) should be destroyed on site according to the 
institution’s standard operating procedure.  Be sure to document removal and 
destruction on drug accountability logs. The appropriate study personnel will 
maintain records of study drug receipt and dispensing. 
 
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. 
 
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. 
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 


Version Date 03-13-18 Amendment 5 
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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.  
 
9. Statistical Considerations: 
 
The study is a multicenter phase I/II trial evaluating the safety and efficacy of MLN9708 
for the prophylaxis of chronic GVHD in patients with hematological malignancies and 
bone marrow failure syndromes undergoing allogeneic HCT. The primary objectives of 
this study is to determine the MTD, DLT, RDP, and safety of MLN9708 as chronic 
GVHD prophylaxis in allogeneic HCT, as well as to evaluate the 1 year cumulative 
incidence of chronic GVHD patients prophylaxis with MLN9708. During the phase I 
portion, dose escalation will be carried out according to standard 3+3 design. MTD will 
be the dose level with ≤1 out of six patients developing DLTs. No intrapatient dose 
escalation will be permitted. Patients undergoing either matched sibling or unrelated 
donor allogeneic HCT will be eligible for phase I study. 
 
Due to the differences in the incidence rates of chronic GVHD after sibling and 
unrelated donor transplantation, this study will be designed to accrue these 2 cohorts 
separately but in parallel, with the null hypothesis of a rate of chronic GVHD at 1-year 
of 55% after sibling transplantation and 65% after unrelated transplantation. The 
alternative hypothesis will be a 25% reduction with the use of new treatment in both 
cohorts. With this hypothesis, using an exact binomial distribution, the probability of 


Version Date 03-13-18 Amendment 5 
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concluding the new treatment is promising, will be 0.80 (statistical power) when the true 
but unknown rate of developing chronic GVHD is 30% or 0.04 (type I error) when the 
true rate is 55% in related donor transplantation (Cohort A [matched sibling donor 
transplantation] with a sample size of 25).  Similarly, the probability of concluding the 
new treatment is promising, will be 0.81 (statistical power) when the true but unknown 
rate of developing chronic GVHD is 40% or 0.05 (type I error) when the true rate is 65% 
in unrelated transplantation (Cohort B [unrelated donor transplantation] with a sample 
size of 26). The efficacy endpoint is chronic GVHD-free at 1 year and there will be no 
interim analysis on efficacy for this multi-center study. In the final analysis in Cohort A, 
if 10 or more of 25 patients have chronic GVHD, we will conclude the new treatment is 
ineffective in Cohort A; for Cohort B, if 13 or more of 26 patients have chronic GVHD, 
we will conclude the new treatment is ineffective in Cohort B. 
 
Demographic and baseline laboratory results will be summarized using descriptive 
statistics, including means with standard deviations, or medians with ranges, histograms 
and box-plot. The chronic GVHD rate at 1-year and its 95% CI will be calculated by 
cumulative incidence method, while accounting for competing events. Progression-free 
survival and overall survival will be estimated using the Kaplan-Meier method. 
Cumulative incidence of acute and chronic GVHD, disease relapse and non-relapse 
mortality will be calculated by accounting for competing events. Competing events for 
acute GVHD disease are relapse or death without acute GVHD, while those for chronic 
GVHD are relapse or death without chronic GVHD. Disease relapse and non-relapse 
mortality are competing events for each other. Toxicity will be reported by type, 
frequency and severity. Worst toxicity grades per patient will be tabulated for selected 
adverse events and laboratory measurements. Patients replaced on the protocol (as 
specified in the Dose Modification Section) will remain evaluable for safety and toxicity 
assessment.  
 
Safety/Stopping Rules: 
For the phase II portion of the study we propose to accrue 51 patients over 24–30 
months, which will enroll about 12 patients every 6 month time period. We plan to 


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monitor and evaluate short term adverse events at each additional 12 patients who have 
been enrolled in the study.  The expected 100 day post-transplant immunologic graft 
rejection (defined as less than 5% donor myeloid cells) rate is approximately 2.5% (in 
absence of relapsed disease) and the enrollment will be put on hold if more than 5% 
graft rejection rate is seen. For the development of grade 3-4 adverse events deemed to 
be related to MLN9708, the true rate is 5% and enrollment will be on hold if more than 
10% adverse events are observed. The stopping boundaries for graft rejection and 
development of grade 3-4 adverse events are shown in Table below. In the case of a 
safety event suspending study, a prompt cumulative examination of all data and 
circumstances of these events will be conducted by the Medical College of Wisconsin 
DSMC to determine whether study should be resumed, whether the protocol will be 
revised or whether the study will be discontinued permanently. 
 
Table. Stopping boundary for adverse events. 
Number of patients 
enrolled 
Stopping boundary for 
immunologic 
graft-rejection 
Stopping boundary for 
developing grade 3-4 adverse 
events related to MLN9708 
12 
≥ 3 
≥ 3 
24 
≥ 3 
≥ 4 
36 
≥ 4 
≥ 6 
48 
≥ 4 
≥ 6 
51 
≥ 5 
≥ 7 
 
Accrual Estimate:  6-12 patients will be enrolled in the phase I part of the protocol. In 
the phase II portion a total of 52 patients (25 sibling and 27 unrelated donor 
transplantation) will be enrolled, with 1-3 per month. Total estimated accrual = 58 
patients. 
Accrual Period :  Approximately 24-30 months 
 
 
Follow-Up Period : Two years to evaluate incidence of acute and chronic GVHD and 
relapse pattern, and five years for survival outcomes. 
 
 
 
 


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10. Adverse Event Reporting Requirements 
 
11. Definitions 
 
The following are definitions of adverse events as defined by 21CFR312.32. 
 
Types of Adverse Events 
 
Adverse Event (AE) means any untoward medical occurrence associated with the use of a 
drug in humans, whether or not consider drug related. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product whether 
or not it is related to the medicinal product.  This includes any newly occurring event, or a 
previous condition that has increased in severity or frequency since the administration of 
study drug. 
 
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, therapeutic intervention, or is considered by the 
investigator to be a clinically significant change from baseline. 
 
Life-threatening adverse event or life-threatening suspected adverse reaction:  An 
adverse event or suspected adverse reaction is considered “life-threatening” if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate 
risk of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
 
Serious adverse event or serious suspected adverse reaction:  An adverse event or 
suspected adverse reaction is considered “serious” if, in the view of the investigator or 
sponsor, it results in any of the following outcomes: 
 
• Death, 
• Is life-threatening (as defined above), 
• Requires inpatient hospitalization or prolongation of an existing hospitalization, 


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• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or 
• A congenital anomaly/birth defect. 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent of the outcomes listed above.   
Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event.  “Reasonable possibility” means there is 
evidence to suggest a causal relationship between the drug and the adverse event.  Suspected 
adverse reaction implies a lesser degree of certainty about causality than adverse reaction, 
which means any adverse event caused by a drug. 
 
Unexpected adverse event or unexpected suspected adverse reaction:  An adverse event 
or suspected adverse reaction is considered “unexpected” if it is not listed in the investigator 
brochure or is not listed at the specificity or severity that has been observed; or, if an 
investigator brochure is not required or available, it is not consistent with the risk 
information currently described.   
 
Unexpected also refers to adverse events or suspected adverse reactions that are mentioned 
in the investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with 
the particular drug under investigation. 
 
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. 
 
 
 
 


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Adverse Event Grading 
 
Grade 
Description 
 
0 
No AE (or within normal limits). 
 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
 
2 
Moderate; minimal, local or noninvasive intervention (e.g., packing 
cautery) indicated; limiting age-appropriate instrumental activities of 
daily living (ADL). 
 
3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL. 
 
4 
Life-threatening consequences; urgent intervention indicated. 
 
5 
Death related to AE 
 
 
Adverse Event Attribution 
 
Relationship 
Attribution 
Description 
Unrelated to investigational 
agent/intervention 
Unrelated 
The AE is clearly NOT related to 
the intervention 
Unlikely 
The AE is doubtfully related to the 
intervention 
Related to investigational 
agent/intervention 
Possible 
The AE may be related to the 
intervention 
Probable 
The AE is likely related to the 
intervention 
Definite 
The AE is clearly related to the 
intervention 
 
 
Reporting of 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 


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investigator must determine both the intensity of the event and the relationship of the event 
to study drug administration.  
AEs which are serious must be reported to Millennium Pharmacovigilance (or designee) 
from the date the participant signs Informed Consent through 30 days after administration of 
the last dose of MLN9708. Any SAE that occurs at any time after completion of MLN9708 
treatment or after the designated follow-up period that the sponsor-investigator and/or sub-
investigator considers to be related to any study drug must be reported to Millennium 
Pharmacovigilance (or designee).  In addition, new primary malignancies that occur during 
the follow-up periods must be reported, regardless of causality to study regimen, for a 
minimum of three years after the last dose of the investigational product, starting from the 
first dose of study drug. All new cases of primary malignancy must be reported to 
Millennium Pharmacovigilance (or designee).    
Planned hospital admissions or surgical procedures for an illness or disease that existed 
before the patient was enrolled in the trial are not to be considered AEs unless the condition 
deteriorated in an unexpected manner during the trial (e.g., surgery was performed earlier or 
later than planned).  All SAEs should be monitored until they are resolved or are clearly 
determined to be due to a patient’s stable or chronic condition or intercurrent illness(es). 
Since this is an investigator-initiated study, the principal investigator Dr. Mehdi Hamadani, 
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 
  See below for contact information for the reporting of SAEs to Millennium 
Pharmacovigilance.   
The sponsor-investigator must fax the SAE Form per the timelines above.  A sample of an 
SAE Form is provided (See Appendix C).   


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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.  The SAE report must 
include event term(s), serious criteria, and the sponsor-investigator’s or sub-investigator’s 
determination of both the intensity of the event(s) and the relationship of the event(s) to 
study drug administration.  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  
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 drug(s), as soon 
as possible but no later than 4 calendar days of such communication. 
SAE and Pregnancy Reporting Contact Information 
Millennium Pharmacovigilance or Designee 
SAE and Pregnancy Reporting Contact Information 
FAX Number 1-800-963-6290 
Email: TakedaOncoCases@cognizant.com 
 


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Suggested Reporting Form:   
• 
SAE Report Form (a sample is provided in Appendix C) 
• 
US FDA MedWatch 3500A:  
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm  
• 
Any other form deemed appropriate by the sponsor-investigator 
 
Because all of the study transplant recipients will be receiving potentially toxic preparative 
therapy, significant regimen related toxicity is expected.  These risks are listed in the 
transplant consent form.  A study specific toxicity CRF will be designed to capture 
information regarding these expected events.  Transplant is also related to a degree of 
mortality and this will also be captured by a study designed CRF.  Unexpected adverse 
events will be reported throughout the study. 
 
Unexpected Adverse Events 
All unexpected grade 3, and all grade 4, and 5 adverse events, as well as any others 
requiring expedited reporting as defined in this protocol, will be reported to the MCW 
Cancer Center DSMC. (Grades 4 & 5 events must be reported to the DSMC within 5 
calendar days of study staff’s knowledge).  If the Grade 3-5 event is determined to be an 
unanticipated problem, the event will be forwarded to the MCW IRB for review as required 
by their policy.  Unexpected adverse events, regardless of severity, will be reported to the 
MCW Cancer Center DSMC and reviewed on a quarterly basis. 
 
Expected Adverse Events 
Expected adverse events that are being captured on the study toxicity form will be reported 
at the time of the form’s scheduled due date.   
 
All MCW Cancer Center DSMC reports and recommendations will be submitted to the IRB 
for their review. 
 
 


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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 non-serious AEs 
(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. 
 
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 Reporting of 
Adverse Events).  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 Reporting of Adverse Events).  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 D)   
 
Adverse Events Occurring after the End of the Study 
 
Follow-up of AEs 
Any unexpected AEs ongoing at the time of study discontinuation will be followed until 
resolution or stable for at least 2 months.  
 


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FDA Reporting Procedures  
 
Commercial Agents:    Commercial agents are those agents not provided under an IND but 
obtained instead from a commercial source.  In some cases an agent obtained commercially 
may be used for indications not included in the package label.  The following procedures 
should be followed to determine if an adverse is reportable to the FDA: 
 
Refer to the pharmaceutical section of the protocol to determine if an agent is 
investigational or commercial.   
• 
WHAT TO REPORT:  An unexpected, life-threatening (Grade 4) or unexpected, fatal 
(Grade 5) adverse event with an attribution of possible, probable or definite. 
 
• 
WHEN TO REPORT:  These events should be reported within (7) working days. 
 
• 
WHERE TO REPORT:  These adverse events with commercial agents must be reported to 
the FDA using the MedWatch form.  A copy of the MedWatch form can be obtained from 
theFDA’s MedWatch web site at www.fda.gov/medwatch.  You can mail the reports to the 
address below or fax it 1-800-332-0178. 
MedWatch 
 
5600 Fishers Lane 
Rockville, MD 20852-9787 
 
12. Administrative Requirements 
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 


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established at the beginning of the study, maintained for the duration of the study and 
retained according to the appropriate regulations.   
 
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 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.    
 
Subject Information and Informed Consent 
 
Written informed consent must be obtained from the subject prior to study 
participation. 
 
The informed consent document must be signed and dated by the subject and 
properly witnessed (if applicable) before initiation of any study procedures including 
any change in medication or initiation of study drug dosing.   
 
Subjects must be consented in accordance with all local regulatory and legal 
requirements.  This process must include a verbal explanation of the nature, scope, 
and possible consequences of the study provided in plain language.  The information 
should be presented by the investigator unless a designee is permitted by local 
regulations.  The potential study subject should be encouraged to ask questions about 
the study.   


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The informed consent document must be prepared in accordance with GCP 
guidelines and with local regulatory and legal requirements.  A copy of the signed 
consent form will be given to the subject and the original document must be safely 
archived by the investigator so that the forms can be retrieved at any time for 
monitoring, auditing, and inspection purposes. 
 
The informed consent will be updated as appropriate (e.g., due to protocol 
amendment or if significant new safety information that may be relevant to consent 
of the subjects becomes available).  If the informed consent is revised, it is the 
investigator’s responsibility to ensure that an amended consent form is reviewed and 
signed by all subjects subsequently entered into the study and those currently in the 
study.     
 
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.   
 
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 


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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.     
 
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.   
   
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.   
 
Product Complaints 
 
A product complaint is a verbal, written, or electronic expression that implies 
dissatisfaction regarding the identity, strength, purity, quality, or stability of a drug 
product.  Individuals who identify a potential product complaint situation should 
immediately contact MedComm Solutions (see below) and report the event.  


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Whenever possible, the associated product should be maintained in accordance with 
the label instructions pending further guidance from a Millennium Quality 
representative. 
For Product Complaints, 
call MedComm Solutions at 
877-674-3784 (877 MPI DRUG)  
(US and International) 
 
Product complaints in and of themselves are not AEs.  If a product complaint results 
in an SAE, an SAE form should be completed and sent to Millennium 
Pharmacovigilance.   
 
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 
• 
Plans to modify, suspend or discontinue the development of the drug.   
 
Record Retention 
 
The investigator will maintain all study records according to the ICH-GCP and 
applicable regulatory requirement(s). 
 


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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.    
 
Peer Review Statement 
  
This study was reviewed and approved by the Medical College of Wisconsin 
Scientific Review Committee on 04/29/2014. 
 
 
 


Version Date 03-13-18 Amendment 5 
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13. References 
1. Deeg HJ. How I treat refractory acute GVHD. Blood. 2007;109(10):4119-4126.  
2. Antin JH, Kim HT, Cutler C, et al. Sirolimus, tacrolimus, and low-dose methotrexate for 
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3. Ratanatharathorn V, Nash RA, Przepiorka D, et al. Phase III study comparing 
methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-
versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation. 
Blood. 1998;92(7):2303-2314.  
4. Nash RA, Antin JH, Karanes C, et al. Phase 3 study comparing methotrexate and 
tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host 
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5. Shlomchik WD, Couzens MS, Tang CB, et al. Prevention of graft versus host disease by 
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6. Ferrara JL and Deeg HJ. Graft-versus-host disease. N Engl J Med. 1991;324(10):667-674.  
7. Blazar BR, Korngold R, Vallera DA. Recent advances in graft-versus-host disease 
(GVHD) prevention. Immunol Rev. 1997;157:79-109.  
8. Lin MT, Storer B, Martin PJ, et al. Relation of an interleukin-10 promoter polymorphism 
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9. Nikolic B, Lee S, Bronson RT, Grusby MJ, Sykes M. Th1 and Th2 mediate acute graft-
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10. Broady R and Levings MK. Graft-versus-host disease: suppression by statins. Nat Med. 
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11. Liao JK and Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol. 
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12. Greenwood J, Steinman L, Zamvil SS. Statin therapy and autoimmune disease: from 
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13. Greenwood J, Walters CE, Pryce G, et al. Lovastatin inhibits brain endothelial cell Rho-
mediated lymphocyte migration and attenuates experimental autoimmune 
encephalomyelitis. FASEB J. 2003;17(8):905-907.  
14. Dunn SE, Youssef S, Goldstein MJ, et al. Isoprenoids determine Th1/Th2 fate in 
pathogenic T cells, providing a mechanism of modulation of autoimmunity by atorvastatin. J 
Exp Med. 2006;203(2):401-412.  
15. Mausner-Fainberg K, Luboshits G, Mor A, et al. The effect of HMG-CoA reductase 
inhibitors on naturally occurring CD4+CD25+ T cells. Atherosclerosis. 2008;197(2):829-
839.  
16. Zeiser R, Youssef S, Baker J, Kambham N, Steinman L, Negrin RS. Preemptive HMG-
CoA reductase inhibition provides graft-versus-host disease protection by Th-2 polarization 
while sparing graft-versus-leukemia activity. Blood. 2007;110(13):4588-4598.  
17. Hamadani M, Awan FT, Devine SM. The impact of HMG-CoA reductase inhibition on 
the incidence and severity of graft-versus-host disease in patients with acute leukemia 
undergoing allogeneic transplantation. Blood. 2008;111(7):3901-3902.  
18. Rotta M, Storer BE, Storb R, et al. Impact of recipient statin treatment on graft-versus-
host disease after allogeneic hematopoietic cell transplantation. Biol Blood Marrow 
Transplant. 2010;16(10):1463-1466.  
19. Rotta M, Storer BE, Storb RF, et al. Donor statin treatment protects against severe acute 
graft-versus-host disease after related allogeneic hematopoietic cell transplantation. Blood. 
2010;115(6):1288-1295.  
20. Kapur R, Ebeling S, Hagenbeek A. B-cell involvement in chronic graft-versus-host 
disease. Haematologica. 2008;93(11):1702-1711.  
21. Fujii H, Cuvelier G, She K, et al. Biomarkers in newly diagnosed pediatric-extensive 
chronic graft-versus-host disease: a report from the Children's Oncology Group. Blood. 
2008;111(6):3276-3285.  
22. Sarantopoulos S, Stevenson KE, Kim HT, et al. High levels of B-cell activating factor in 
patients with active chronic graft-versus-host disease. Clin Cancer Res. 2007;13(20):6107-
6114.  
23. Sarantopoulos S, Stevenson KE, Kim HT, et al. Altered B-cell homeostasis and excess 
BAFF in human chronic graft-versus-host disease. Blood. 2009;113(16):3865-3874.  
24. She K, Gilman AL, Aslanian S, et al. Altered Toll-like receptor 9 responses in 
circulating B cells at the onset of extensive chronic graft-versus-host disease. Biol Blood 
Marrow Transplant. 2007;13(4):386-397.  


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25. Allen JL, Fore MS, Wooten J, et al. B cells from patients with chronic GVHD are 
activated and primed for survival via BAFF-mediated pathways. Blood. 2012;120(12):2529-
2536.  
26. Srinivasan M, Flynn R, Price A, et al. Donor B-cell alloantibody deposition and 
germinal center formation are required for the development of murine chronic GVHD and 
bronchiolitis obliterans. Blood. 2012;119(6):1570-1580.  
27. Young JS, Wu T, Chen Y, et al. Donor B cells in transplants augment clonal expansion 
and survival of pathogenic CD4+ T cells that mediate autoimmune-like chronic graft-versus-
host disease. J Immunol. 2012;189(1):222-233.  
28. Cutler C, Kim HT, Bindra B, et al. Rituximab prophylaxis prevents corticosteroid-
requiring chronic GVHD after allogeneic peripheral blood stem cell transplantation: results 
of a phase II trial. Blood. 2013.  
29. Miklos DB, Kim HT, Miller KH, et al. Antibody responses to H-Y minor 
histocompatibility antigens correlate with chronic graft-versus-host disease and disease 
remission. Blood. 2005;105(7):2973-2978.  
30. Kharfan-Dabaja MA, Mhaskar AR, Djulbegovic B, Cutler C, Mohty M, Kumar A. 
Efficacy of rituximab in the setting of steroid-refractory chronic graft-versus-host disease: a 
systematic review and meta-analysis. Biol Blood Marrow Transplant. 2009;15(9):1005-
1013.  
31. Khouri IF, Lee MS, Saliba RM, et al. Nonablative allogeneic stem cell transplantation 
for chronic lymphocytic leukemia: impact of rituximab on immunomodulation and survival. 
Exp Hematol. 2004;32(1):28-35.  
32. Arai S, Sahaf B, Narasimhan B, et al. Prophylactic rituximab after allogeneic 
transplantation decreases B-cell alloimmunity with low chronic GVHD incidence. Blood. 
2012;119(25):6145-6154.  
33. McIver Z, Stephens N, Grim A, Barrett AJ. Rituximab administration within 6 months of 
T cell-depleted allogeneic SCT is associated with prolonged life-threatening cytopenias. 
Biol Blood Marrow Transplant. 2010;16(11):1549-1556.  
34. Ghosh S, May MJ, Kopp EB. NF-kappa B and Rel proteins: evolutionarily conserved 
mediators of immune responses. Annu Rev Immunol. 1998;16:225-260.  
35. Finn PW, Stone JR, Boothby MR, Perkins DL. Inhibition of NF-kappaB-dependent T 
cell activation abrogates acute allograft rejection. J Immunol. 2001;167(10):5994-6001.  
36. Nencioni A, Schwarzenberg K, Brauer KM, et al. Proteasome inhibitor bortezomib 
modulates TLR4-induced dendritic cell activation. Blood. 2006;108(2):551-558.  


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37. Blanco B, Perez-Simon JA, Sanchez-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;94(7):975-983.  
38. Blanco B, Perez-Simon JA, Sanchez-Abarca LI, et al. Bortezomib induces selective 
depletion of alloreactive T lymphocytes and decreases the production of Th1 cytokines. 
Blood. 2006;107(9):3575-3583.  
39. Vodanovic-Jankovic S, Hari P, Jacobs P, Komorowski R, Drobyski WR. NF-kappaB as 
a target for the prevention of graft-versus-host disease: comparative efficacy of bortezomib 
and PS-1145. Blood. 2006;107(2):827-834.  
40. 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;101(21):8120-8125.  
41. Mateos-Mazon J, Perez-Simon JA, Lopez O, Hernandez E, Etxebarria J, San Miguel JF. 
Use of bortezomib in the management of chronic graft-versus-host disease among multiple 
myeloma patients relapsing after allogeneic transplantation. Haematologica. 
2007;92(9):1295-1296.  
42. Wang XC, Jobin C, Allen JB, Roberts WL, Jaffe GJ. Suppression of NF-kappaB-
dependent proinflammatory gene expression in human RPE cells by a proteasome inhibitor. 
Invest Ophthalmol Vis Sci. 1999;40(2):477-486.  
43. El-Cheikh J, Michallet M, Nagler A, et al. High response rate and improved graft-
versus-host disease following bortezomib as salvage therapy after reduced intensity 
conditioning allogeneic stem cell transplantation for multiple myeloma. Haematologica. 
2008;93(3):455-458.  
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;30(26):3202-3208.  
45. Chauhan D, Tian Z, Zhou B, et al. In vitro and in vivo selective antitumor activity of a 
novel orally bioavailable proteasome inhibitor MLN9708 against multiple myeloma cells. 
Clin Cancer Res. 2011;17(16):5311-5321.  
46. Chow LQ. MLN9708, an investigational proteasome inhibitor, in patients with solid 
tumors; Updated phase 1 results in Head and Neck Symposium. 2012. Phoenix, AZ  
 . In: Anonymous .  
47. Assouline S. 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. .  


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48. Lonial S. 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. .  
49. Kumar S. 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. .  
50. Merlini G. 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. .  
51. Kumar S. 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. .  
52. Richardson PG. 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. .  
53. San Miguel J. 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. .  
54. Kumar S. Weekly Dosing of the Investigational Oral Proteasome Inhibitor MLN9708 in 
Patients with Relapsed and/or Refractory Multiple Myeloma: Results From a Phase 1 
DoseEscalation Study in 53rd ASH Annual Meeting and Exposition. 2011. San Diego, CA.  
55. Kumar S. 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. .  
56. Sanchorawala V. Poster Presentation: Phase 1 study of MLN9708, a novel, 
investigational oralproteasome inhibitor, in patients with relapsed or refractory light-chain 
amyloidosis.XIII International Symposium on Amyloidosis, Groningen, The Netherlands 
2012. .  
57. Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD 
Grading. Bone Marrow Transplant. 1995;15(6):825-828.  
58. Pavletic SZ, Martin P, Lee SJ, et al. Measuring therapeutic response in chronic graft-
versus-host disease: National Institutes of Health Consensus Development Project on 


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Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. Response Criteria 
Working Group report. Biol Blood Marrow Transplant. 2006;12(3):252-266.  
59. Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus 
development project on criteria for clinical trials in chronic graft-versus-host disease: I. 
Diagnosis and staging working group report. Biol Blood Marrow Transplant. 
2005;11(12):945-956.  
 
 
 


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14. Appendix A Assessment of Acute GVHD 
 
 
 
 
 
 


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15. Appendix B Grading of Chronic GVHD (NIH Criteria) 
 


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16. Appendix C. Sample SAE Form 
 
(please see on the following page)


 
 
 
 
 
 
 
 


 
 
 
 
 
 
Page 2 of 3 


 
 
 
 
 
 
 
 
 
 
Page 3 of 3 


 
 
 
17. Appendix D. Millennium Pregnancy Reporting Form 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
  

ICF_001.pdf: 
Consent title:  X16034: MLN9708 for the prophylaxis of chronic graft-versus-host disease 
in patient undergoing allogeneic transplantation 
 
Document date:  04-09-2018 
 
NCT number:  NCT02250300 


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A – Version October 31, 2016 
IRB Protocol Number: PRO00022660 
IRB Approval Period: 04/09/2018 – 08/20/2018 
Page 1 of 15 
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Medical College of Wisconsin and Froedtert Hospital 
CONSENT TO PARTICIPATE IN RESEARCH 
 
Name of Study Subject: ____________________________ 
 
X16034: MLN9708 for the prophylaxis of chronic graft-versus-host disease in 
patient undergoing allogeneic transplantation 
 
Mehdi Hamadani, MD 
Froedtert & Medical College of Wisconsin 
Division of Hematology and Oncology 
9200 W. Wisconsin Avenue 
Milwaukee, WI 53226-0509 
414-805-6700 
 
You are invited to take part in this research study. This form tells you why this research 
study is being done, what will happen in the research study, possible risks and benefits 
to you, your choices, and other important information. If there is anything that you do not 
understand, please ask questions. Then you can decide if you want to join this study or 
not.   
 
A1. INTRODUCTION – WHY ARE WE ASKING YOU ABOUT THIS STUDY? 
We invite you to participate in this study because you have had or plan to have an 
allogeneic (a bone marrow or peripheral blood stem cells from another person—usually 
a sibling but sometimes from an unrelated donor) transplant and are at risk of suffering 
a common problem called chronic graft-versus-host disease (cGVHD).    
 
A total of about 58 people are expected to participate in this study at the Medical 
College of Wisconsin/Froedtert Hospital. 
 
The Director of the study is Mehdi Hamadani, MD in the Department of Medicine. A 
study team works with Dr. Hamadani. You can ask who these people are.  
 
Millennium Pharmaceuticals, Inc. provides financial support to the Medical College of 
Wisconsin, including Dr. Hamadani and other key members of his/her study staff, for 
work on this study as well as others being conducted at the Medical College of 
Wisconsin.  Previously a sub-investigator reviewed safety data for another Millennium 
study.  This sub-investigator received compensation for the work he did reviewing the 
safety data. 
  
A2. DO I HAVE TO BE IN THIS STUDY? 
You can decide whether to take part in this study or not. You are free to say yes or no. If 
you say no, your regular medical care will not change. Even if you join this study, you do 
not have to stay in it. You may stop at any time.  


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A – Version October 31, 2016 
IRB Protocol Number: PRO00022660 
IRB Approval Period: 04/09/2018 – 08/20/2018 
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MCW Version:03-13-18 
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04/09/2018 
 
MCW/FH IRB
 
A research study is different from routine medical care in three ways: 1) there are extra 
risks that we will tell you about in this form; 2) you may have some extra medical tests 
and visits; 3) the study procedures, tests and visits follow a set plan that must be kept. 
 
A3. WHY IS THIS RESEARCH STUDY BEING DONE? 
MLN9708 (ixazomib) is a new drug which so far has been mostly used in studies for 
multiple myeloma patients either alone or with other combination of drugs.  To date 
approximately 300 patients have been treated with oral MLN9708 either alone or with 
other combinations of drugs. 
  
Patients who undergo allogeneic transplants are at risk of suffering a common problem 
called graft-versus-host disease (GVHD).  GVHD is a complication where the donor 
cells (graft) received during transplant attacks and damages the patient’s (transplant 
recipient) tissues.  GVHD can cause skin rash, intestinal problems such as diarrhea, 
nausea, vomiting and decrease liver function or liver failure, lung damage, dry eyes, dry 
mouth, tightening of skin, joint problems, increased risk of infections etc.  These 
symptoms can range from mild to severe and may be life threatening and may be fatal 
in some cases. GVHD disease can occur early (within three months of transplant) or 
later after an allogeneic transplant). There are no approved therapies for preventing late 
(also called chronic) GVHD. 
 
The purpose of this study is to learn if prescribing MLN9708 to you starting about two 
months after transplant will help prevent chronic or late form of GVHD.  We also want to 
see if MLN9708 is safe to use in transplant patients. 
 
MLN9708 is currently not approved by the Food and Drug Administration to treat or 
prevent GVHD. This means that the use of MLN9708 in this study is considered 
investigational (or experimental). 
 
B1. WHAT WILL HAPPEN IF I TAKE PART IN THE STUDY?   
 
The study doctor or a member of the study staff will discuss with you the requirements 
for being in this study.  They will evaluate your ability to be in the study. 
 
Before you begin the study: 
 
You will have the following exams, tests or procedures to find out if you can be in the 
study.  These exams, tests, or procedures are part of regular cancer care and may be 
done even if you do not join the study.  If you have had some of them recently, they may 
not need to be repeated.  This will be up to your study doctor. 
 
Baseline tests include: 
 Medical history and physical examination (includes vital signs, height, 
weight, and current medications and your current GVHD status) 


Medical College of Wisconsin & Froedtert Hospital  
 
 
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IRB Approval Period: 04/09/2018 – 08/20/2018 
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 Routine blood tests to check your blood counts, organ function and post-
transplant status. 
 A blood test to check for pregnancy for women of childbearing potential 
 Karnofsky Performance Status (KPS) to see how well you perform daily 
activities 
 GVHD Assessments 
 
During the study: 
 
If the exams, tests and procedures show that you can be in the study, and you choose 
to take part then you will be enrolled in the study.  
 
Treatment:  There is no universally accepted standard treatment to prevent GVHD, and 
different transplant centers in the country use a variety of treatments to prevent this 
complication. In this study you will be given the standard treatment normally provided at 
this site to help prevent GVHD.  Your study doctor will help you understand the risks 
involved with these drugs as well. 
 
You will take the usual (or standard) prophylaxis of GVHD until your doctor feels it is 
safe to quit taking it but in most cases it will be at least until Day 180 post-transplant.   
 
The study consists of a phase I portion and a phase II portion. 
 
Phase I 
The purpose of the phase I portion of the study is to find out the maximum dose of study 
drug (i.e. MLN9708), which is safe for administration in post allogeneic transplant 
patients  The first few  patients enrolled will participate in the phase I part of the study. 
In phase I, the dose of the study drug is gradually and carefully increased in successive 
groups of 6-9 patients.  Starting on day +60 to +74 after your allogeneic transplant, you 
will take MLN9708 by mouth on days 1,8,15 and 22.  It was determined that the 
maximum tolerated dose is 4mg. Phase I is closed. 
 
Phase II 
The maximum safe dose was determined to be 4mg.  All remaining patients will receive 
MLN9708 (ixazomib) 4mg in the phase II portion of the study.  
 
You will start taking the MLN9708 study medication weekly for four weeks, 
approximately two to three months after your donor allogeneic transplant  
 
You will need to keep taking MLN9708 (the study drug) until one of the following 
happens: 
 You finish four weekly oral doses 
 You develop a moderate grade of acute GVHD, which normally occurs within the 
first 100 days of the transplant 


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 You develop severe chronic GVHD 
 You have a serious side effect or reaction to the study drug (MLN9708) 
 
On Study Tests: 
 
Post-transplant visits follow routine care practice at our center.  The following routine 
clinical tests, procedures, and assessments may be done: 
 Physical examinations (includes vital signs, height, weight) 
 Routine blood tests to check your blood counts, organ function and post-
transplant status. 
 Karnofsky Performance Status (KPS) to see how well you perform daily 
activities 
 Research blood samples 
 GVHD assessments 
 
We will talk to you about any side effects you may have experienced during this study at 
your normal clinic visits of hospital stays. 
 
Follow-up: 
 
During the follow up period we will follow you for disease status and GVHD status. 
 
Samples for Optional Research 
 
Throughout the study we would like to draw some of your blood and store it to do 
research related to this study.  This will be stored in a laboratory at the Medical College 
of Wisconsin.  We will keep these samples for as long as we need to complete the 
research.  We will do tests to look at parts of your blood that might help us learn more 
about this study.  The lab testing of your samples could involve both genetic and non-
genetic tests.  The genetic tests do not involve research about diseases being passed 
on in families. 
Approximately 6 tablespoons will be collected at each visit during the two years you are 
in the study for the optional research samples.    
 
You do not have to agree to store your blood for research to be in the main part of this 
study.  
 
Please indicate next to one of the statements below whether or not you agree to allow 
storages of your samples for research related to this study. 
 
Yes_____ 
No _____ I agree to allow blood samples to be stored for research. 
 
 
 


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B2. HOW LONG WILL I BE IN THE STUDY? 
 
You will be in this research study for about 5 years. 
 
B3. CAN I STOP BEING IN THE STUDY?   
 
You are free to withdraw from the study at any time. If you leave, your regular medical 
care will not change. If you are thinking about leaving, please tell the study doctor.  
 The doctor can tell you about the effects of stopping, and you and the doctor can talk 
about what follow-up care would help you the most. 
 You might be asked to come back for one more visit to check your health. 
 
The study doctor may take you out of this study at any time. This would happen if: 
 
They think it is in your best interest. 
 
You do not follow the study rules. 
 
The whole study is stopped. 
If this happens, the study doctor will tell you. 
 
B4. ARE THERE ANY SPECIAL INSTRUCTIONS WHILE I AM IN THE STUDY? 
 
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.   
 
MLN9708 should not be taken if you have ever had an allergic reaction to boron or 
boron containing products. 
 
C1. WHAT HEALTH RISKS OR PROBLEMS CAN I EXPECT FROM THE STUDY? 
There are risks to taking part in any research study. There is a risk that you may get a 
drug, drug combination or dose of a drug that does not help your condition or may make 
it worse.  There also may be problems (side effects) we do not know about yet, from 
drug itself, or how it combines with other drugs you are taking. If we learn about new 
important side effects, we will tell you.  
 
We watch everyone in the study for problems (side effects). You need to tell the study 
doctor or a member of the study team immediately if you experience any 
problems, side effects, or changes in your health.  If you have problems, call Dr. 
Hamadani immediately at 414-805-6800. In an emergency, call 911. 
 
C2. RISKS OF TREATMENT 
The research drug itself may cause problems (side effects).  Side effects may be mild or 
very serious.  Some can last a long time or never go away.  Many go away soon after 
you stop taking the drug. Drugs can affect individuals in different ways.  


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Complications of some of the side effects below may lead to life-threatening events 
such and possibly death. 
 
Side Effects of Study Drugs and Treatments 
All drugs can have side effects, including the standard therapy for GVHD (steroids). 
Your doctor will watch you carefully and will change your treatment if side effects 
develop.  
 
Infections 
Because chronic GVHD is caused by an immune attack on your tissues from the 
transplanted donor cells, all treatments for chronic GVHD include drugs to control 
(suppress) that immune attack.  There is a higher risk of infection in patients with 
chronic GVHD and in people who take steroids like prednisone or methylprednisolone, 
the standard therapy for chronic GVHD.   
You will need to take several antibiotics to prevent infection.  You will also be watched 
carefully for any infections while you are being treated for chronic GVHD. Tell your 
doctors promptly if you get a fever, chills, cough or any other symptoms that might be a 
sign of an infection. 
 
Possible Discomforts and Risks of MLN9708 (Study drug) 
 
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.    
 
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.  
 
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: 
 
o Low platelet count which may increase the chance of bleeding;  
o Skin rash which may range from some red areas, small flat spots, or small 
raised bumps that may or may not be itchy in a few areas or all over the 
body  
o Feeling tired or weak  
o Nausea  


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o Vomiting  
o Diarrhea  
o Numbness or tingling or pain feelings in hands and feet  
o Constipation  
o Lowered red cells or anemia which may make you feel tired 
o Lowered white blood cells called neutrophils that may increase your risk of 
infection and may be associated with fever  
 
 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  
o Electrolyte imbalance (blood chemical imbalance)  
o Loss of water from the body (dehydration) because of vomiting and/or 
loose stools  
o High blood creatinine and renal failure which creatinine means your 
kidneys are having trouble working well; Patients who had lost body water 
(dehydration) because of vomiting and/or loose stools have had high 
levels of creatinine indicating that the kidneys were failing to function 
adequately. In some severe situations, less kidney function may require 
temporary treatment with a machine that supports the function of the 
kidney (dialysis)  
o Flu-like symptoms and other upper respiratory tract infections  
o Lung infections including pneumonia or pneumonitis  
o Chills  
o Pain in the abdomen or back  
o Swelling or fluid buildup in the arms or legs  
o Lowered blood pressure that can commonly cause you to feel light 
headed, faint or pass out when you stand up  
o Lowered white blood cells called lymphopenia 
o Pain (muscular) in extremities  
 
The following 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 
diseases.  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.  
 
Toxic epidermal necrolysis (TEN) and DRESS syndrome have also been reported in 
MLN9708 studies.  TEN is a disease that causes the top layer of skin to detach from the 
lower layers of the skin leaving the body susceptible to severe infection.   


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DRESS syndrome may cause rash, fever, inflammation of internal organs, enlarged 
lymph nodes and abnormalities In the blood. 
 
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, 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.  
 
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 PML.  
 
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. 
 
C3. OTHER RISKS OF THIS RESEARCH STUDY 
 
Other procedures that are part of the study also involve some risks: 
  
Venipuncture:  Although you may require a central venous catheter to donate cells, 
there may be an occasional need to have an intravenous catheter placed in your arm(s) 
or you may need to have blood withdrawn from the veins of your arm(s).  Drawing blood 
from the arm may be associated with bleeding into the skin and may very rarely result in 
an infection. 
 
C4. REPRODUCTIVE RISKS 
 
Risks to women who could become pregnant 
 
The drugs in this study might affect a baby, before or after the baby is born. We do not 
know if the drugs causes harm to a baby, so we do not want anyone who might be 
pregnant to enter the study. You should not become pregnant or nurse a baby while in 
this study.  


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


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Highly effective methods 
Other effective methods (barrier 
methods) 
Vasectomy         
Latex or non-latex condom  with or 
without a spermicidal agent   
 
Diaphragm with spermicide; Cervical 
cap with spermicide; Sponge with 
spermicide 
If one of the highly effective methods cannot be used, using two effective 
methods at the same time are recommended.  
 
All subjects (male or female): If you or your partner becomes pregnant during this study, 
you must tell the study doctor immediately.  The doctor will advise you of the possible 
risks to your unborn child and discuss options for managing the pregnancy with 
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 think that you have fathered a baby while you are taking this experimental drug or 
within 90 days after you have stopped taking it, we ask that you inform the study doctor 
immediately. At that time the study doctor will ask permission of your partner for the use 
and disclosure of her health information regarding the pregnancy. She will be asked to 
sign a separate consent form. She can choose to do this or not. She will be asked to 
sign this form to allow your study doctor to contact her obstetrician to collect information 
on the progress of the pregnancy and its outcome. The study doctor will make this 
information available to the study sponsor for safety monitoring. 
 
If you do not understand what any of these discomforts and risks mean, please ask the 
study doctor or study staff to explain these terms to you. 
 
C5. ARE THERE ANY BENEFITS TO TAKING PART IN THE STUDY? 
 
We don’t know if this study will help you. Your condition may get better but it could stay 
the same or even get worse. We hope the information from this study will help us 
prevent late GVHD. Information obtained from this study may benefit other patients in 
the future. 
 
D1. ARE THERE ANY COSTS TO BEING IN THE STUDY? 
 
Most of the medical care that you will receive in this study is considered routine care for 
your condition and would be recommended whether you join the study or not.  Costs for 
routine care will be billed to you or your insurance carrier.   
 
Activities / costs that are part of the study will not be billed to you or your insurance 
company. These are the study drug MLN9708,and the processing and storage of 
research samples.  


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Some insurers will not pay for drugs, tests or hospitalization that are part of research 
studies, so check with your insurer before you join this study. If you have questions 
regarding study costs, please contact Dr. Hamadani. 
 
If you participate in this research study, the costs of any necessary emergency medical 
treatment in the event of a research-related injury will be billed to you or your health 
insurance 
 
D2. WILL I BE PAID FOR PARTICIPATING IN THE STUDY? 
 
There is no payment for being in this study  
 
D3. WHAT OTHER HEALTHCARE CHOICES DO I HAVE? 
 
You do not have to join this study. You are free to say yes or no. If you do not join this 
study, your doctor can discuss other healthcare choices with you.  
Your other choices may include: 
 
Routine care for this condition or symptoms 
 
Joining a different research study 
 
D4. WILL I BE GIVEN NEW INFORMATION ABOUT THE STUDY? 
 
If we learn any important new information about the drug that might change your mind 
about being in the study, we will tell you about it right away.  You can then decide if you 
want to stay in the study. 
 
D5. WHAT HAPPENS IF I AM HARMED BECAUSE I TOOK PART IN THE STUDY?  
 
Emergency medical treatment for injuries directly related to your participation in this 
research study will be provided to you. You or your health insurance will be billed for the 
costs of this emergency treatment.  MCW will decide on a case by case basis if they will 
reimburse you or your insurer for emergency treatment costs.  If your research-related 
injury requires medical care beyond this emergency treatment, you or your insurer will 
be responsible for the costs of this follow-up care.  
 
At this time, there is no plan for any additional financial payments. 
 
If you believe that you have been injured because of your participation in this study, 
contact the study doctors right away.  Contact information: Dr. Hamadani at 414-805-
6700.  
 
Nothing in this consent form affects any legal rights you may have nor does it 
release the investigator, the sponsor, the institution, or its agents from liability for 
negligence. 
 


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D6. WHO CAN ANSWER MY QUESTIONS ABOUT THE STUDY? 
 
If you have more questions about this study at any time, you can call Dr. Hamadani 
at 414-805-6700. 
 
If you have questions about your rights as a study participant, want to report any 
problems or complaints, obtain information about the study, or offer input, you can 
call the MCW/Froedtert Hospital Research Subject Advocate at 414-955-8844. 
 
E. PERMISSION TO COLLECT, USE AND SHARE HEALTH INFORMATION 
 
E1. What health information will be collected and used for this study? 
To do this research study, we need your permission to collect and use some of your 
health information, or you cannot be in the study. This information may come from 
questions we ask, forms we ask you to fill out, or your medical record, as described 
below. We will only collect and use information needed for the study.  
 
The health information to be collected and used for this study is:  
All or portions of your medical chart: 
 Hospital/Medical Records 
 Physician/Clinical Records 
 Lab and/or Pathology Reports 
 Radiology Reports 
 Biological Samples 
 
E2. Who will see the health information collected for this study? 
The only MCW/Froedtert Hospital employees allowed to handle your health information 
are those on the study team, those on the Institutional Review Board (IRB) and those 
who check on the research activities to make sure the hospital’s rules are followed. 
 
If the costs of any necessary emergency medical treatment in the event of a research-
related injury are billed to your health insurance, your health information may need to be 
disclosed to the insurer for billing purposes. 
 
The study team may share your information with people who don’t work at 
MCW/Froedtert Hospital because they planned, pay for, or work with us on this study.  
The federal Privacy Rule may no longer protect your health information once it leaves 
MCW/Froedtert Hospital.  For this study, we plan to share information with those 
doctors, researchers or government representatives working with us on this study at the 
institutions or companies listed here: 
 U.S. Food and Drug Administration, Rockville, MD     
 Millennium and its collaborators or designees 
 Representatives of Central Laboratories  
 Any Independent ethics committee, which approved this study 
 Other Regulatory Agencies and/or Their Designated Representatives   
 Those required by law 


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We may record your research information, including results of tests and procedures 
done for research, in your Froedtert Hospital and/or Medical College of Wisconsin 
medical record.  As a result, this research information may be seen by people allowed 
to see your medical records for healthcare operations or treatment, by those you allow 
to see your medical records by giving written permission, and by others when required 
by law. 
 
We will not use your personal health information for a different study without your 
permission or the permission of a hospital research review board (IRB). Once all 
personal identification is removed, the information might be used or released for other 
purposes without asking you. Results of the study may be presented in public talks or 
written articles, but no information will be presented that identifies you. 
  
E3. What are the risks of sharing this health information? 
One risk of taking part in a research study is that more people will handle your personal 
health information collected for this study. The study team will make every effort to 
protect the information and keep it confidential, but it is possible that an unauthorized 
person might see it. Depending on the kind of information being collected, it might be 
used in a way that could embarrass you or affect your ability to get insurance. If you 
have questions, you can talk to the study doctor about whether this could apply to you.  
 
E4. How long will you keep the health information for this study? 
If you sign this form, we plan to keep your information without any end-date in case we 
need to check it again for this study. 
 
E5. Can I cancel my permission to share this health information? 
If you change your mind later and do not want us to collect or share your health 
information, you need to send a letter to: 
Mehdi Hamadani, MD 
Froedtert & Medical College of Wisconsin 
Division of Hematology and Oncology 
9200 W. Wisconsin Avenue 
Milwaukee, WI  53226 
 
The letter must say that you have changed your mind and do not want the researcher to 
collect and share your health information. At that time, we may decide that you cannot 
continue to be part of the study. We may still use the information we have already 
collected.  
 
 
 
 
 
 


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F1. FOR MORE INFORMATION ABOUT THE STUDY 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site 
at any time. 
 
You can look up this study by referring to the ClinicalTrials.gov number (NCT02250300) 
or by asking the study team for a printed copy.    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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CONSENT TO PARTICIPATE IN THE STUDY 
 
By signing my name below, I confirm the following: 
 I have read (or had read to me) this entire consent document.  All of my questions 
have been answered to my satisfaction. 
 The study’s purpose, procedures, risks and possible benefits have been explained to 
me.   
 I agree to let the study team use and share the health information and other 
information gathered for this study. 
 I voluntarily agree to participate in this research study.  I agree to follow the study 
procedures as directed.  I have been told that I can stop at any time. 
 
IMPORTANT: You will receive a signed and dated copy of this consent form.  Please 
keep it where you can find it easily.  It will help you remember what we discussed today. 
 
 
 
 
Subject's Name please print  
Subject's Signature 
Date    
 
 
 
Name of Legally Authorized 
Representative (if applicable)  
please print  
Signature of Legally Authorized 
Representative 
Date 
 
 
 
Name of Witness (if applicable) please 
print  (for short form consent process, or 
consent of blind or illiterate subject) 
Signature of Witness 
 
Date 
 
 
 
* Name of person discussing/ 
obtaining consent please print  
Signature of person 
discussing/obtaining consent 
Date 
* A member of the study team trained and authorized by the Principal Investigator to act on her/his behalf 
in obtaining informed consent according to the protocol.  In all research study protocols the Principal 
Investigator is responsible and accountable for the study.