Clinical trial NCT02168101
Conditions: Multiple Myeloma
Keywords: MLN9708 allogeneic stem cell transplant multiple myeloma ixazomib autologous stem cell transplant
Sponsor: SCRI Development Innovations, LLC
Start date: 2014-09-01; Completion date: 2019-02-01
Enrollment: 9 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the study is to determine the safety of MLN9708 as maintenance therapy following allogeneic stem cell transplant in patients with multiple myeloma.

Detailed description:
Although multiple myeloma is considered fatal, survival has dramatically improved over the last two decades with the introduction of more effective treatment options. Proteasome inhibitors have an anti-myeloma effect and are often used as either initial treatment or at relapse in patients with multiple myeloma. MLN9708 is an orally bioavailable, potent, reversible inhibitor of the 20S proteasome. Phase I studies have shown MLN9708 to be very well tolerated with minimal peripheral neuropathy. It has also shown impressive anti-myeloma activity in both the relapsed/refractory setting and the upfront setting (Kumar et al. 2011, Berdeja et al. 2011, Richardson et al. 2011). These characteristics make MLN9708 an ideal proteasome inhibitor to use after allogeneic stem cell transplant. In this Phase II, open-label, multicenter, non-randomized study the investigators will investigate the role of MLN9708 as maintenance after allogeneic stem cell transplant in patients with high-risk multiple myeloma, and in patients with multiple myeloma who have relapsed after an autologous stem cell transplant.

Arms: arm 1: Patients will be enrolled between Days 45 and 120 after allogeneic transplant and will receive a weekly dose of 2.3 mg of MLN9708 on Days 1, 8, and 15 of each 28-day cycle for 6 cycles. arm 2: Patients will be enrolled between Days 45 and 120 after allogeneic transplant and will receive a weekly dose of 3 mg of MLN9708 on Days 1, 8, and 15 of each 28-day cycle for 6 cycles. arm 3: Patients will be enrolled between Days 45 and 120 after allogeneic transplant and will receive a weekly dose of 4 mg of MLN9708 on Days 1, 8, and 15 of each 28-day cycle for 6 cycles.
Interventions: intervention 1: MLN9708
Intervention descriptions: intervention 1: Patients will be enrolled between Days 45 and 120 after allogeneic transplant and will receive MLN9708 orally (PO) as monotherapy on Days 1, 8, and 15 of each 28-day cycle for 6 cycles. Up to 18 patients will be enrolled in a dose-escalation phase to determine the maximum tolerated dose (MTD).

Dose-Escalation Phase: MLN9708 will be administered orally (PO) as monotherapy. Dosing will start at 2.3 mg. If acceptable tolerability is demonstrated, escalations will be made to 3 mg and to a maximum-planned dose (MPD) of 4 mg.

Protocol documents:
Prot_000.pdf: 
 
CONFIDENTIAL 
THIS DOCUMENT IS CONFIDENTIAL AND IS THE PROPERTY OF SCRI DEVELOPMENT INNOVATIONS, LLC.  NO PART OF THIS 
DOCUMENT MAY BE TRANSMITTED, REPRODUCED, PUBLISHED, OR USED BY OTHER PERSONS WITHOUT PRIOR WRITTEN 
AUTHORIZATION FROM SCRI DEVELOPMENT INNOVATIONS, LLC. 
 
MM 42 
Open-Label Study to Determine the Feasibility of MLN9708 as Maintenance 
after Allogeneic Stem Cell Transplant for Multiple Myeloma, Followed by an 
Expansion Phase at the Maximum-Tolerated Dose (MTD) 
 
SCRI INNOVATIONS STUDY NUMBER: 
MM 42 
 
STUDY DRUG: 
MLN9708 
SPONSOR: 
SCRI Development Innovations, LLC  
(SCRI Innovations) 
3322 West End Avenue , Suite 900 
Nashville, TN  37203 
1-877-MY-1-SCRI 
asksarah@scresearch.net 
STUDY CHAIR: 
Carlos Bachier, MD 
Program Director, Blood and Marrow Transplant 
Sarah Cannon Center for Blood Cancer 
250 25th Ave North 
Nashville, TN 37203 
615-342-4914 Office 
210-364-3897 Cell 
 
 
DATE FINAL: 
11 April 2014 
AMENDMENT NUMBER 1: 
Date Final:  13 May 2014 
AMENDMENT NUMBER 2: 
Date Final:  07 May 2015 
AMENDMENT NUMBER 3: 
Date Final:  11 February 2016 
 


 
 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
VERSION 4 
Page 2 of 86 
 
Clinical Study Statement of Compliance 
Open-Label Study to Determine the Feasibility of MLN9708 as Maintenance 
after Allogeneic Stem Cell Transplant for Multiple Myeloma, Followed by an 
Expansion Phase at the Maximum-Tolerated Dose (MTD) 
 
 This clinical study shall be conducted in compliance with the protocol, as referenced herein, 
and all applicable local, national, and international regulatory requirements to include, but not 
be limited to: 
 
International Conference on Harmonisation (ICH) Guidelines on Good Clinical 
Practice (GCP) 
 
Ethical principles that have their origins in the Declaration of Helsinki  
 
US Food and Drug Administration (FDA) Code of Federal Regulation (CFR): 
o 
Title 21CFR Part 50 & 45 CFR Part 46, Protection of Human Subjects 
o 
Title 21CFR Part 54, Financial Disclosure by Clinical Investigators 
o 
Title 21CFR Part 56, Institutional Review Boards 
o 
Title 21CFR Part 312, Investigational New Drug Application 
o 
Title 45 CFR Parts 160, 162, and 164, Health Insurance Portability and 
Accountability Act (HIPAA) 
 
As the Study Chair and/or Principal Investigator, I understand that my signature on the 
protocol constitutes my agreement and understanding of my responsibilities to conduct the 
clinical study in accordance to the protocol and applicable regulations.  Furthermore, it 
constitutes my understanding and agreement that any changes initiated by myself, without 
prior agreement in writing from the Sponsor, shall be defined as a deviation from the protocol, 
and shall be formally documented as such. 
 




 
 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
VERSION 4 
Page 4 of 86 
Clinical Study Principal Investigator Signature Form 
Open-Label Study to Determine the Feasibility of MLN9708 as Maintenance 
after Allogeneic Stem Cell Transplant for Multiple Myeloma, Followed by an 
Expansion Phase at the Maximum-Tolerated Dose (MTD) 
 
SCRI INNOVATIONS STUDY NUMBER:
MM 42
DATE FINAL: 
11 APRIL 2014 
Amendment Number: 
1 
Amendment Date: 
13 May 2014 
Amendment Number: 
2 
Amendment Date: 
07 May 2015 
Amendment Number: 
3 
Amendment Date: 
11 February 2016 
 
 
 
By signing this protocol acceptance page, I confirm I have read, understand, and agree to conduct the 
study in accordance with the current protocol. 
 
 
 
 
__________________________ 
__________________________         ______________  
Principal Investigator Name 
 
 
Principal Investigator Signature 
 
Date 
 
Please retain a copy of this page for your study files and return the original signed and dated form to: 
 
SCRI Development Innovations 
3322 West End Avenue, Suite 900 
10th Floor MM 42 Study 
Nashville, TN 37203 


 
 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
VERSION 4 
Page 5 of 86 
MM 42 Protocol Summary of Changes 
AMENDMENT NUMBER: 
3 
AMENDMENT DATE:  
11 February 2016 
Additions are noted by bolding.  Deletions are noted by cross-outs. 
Exclusion Criteria 
2. Umbilical cord blood or haploidentical allogeneic stem cell transplant 
Section 1.2.8 
Allogeneic stem cell transplant can achieve better control of multiple myeloma, but carries a 
higher mortality as a consequence of complications related to graft-versus-host disease (GVHD) 
(Kumar et al. 2011).  In GVHD, donor cells recognize the recipient as a foreign object and mount 
an immune reaction.  Haploidentical blood or marrow stem cell transplantation has 
historically been limited by unacceptable rates of GVHD, graft failure, and nonrelapse 
mortality.  As a result, patients with this type of transplantation were previously excluded 
from this protocol.  However, modern transplant techniques have remarkably reduced 
GVHD and have led to the increasing utilization of haploidentical donors.  The feasibility 
of haploidentical transplantation has dramatically expanded the donor pool, making 
allogeneic transplantation available for the vast majority of patients (McCurdy and Fuchs 
2015, Kanate et al 2015).  With the introduction of Protocol Amendment 3, haploidentical 
allogeneic transplantion is allowed. 
 
 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
VERSION 4 
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MM 42 PROTOCOL SYNOPSIS 
Title of Study: 
Open-Label Study to Determine the Feasibility of MLN9708 as Maintenance after 
Allogeneic Stem Cell Transplant for Multiple Myeloma, Followed by an Expansion Phase at 
the Maximum-Tolerated Dose (MTD) 
SCRI Innovations 
Study Number: 
MM 42 
Sponsor: 
SCRI Development Innovations, LLC, Nashville, TN 
Study Duration: 
The total duration of the study from first patient in to last patient out is planned to be 
~3 years. 
Study Centers: 
This study will be conducted at up to 5 centers in the United States (US). 
Number of 
Patients: 
Up to 38 patients are planned to be enrolled in this study. 
Objectives: 
Primary Objectives 
The primary objectives of this study are to assess the: 
 
Maximum-tolerated dose (MTD) of MLN9708 in this patient population 
 
Safety of MLN9708 when used as maintenance after allogeneic stem cell transplant 
for multiple myeloma. 
Secondary Objectives 
The secondary objectives of this study are to determine the: 
 
Progression-free survival (PFS) at 2 years after initiation of maintenance therapy. 
 
Overall survival (OS) at 2 years after allogeneic stem cell transplant. 
 
Incidence of graft-versus-host disease (GVHD) in patients receiving allogeneic 
stem cell transplant and maintenance with MLN9708. 
 
Effect of MLN9708 on immune effector cells after allogeneic stem cell transplant. 
Study Design: 
This is a Phase II, open-label, multicenter, non-randomized study to determine the feasibility 
of MLN9708 as maintenance after allogeneic stem cell transplant for multiple myeloma.  
Patients will be enrolled between Days 45 and 120 after allogeneic transplant and will 
receive MLN9708 on Days 1, 8, and 15 of each 28-day cycle for 6 cycles.  Up to 18 patients 
will be enrolled in the dose-escalation phase to define the MTD of MLN9708.  An additional 
20 patients will be enrolled in the expansion phase at the MTD. 
Study Drugs, 
Doses, and Modes 
of Administration: 
MLN9708 will be administered orally as monotherapy.  Dosing will start at 2.3 mg.  If 
acceptable tolerability is demonstrated, escalations will be made to 3 mg and to a maximum-
planned dose (MPD) of 4 mg.  Once the MTD is determined, enrollment into the expansion 
phase will proceed at that dose. 
Inclusion Criteria 
Patients must meet the following criteria in order to be included in this research study: 
1. Symptomatic multiple myeloma or asymptomatic myeloma with myeloma-related organ 
damage diagnosed according to standard criteria in patients who received allogeneic 
transplant due to high-risk prognostic features, such as, but not limited to: 
 
Chromosome 17p, partial deletion [del(17p)], t(4;14), t(14;16), t(14;20) 
 
Plasma cell leukemia 
 
PFS of less than 2 years after autologous stem cell transplant 
2. Evidence of engraftment of neutrophils (absolute neutrophil count [ANC] 
>1000 cells/mm3) and platelets (platelets >60,000 cells/mm3 [dose escalation phase] and 
>50,000 cells/mm3 [dose expansion phase]) 
3. Achievement of at least a PR prior to allogeneic stem cell transplant. 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
VERSION 4 
Page 7 of 86 
 
MM 42 PROTOCOL SYNOPSIS 
Inclusion Criteria 
(continued): 
4. Adequate liver function defined as: 
 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 x the 
upper limit of normal (ULN) 
 
Total bilirubin ≤2.0 x ULN 
5. Adequate renal function defined as creatinine clearance ≥30 mL/min, estimated or 
calculated. 
6. Age ≥18 years and ≤70 years, at time of enrollment 
7. Ability to swallow oral medication 
8. Absence of gastrointestinal symptoms that precludes oral intake and absorption of 
MLN9708 (nausea, vomiting, diarrhea, malabsorption) 
9. Off antibiotics and amphotericin B formulations, voriconazole or other anti-fungal 
therapy for the treatment of proven, probable or possible infections (defined in 
accordance with the European Organization for Research and Treatment of 
Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of 
Allergy and Infectious Diseases Mycoses Study Group [EORTC/MSG] criteria) 
10. Eastern Cooperative Oncology Group (ECOG) Performance Status score of ≤ 2 
(Appendix A). 
11. Life expectancy ≥3 months 
12. Male patients with female partners of childbearing potential and women patients of 
childbearing potential are required to use two forms of acceptable contraception, 
including one barrier method, during their participation in the study and for 90 days 
following last dose of study drug.  Male patients must also refrain from donating sperm 
during their participation in the study (Appendix C). 
13. Ability to understand the nature of this study and give written informed consent before 
performance of any study-related procedure not part of standard medical care, with the 
understanding that consent may be withdrawn by the patient at any time without 
prejudice to future medical care. 
Exclusion 
Criteria: 
Patients who meet any of the following criteria will be excluded from study entry: 
1. Patients who have progressive disease when compared to pre-transplant staging as 
defined by IMWG Uniform Response criteria for Multiple Myeloma (see Appendix E). 
2. Umbilical cord blood transplant 
3. Patients with > Grade 2 peripheral neuropathy with pain, or ≥ Grade 3 peripheral 
neuropathy per National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) Version 4.0 
4. Patients with uncontrolled bacterial, viral, or fungal infections 
5. New York Heart Association (NYHA) Class III or IV heart failure uncontrolled angina, 
severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute 
ischemia or active conduction system abnormalities (see Appendix B).  Prior to study 
entry, any electrocardiogram (ECG) abnormality at Screening has to be documented by 
the Investigator as not medically relevant. 
6. Patients who are pregnant (positive beta-human chorionic gonadotropin [β-HCG]) or 
breastfeeding 
7. Most recent chemotherapy ≤21 days and ≤ Grade 1 chemotherapy-related side effects, 
with the exception of alopecia 
8. Use of a study drug ≤21 days or 5 half-lives (whichever is shorter) prior to the first dose 
of MLN9708.  For study drugs for which 5 half-lives is ≤21 days, a minimum of 10 days 
between termination of the study drug and administration of MLN9708 is required. 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
VERSION 4 
Page 8 of 86 
MM 42 PROTOCOL SYNOPSIS 
Exclusion 
Criteria 
(continued): 
9. Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) 
administered ≤14 days or limited field radiation for palliation ≤7 days prior to starting 
study drug or has not recovered from side effects of such therapy 
10. Major surgical procedures ≤14 days of beginning study drug, or minor surgical 
procedures ≤7 days.  No waiting is required following port-a-cath placement. 
11. Ongoing or active systemic infection.  Known diagnosis of human immunodeficiency 
virus, hepatitis B, or hepatitis C 
12. Central nervous system involvement 
13. Known allergy to any of the study medications, their analogues, or excipients in the 
various formulations of any agent. 
14. Systemic treatment with strong inhibitors of cytochrome P450 (CYP) 1A2 (CYP1A2) 
(fluvoxamine, enoxacin, ciprofloxacin), moderate inhibitors of CYP1A2 (mexiletine, 
propafenone, and zileuton), strong inhibitors of CYP3A (clarithromycin, telithromycin, 
itraconazole, voriconazole, ketoconazole, posaconazole, and nefazodone), moderate 
CYP3A inhibitors (amprenavir, aprepitant, diltiazem, erythromycin, fosamprenavir, 
grapefruit-containing products including grapefruit juice, and verapamil), or clinically 
significant CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, 
oxcarbazepine, primidone, phenytoin, phenobarbital), or use of Ginkgo biloba or St. 
John’s wort within 14 days before study drug administration in the study. 
15. Presence of other active cancers, or history of treatment for invasive cancer ≤5 years.  
Patients with Stage I cancer who have received definitive local treatment and are 
considered unlikely to recur are eligible.  All patients with previously treated in situ 
carcinoma (i.e., non-invasive) are eligible, as are patients with history of non-
melanoma skin cancer. 
16. Psychological, familial, sociological, or geographical conditions that do not permit 
compliance with the protocol. 
17. Graft versus host disease > Grade 2; or GVHD grade 1 or Grade 2 which requires 
>0.5 mg/kg methylprednisolone, or equivalent. 
Correlative 
Testing: 
Immune analysis from the peripheral blood will include: 
 
CD3+, CD4+, CD8+, CD45+, CD19+ and CD56+/CD16+ cells by fluorescence-
activated cell sorting 
 
Regulatory T cells by intracellular staining of FoxP3 and surface staining of CD4+ 
and CD25+ cells 
 
Inflammatory cytokines including IL-1β, IL-6, IL-8, IL-10 and TNF-α 
Participating sites will process the samples, analyse and report data for the flow cytometric 
analysis.  Samples for cytokine analysis will be shipped to a central laboratory for analysis.  
Samples will be collected on Days 1 (pre-dose), 4, 8, and 15 of Cycle 1 and Day 1 (pre-
dose) of Cycle 2 from 3 patients at each dose level and from 5 patients at the MTD/MPD. 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
VERSION 4 
Page 9 of 86 
MM 42 PROTOCOL SYNOPSIS 
 
Statistical 
Methodology: 
Safety of MLN9708 when used in this indication (primary endpoint) will be evaluated as 
follows.  Toxicity profile data will include adverse events (AEs), laboratory parameters, 
vital signs, and other protocol-specified tests that are deemed critical to the safety 
evaluation.  Safety data will be tabulated for all patients who receive any amount of study 
medication.  Adverse events will be tabulated by system organ class, preferred term, 
severity, and relation to treatment.  The tabulation of laboratory parameters will indicate the 
normal range of each parameter.  Each analyte value will be classified as falling above, 
below, or within the normal range. 
Progression-free survival and OS (efficacy secondary endpoints) estimates will be 
generated using Kaplan-Meier methods, both for all patients enrolled and those patients 
receiving the MTD.  Two-year PFS and OS estimates with 95% confidence intervals (CIs), 
and median PFS and OS with 95% CIs, will be generated and reported accordingly. 
Incidence of GVHD (safety secondary endpoint) will reported in a manner consistent with 
the AE reporting previously described. 
Demographic data and baseline disease characteristics will be summarized using 
descriptive statistics. 
All statistical analyses will be performed using SAS 9.3 or the current version of SAS 
available at the time of analysis. 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
VERSION 4 
Page 10 of 86 
MM 42 CONTACT INFORMATION 
SCRI Innovations  
Contact Information: 
SCRI Development Innovations, LLC 
3322 West End Avenue, Suite 900 
Nashville, TN  37203 
1-877-MY-1-SCRI 
asksarah@scresearch.net 
 
Study Chair: 
Carlos Bachier, MD 
Program Director, Blood and Marrow Transplant 
Sarah Cannon Center for Blood Cancer 
250 25th Ave North 
Nashville, TN 37203 
615-342-4914 Office 
210-364-3897 Cell  
 
Safety Dept. Phone # / Fax #: 
Safety Dept. Email: 
1-615-329-7358/1-866-807-4325 
CANN.SAE@scri-innovations.com 
Regulatory Phone #:  
Regulatory Email: 
1-877-MY-1-SCRI  
SCRIRegulatory@scresearch.net 
SCRI Innovations Enrollment  Phone #: 
SCRI Innovations Enrollment Fax #: 
SCRI Innovations Enrollment Email: 
1-877-MY-1-SCRI  
1-866-346-1062 or 615-524-4012 
CANN.SCRIInnovationsEnr@scri-innovations.com 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
VERSION 4 
Page 11 of 86 
LIST OF ABBREVIATIONS 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
β-HCG 
Beta-human chorionic gonadotropin 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CMP 
Comprehensive metabolic profile 
CO2 
Carbon dioxide 
CR 
Complete remission 
CYP 
Cytochrome P450 
del(17p) 
Chromosome 17p, partial deletion 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EORTC/MSG 
European Organization for Research and Treatment of Cancer/Invasive Fungal 
Infections Cooperative Group and the National Institute of Allergy and Infectious 
Diseases Mycoses Study Group 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
GVHD 
Graft-versus-host disease 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator Brochure 
ICF 
Informed consent form 
ICH 
International Congress on Harmonisation 
IRB 
Institutional Review Board 
LDH 
Lactate dehydrogenase 
LVEF 
Left ventricular ejection fraction 
MPD 
Maximum-planned dose 
MRD 
Minimal residual disease 
MTD 
Maximum-tolerated dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NSAID 
Nonsteroidal anti-inflammatory drug 
NYHA 
New York Heart Association 
OS 
Overall survival 
PD 
Progressive disease 
PHI 
Protected health information 
PFS 
Progression-free survival 
PR 
Partial response 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
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SAE 
Serious adverse event 
SCRI 
Sarah Cannon Research Institute 
SD 
Stable disease 
SFLC 
Serum free light chains 
SPEP 
Serum protein electrophoresis 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
ULN 
Upper limit of normal 
UPEP 
Urine protein electrophoresis 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
VERSION 4 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ................................................................................................. 18 
1.1 
Background ........................................................................................................... 18 
1.2 
MLN9708 .............................................................................................................. 18 
1.2.1 
Safety Pharmacology and Toxicology .................................................................. 19 
1.2.2 
Preclinical Experience ........................................................................................... 19 
1.2.3 
Clinical Experience ............................................................................................... 19 
1.2.4 
Pharmacokinetics and Drug Metabolism .............................................................. 19 
1.2.5 
Clinical Trial Experience Using the Oral Formulation of MLN9708 ................... 20 
1.2.6 
Relapsed and/or Refractory Multiple Myeloma .................................................... 24 
1.2.7 
Newly Diagnosed Multiple Myeloma (NDMM) ................................................... 25 
1.2.8 
Rationale for the Study .......................................................................................... 25 
2. 
STUDY OBJECTIVES ......................................................................................... 26 
2.1 
Primary Objectives ................................................................................................ 26 
2.2 
Secondary Objectives ............................................................................................ 26 
3. 
STUDY PATIENT POPULATION AND DISCONTINUATION ...................... 26 
3.1 
Inclusion Criteria ................................................................................................... 26 
3.2 
Exclusion Criteria .................................................................................................. 27 
3.3 
Discontinuation from Study Treatment ................................................................. 29 
4. 
STUDY REGISTRATION.................................................................................... 30 
5. 
STUDY DESIGN .................................................................................................. 30 
5.1 
Treatment Plan ...................................................................................................... 31 
5.1.1 
Dose Escalation Procedure .................................................................................... 32 
5.1.2 
Dose-Limiting Toxicity ......................................................................................... 32 
5.1.3 
Maximum-Tolerated Dose .................................................................................... 33 
5.1.4 
Expansion after Determination of the Maximum-Tolerated Dose ........................ 33 
5.2 
Treatment Duration ............................................................................................... 34 
5.3 
Concomitant Medications...................................................................................... 34 
5.3.1 
Permitted Concomitant Medications and Procedures ........................................... 34 
5.3.2 
Prohibited Concomitant Medications and Procedures .......................................... 35 
5.4 
Precautions and Restrictions ................................................................................. 35 
5.5 
Correlative Studies ................................................................................................ 36 
6. 
DOSE MODIFICATIONS .................................................................................... 36 
6.1 
Dose Modifications Due to Hematologic Toxicity ............................................... 36 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
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6.1.1 
Recommended MLN9708 Criteria for Beginning or Delaying a Subsequent 
Treatment Cycle & Dose Modifications for Treatment Associated Toxicity on 
Day 1 of a New Cycle ........................................................................................... 37 
6.2 
Dose Modifications due to Non-Hematologic Toxicity ........................................ 38 
6.3 
Specific Recommendations for Management of Clinical Events .......................... 39 
6.3.1 
Prophylaxis against Risk of Infection ................................................................... 39 
6.3.2 
Nausea and/or Vomiting ........................................................................................ 39 
6.3.3 
Diarrhea ................................................................................................................. 39 
6.3.4 
Erythematous Rash With or Without Pruritus ....................................................... 40 
6.3.5 
Thrombocytopenia................................................................................................. 40 
6.3.6 
Neutropenia ........................................................................................................... 40 
6.3.7 
Fluid Deficit .......................................................................................................... 41 
6.3.8 
Hypotension........................................................................................................... 41 
6.3.9 
Posterior Reversible Encephalopathy Syndrome .................................................. 41 
6.3.10 
Transverse Myelitis ............................................................................................... 41 
7. 
STUDY ASSESSMENTS AND EVALUATIONS .............................................. 41 
7.1 
Overview ............................................................................................................... 41 
7.2 
Baseline Study Assessments ................................................................................. 42 
7.3 
Study Treatment Assessments ............................................................................... 44 
7.3.1 
All Cycles Day 1 (± 2 days) .................................................................................. 44 
7.3.2 
Cycle 1 Days 4, 8, and 15 ...................................................................................... 44 
7.3.3 
Cycles 2 through 6 Days 8 and 15 ......................................................................... 45 
7.4 
Response Assessments .......................................................................................... 45 
7.5 
End-of-Treatment Visit ......................................................................................... 46 
7.6 
Follow-up .............................................................................................................. 47 
8. 
DRUG FORMULATION, AVAILABILITY, ADMINISTRATION, AND 
TOXICITY INFORMATION ............................................................................... 47 
8.1 
MLN9708 .............................................................................................................. 47 
8.1.1 
Labeling, Packaging, and Supply .......................................................................... 47 
8.1.2 
Storage and Handling ............................................................................................ 48 
8.1.3 
Study Compliance ................................................................................................. 48 
8.1.4 
Preparation and Administration of MLN9708 ...................................................... 48 
8.1.5 
Precautions and Risks Associated with Handling MLN9708 ............................... 49 
8.1.6 
Potential Risks and Benefits .................................................................................. 49 
8.2 
Accountability for All Study drugs ....................................................................... 49 
8.3 
MLN9708 Destruction .......................................................................................... 49 
9. 
RESPONSE EVALUATIONS AND MEASUREMENTS .................................. 50 
10. 
STATISTICAL CONSIDERATIONS .................................................................. 50 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
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10.1 
Statistical Design ................................................................................................... 50 
10.2 
Sample Size Considerations .................................................................................. 50 
10.3 
Analysis Population ............................................................................................... 50 
10.4 
Data Analysis ........................................................................................................ 51 
10.4.1 
Demographics and Baseline Characteristics ......................................................... 51 
10.4.2 
Efficacy Analysis .................................................................................................. 51 
10.4.3 
Safety Analysis ...................................................................................................... 52 
10.4.4 
Planned Interim Analysis ...................................................................................... 52 
11. 
SAFETY REPORTING AND ANALYSES ......................................................... 52 
11.1 
Definitions ............................................................................................................. 53 
11.1.1 
Pretreatment Event Definition ............................................................................... 53 
11.1.2 
Adverse Events ...................................................................................................... 53 
11.1.3 
Serious Adverse Event .......................................................................................... 53 
11.1.4 
Adverse Event of Special Interest Definition ........................................................ 54 
11.1.5 
Adverse Reaction .................................................................................................. 54 
11.1.6 
Suspected Adverse Reaction ................................................................................. 54 
11.1.7 
Recording and Reporting of Adverse Events ........................................................ 54 
11.1.8 
Assessment of Adverse Events .............................................................................. 55 
11.2 
Serious Adverse Event Reporting by Investigators ............................................... 56 
11.3 
Recording of Adverse Events and Serious Adverse Events .................................. 56 
11.3.1 
Diagnosis versus Signs and Symptoms ................................................................. 56 
11.3.2 
Persistent or Recurrent Adverse Events ................................................................ 57 
11.3.3 
Abnormal Laboratory Values ................................................................................ 57 
11.3.4 
Deaths .................................................................................................................... 57 
11.3.5 
Hospitalization, Prolonged Hospitalization, or Surgery ........................................ 57 
11.3.6 
Pre-Existing Medical Conditions .......................................................................... 58 
11.3.7 
New Cancers.......................................................................................................... 58 
11.3.8 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies ................................. 58 
11.3.9 
MLN9708 Overdose .............................................................................................. 59 
11.4 
Sponsor Serious Adverse Event Reporting Requirements .................................... 59 
11.4.1 
Procedures for Reporting AESIs ........................................................................... 60 
11.4.2 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events ... 60 
11.4.3 
Sponsor Assessment of Unexpected...................................................................... 60 
11.4.4 
Sponsor Reporting for Clinical Studies Under an Investigational New Drug 
Application ............................................................................................................ 61 
12. 
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS ............ 61 
12.1 
Institutional Review Board Approval.................................................................... 61 
12.2 
Regulatory Approval ............................................................................................. 62 
12.3 
Informed Consent .................................................................................................. 62 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
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12.3.1 
Confidentiality ....................................................................................................... 63 
12.4 
Financial Information ............................................................................................ 64 
12.5 
Investigator Compliance ........................................................................................ 64 
13. 
RESEARCH RETENTION AND DOCUMENTATION OF THE STUDY ........ 64 
13.1 
Amendments to the Protocol ................................................................................. 64 
13.2 
Documentation Required to Initiate the Study ...................................................... 65 
13.3 
Study Documentation and Storage ........................................................................ 65 
13.4 
Data Collection ...................................................................................................... 67 
13.5 
Study Monitoring, Auditing, and Inspecting ......................................................... 67 
13.6 
Quality Assurance and Quality Control ................................................................ 67 
13.7 
Disclosure and Publication Policy ......................................................................... 68 
13.8 
Investigator and Site Responsibility for Drug Accountability .............................. 68 
13.9 
Product Complaints ............................................................................................... 68 
13.10 
Closure of the Study .............................................................................................. 69 
13.11 
Record Retention ................................................................................................... 69 
14. 
USE OF INFORMATION .................................................................................... 69 
15. 
REFERENCES ...................................................................................................... 70 
16. 
APPENDICES ....................................................................................................... 75 
 
LIST OF TABLES 
Table 1 
Overview of Clinical Studies of Oral MLN9708 ..................................... 21 
Table 2 
Overall Safety Population: Treatment-Emergent Adverse Events 
Reported by ≥ 10% of Patients ................................................................ 23 
Table 3 
Dose Escalation (3 + 3) Design ............................................................... 32 
Table 4 
Dose Modifications Due to Hematologic Toxicities within a 
Treatment Cycle (Day 8 and Day 15 of a Treatment Cycle) ................... 38 
Table 5 
Dose Reductions for Grade 3 or 4 Non-Hematologic Toxicities ............. 38 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
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LIST OF FIGURES 
Figure 1 
Study Schema........................................................................................... 31 
 
LIST OF APPENDICES 
Appendix A: 
ECOG Performance Status Criteria ......................................................... 75 
Appendix B: 
New York Heart Association (NYHA) Classification of Cardiac 
Disease ..................................................................................................... 76 
Appendix C: 
Guidelines for Women of Childbearing Potential and Fertile Male 
Patients ..................................................................................................... 77 
Appendix D: 
MM 42 Schedule of Assessments ............................................................ 78 
Appendix E: 
International Myeloma Working Group Uniform Response Criteria ...... 80 
Appendix F: 
National Institutes of Health Consensus Development Project on 
Criteria for Clinical Trials in Acute and Chronic Graft-Versus-Host 
Disease ..................................................................................................... 82 
Appendix G: 
Pregnancy Reporting Form ...................................................................... 85 
 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
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1. 
INTRODUCTION 
1.1 
Background 
Multiple myeloma is a clonal disease of plasma cells that is characterized by the accumulation of 
plasma cells in the bone marrow (and other organs) and commonly results in bone marrow 
failure, bone destruction, hypercalcemia, and renal failure.  Multiple myeloma accounts for 
approximately 1% of all reported neoplasms and approximately 13% of hematologic cancers 
worldwide (Palumbo and Anderson. 2011).  In North and South America and Western European 
countries, an estimated 5-to-7 new cases of multiple myeloma are diagnosed per 100,000 people 
each year (Palumbo and Anderson. 2011, Landgren and Weiss. 2009, Harousseau et al. 2008).  
In the United States (US), approximately 20,000 cases of multiple myeloma are diagnosed each 
year and 10,650 deaths per year are due to the disease (~2% of all cancer deaths).  Although 
generally less common in Asian countries, in those with larger populations, multiple myeloma is 
a growing health problem, with an incidence approaching that of Western countries (Huang et al. 
2007, Qiu et al. 2008). 
Although multiple myeloma is considered fatal, survival has dramatically improved over the last 
2 decades with the introduction of more effective treatment options.  Multiple myeloma is 
sensitive to a number of cytotoxic drugs (e.g., alkylating agents and anthracyclines) and 
corticosteroids that are commonly used for initial treatment and for relapsed disease.  Between 
1990 and 2007, the cancer death rate for people with multiple myeloma in the US decreased by 
approximately 9% for males and 13% for females owing to the introduction of stem cell 
transplant and novel agents VELCADE® (bortezomib) for Injection, thalidomide, and 
lenalidomide (Jemal et al. 2010).  In addition, 5-year survival improved from 25% in 1975 to 
39% in 2006 (National Comprehensive Cancer Network. 2010).  Most patients receive multiple 
lines of therapy over the course of their disease; however, responses remain transient.  
Bortezomib, the first proteasome inhibitor, has shown marked response in the relapsed setting 
and is also an effective agent in the pretransplant setting (Kumar et al. 2008). 
Despite an increasing number of therapeutic options, multiple myeloma is generally considered 
incurable and there is considerable need for better agents.  In an effort to further target the 
proteasome with improved activity in multiple myeloma and other cancers, Millennium has 
developed MLN9708, a small molecule 20S proteasome inhibitor. 
1.2 
MLN9708 
MLN9708 is an orally bioavailable, potent, reversible inhibitor of the 20S proteasome.  In Phase 
I studies it has been shown to be very well tolerated with minimal peripheral neuropathy.  It has 
also shown impressive anti-myeloma activity in both the relapsed/refractory setting and the 
upfront setting (Kumar et al. 2011, Berdeja et al. 2011, Richardson et al. 2011).  These 
characteristics make MLN9708 an ideal proteasome inhibitor to use after allogeneic stem cell 
transplant. 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
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1.2.1 
Safety Pharmacology and Toxicology 
A comprehensive set of nonclinical studies have been conducted to support development of 
MLN9708.  Detailed information regarding the nonclinical pharmacology and toxicology of 
MLN9708 may be found in the current Investigator’s Brochure (IB). 
1.2.2 
Preclinical Experience 
Please refer to the current MLN9708 IB and its Safety Management Attachment (SMA) provided 
by Millennium. 
1.2.3 
Clinical Experience 
MLN9708 is a peptide boronic acid that is structurally different from bortezomib. MLN9708 is 
the first investigational oral proteasome inhibitor to enter clinical trials. Phase I, Phase I/II, and 
Phase II trials are ongoing or being initiated in MM and lymphoma. Phase III trials in relapsed 
and/or refractory multiple myeloma (RRMM), newly diagnosed multiple myeloma (NDMM), 
and relapsed or refractory systemic light-chain amyloidosis (RRAL amyloidosis) are underway.   
As of 27 March 2014, data are available from 637 patients who have received at least 1 dose of 
MLN9708 across the clinical development program.  In addition, 817 patients have enrolled in 
Phase III clinical trials, either placebo-controlled Studies C16010 or C16014 (and received either 
MLN9708 or placebo in combination with lenalidomide and dexamethasone [LenDex]), or in 
Study C16011 (and received either MLN9708 and dexamethasone or physician’s choice of a 
dexamethasone-containing regimen). 
MLN9708 is available as an IV and oral formulation; however, only the oral formulation is 
currently being developed for commercialization.  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, 
and in the weekly dosing schedule MLN9708 is given on Days 1, 8, and 15 of a 28-day cycle.  
Schedules with longer cycles are being investigated in Study C16006.   
The following oncology indications are being studied: RRMM, NDMM, RRAL amyloidosis, 
solid tumors, and lymphoma.  Ongoing studies are investigating both single agent MLN9708 and 
MLN9708 in combination with standard treatments.  
1.2.4 
Pharmacokinetics and Drug Metabolism 
The PK of MLN9708 after IV dosing is characterized by a multi-exponential disposition profile 
in plasma with the terminal half-life after multiple doses ranging from 2.8 to 12.2 days.  Plasma 
exposures increase proportionally over the dose range of 0.5 to 3.11 mg/m2 (0.8-6.8 mg actual 
administered dose range).  Renal elimination appears to be a minor clearance pathway for 
MLN9708 as renal clearance is less than 5% of the total body clearance estimate from the 
population PK analysis.  After both once- and twice-weekly oral dosing, MLN9708 is rapidly 
absorbed with a median Tmax of 1 hour.  The observed range for the terminal half-life after 
multiple doses is 2.1 to 11.3 days.  Dose proportionality has been observed for doses between 
0.48 and 3.95 mg/m2 (0.8-8.9 mg actual administered dose range). 
Pharmacokinetic parameters for MLN9708 coadministered with LenDex (Studies C16005 and 
C16008), or MP (Study C16006), appear to be similar to those observed when MLN9708 is 
administered as a single agent.  This suggests that there is no readily apparent effect of 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
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coadministration of LenDex, or MP, on the clinical PK of MLN9708.  Likewise, no apparent 
differences in the PK of MLN9708 have been noted between patients with different 
malignancies. 
After once-weekly dosing, Day 1 geometric mean dose-normalized MLN9708 exposures in 
Japanese and Asian patients receiving MLN9708 plus LenDex are similar to the observed values 
in Western patients (Studies C16004, C16005, and C16007).  On Day 15, the geometric mean 
dose-normalized MLN9708 AUC0-168 in Asian patients is approximately 45% higher than the 
observed values in Western patients.  A high-fat meal decreased both the rate and extent of 
absorption of MLN9708.  Therefore, MLN9708 will continue to be administered on an empty 
stomach (no food for 2 hours before and for 1 hour after dosing). 
A population PK analysis has been performed using preliminary PK data from 137 patients 
treated with IV and PO MLN9708 as a single agent across 4 ongoing, Phase I studies (intensive 
PK sampling) in Western patient populations. Patients with solid tumors, lymphoma, or MM 
were administered MLN9708 via IV or PO routes using BSA-based dosing on a twice-weekly 
(Days 1, 4, 8, and 11; 21-day cycle) or weekly (Days 1, 8, and 15; 28-day cycle) schedule.   
There is a lack of a discernible relationship between BSA and MLN9708 clearance over a 
relatively wide BSA range (1.4-2.6 m2) indicating that total systemic exposure (AUC) following 
fixed dosing should be independent of the individual patient’s BSA.  Therefore, BSA is not 
expected to affect Cmax or AUC after IV or oral dosing, and thus fixed dosing is appropriate for 
both oral and IV routes of administration.  The clinical development of MLN9708 has therefore 
transitioned from the use of BSA-based dosing to fixed dosing. 
Accordingly, the starting dose of MLN9708 in the Phase III study in RRMM (Study C16010) is 
a fixed dose of 4.0 mg, on the basis of the recommended dose of 2.23 mg/m2 (using mean patient 
BSA of 1.86 m2 from the 2208 patients with MM in bortezomib clinical studies for conversion to 
a fixed dose).  Also, no relationship between creatinine clearance and CL was observed in 
patients with a wide range of renal function (creatinine clearance range: 21.9-236.1 mL/min), so 
starting dose adjustment is not required in patients with mild (60-90 mL/min) and moderate (30-
60 mL/min) renal impairment in clinical studies (Gupta et al. 2011).  Further details on these 
studies are provided in the IB. 
1.2.5 
Clinical Trial Experience Using the Oral Formulation of MLN9708 
As of 27 March 2014, a total of 491 patients with differing malignancies (MM, systemic light-
chain amyloidosis [AL amyloidosis], lymphoma, and nonhematologic cancers) have received at 
least 1 dose of MLN9708 in Phase I, Phase I/II, and Phase II studies evaluating the oral 
MLN9708 formulation.  These patients have been treated with different doses of MLN9708 
either as a single-agent treatment (241 patients) or in combination with currently clinically 
available treatments (250 patients).  In addition, 817 patients have enrolled in Phase II Studies 
C16010 and C16014 (double-blind, placebo–controlled studies in MM) and Study C16011 
(open–label study in AL amyloidosis).  Information regarding the ongoing studies, patient 
populations, and doses investigated are included in Table 1. 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
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Table 1 
Overview of Clinical Studies of Oral MLN9708 
Indication 
Line 
MLN9708 Schedule and Combination 
Therapies 
Enrollment 
Status 
Multiple 
Myeloma 
Newly 
Diagnosed 
Ph I/II QW + LenDex (C16005) 
Closed 
Ph I/II TW + LenDex (C16008) 
Closed 
Ph I/II QW or TW + MP (C16006) 
Enrolling 
Ph III QW + LenDex vs placebo + LenDex 
(C16014) 
Enrolling 
Ph II QW + CD (C16020) 
Enrolling 
Relapsed/ 
Refractory 
Ph I QW (C16004) 
Closed 
Ph I TW (C16003) 
Closed 
Ph III QW + LenDex vs placebo + LenDex 
(C16010) 
Enrolling 
Ph I QW + LenDex in Asia (C16013) 
Enrolling 
Ph I QW single agent or + LenDex in Japanese 
pts 
(TB-MC010034) 
Closed 
Amyloid 
Ph I QW (C16007) 
Closed 
Ph III QW + Dex vs physician’s choice 
(C16011) 
Enrolling 
Lymphoma 
Advanced 
Disease 
Ph I QW (C16017) 
Enrolling 
Clin Pharm 
DDI, FE, BA QW (C16009) 
Enrolling 
Renal impairment pts (C16015) 
Enrolling 
Hepatic impairment QW (C16018) 
Enrolling 
ADME QW (C16016) 
Enrolling 
Abbreviations: ADME = absorption, distribution, metabolism, and excretaion; BA = bioavailability; CD = cyclophosphamide and 
dexamethasone; Clin Pharm = clinical pharmacology; DDI = drug-drug interaction; Dex = dexamethasone; FE = food effect; 
LenDex = lenalidomide and dexamethasone; MP = melphalan and prednisone; Ph = phase; pts = patients; QW = weekly; TW = 
twice weekly.  Gray background = Phase III trial. 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
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Additional detailed information regarding the clinical experience of MLN9708 may be found in 
the IB, including information on the IV formulation. 
Most Frequent Adverse Events in the Overall Safety Population 
The most frequent AEs (those reported in at least 10% of the total safety population, excluding 
ongoing Phase III Studies C16010, C16011, and C16014), regardless of study drug causality, are 
shown in Table 2.  Adverse events (AEs) observed to date (as of 27 March 2014) are generally 
reversible, manageable with standard medical interventions, and are dose dependent.  The type of 
AEs are generally consistent across the patient populations treated to date, though some AEs 
may be more common either due to the patient population or the regimen being studied (e.g., 
thrombocytopenia is more common with weekly single-agent MLN9708 in RRMM than in 
RRAL amyloidosis; in RRMM, thrombocytopenia is more common with weekly single agent 
MLN9708 than when given in combination with LenDex; nausea is common across studies; 
diarrhea is more common with weekly MLN9708 in combination with LenDex than with single-
agent MLN9708).  Such differences may illustrate effects of the disease or prior therapy on the 
body (e.g., on the bone marrow) as well as the side effect profile of the agents in a combination 
regimen. 
The more commonly observed (≥ 30% incidence) treatment-emergent AEs (TEAEs) from pooled 
data across clinical studies with oral MLN9708 include nausea (47%), diarrhea (47%), fatigue 
(45%), rash (all terms; 40%), vomiting (37%), and thrombocytopenia (33%).  The frequency of 
rash is noted in an aggregate because it is characterized in different ways; however, it is less 
common when considering individual preferred terms.  The rash may range from limited 
erythematous areas, macular and/or small papular bumps that may or may not be pruritic over a 
few areas of the body, to a more generalized eruption that is predominately on the trunk or 
extremities.  Therefore, Table 2 includes the number of patients experiencing a rash of any term, 
in addition to the most frequently reported preferred terms, for added clarity about frequency. 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
VERSION 4 
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Table 2 
Overall Safety Population: Treatment-Emergent Adverse Events Reported 
by ≥ 10% of Patients 
Primary System Organ Class 
      Preferred Term 
IV Studiesa 
N = 146 
Oral Studiesb 
N = 491 
Total 
N = 637 
Subjects with at Least One Adverse 
Event 
145 (99) 
482 (98) 
627 (98) 
Gastrointestinal disorders 
115 (79) 
400 (81) 
515 (81) 
 Nausea 
59 (40) 
230 (47) 
289 (45) 
 Diarrhea 
51 (35) 
230 (47) 
281 (44) 
 Vomiting 
60 (41) 
181 (37) 
241 (38) 
 Constipation 
36 (25) 
134 (27) 
170 (27) 
 Abdominal pain 
28 (19) 
60 (12) 
88 (14) 
General disorders and 
administration site conditions 
118 (81) 
363 (74) 
481 (76) 
 Fatigue 
89 (61) 
223 (45) 
312 (49) 
 Pyrexia 
45 (31) 
112 (23) 
157 (25) 
 Edema peripheral 
31 (21) 
122 (25) 
153 (24) 
 Asthenia 
10 (7) 
74 (15) 
84 (13) 
Nervous system disorders 
87 (60) 
272 (55) 
359 (56) 
 Headache 
25 (17) 
85 (17) 
110 (17) 
 Dizziness 
31 (21) 
74 (15) 
105 (16) 
 Neuropathy peripheral 
17 (12) 
81 (16) 
98 (15) 
Metabolism and nutrition disorders 
89 (61) 
267 (54) 
356 (56) 
 Decreased appetite 
56 (38) 
120 (24) 
176 (28) 
 Dehydration 
25 (17) 
61 (12) 
86 (14) 
 Hypokalemia 
11 (8) 
57 (12) 
68 (11) 
Blood and lymphatic system 
disorders 
88 (60) 
256 (52) 
344 (54) 
 Thrombocytopenia 
65 (45) 
161 (33) 
226 (35) 
 Anemia 
28 (19) 
114 (23) 
142 (22) 
 Neutropenia 
16 (11) 
103 (21) 
119 (19) 
 Lymphopenia 
16 (11) 
61 (12) 
77 (12) 
Skin and subcutaneous tissue 
disorders 
84 (58) 
255 (52) 
339 (53) 
 Rash (all terms) 
73 (50) 
197 (40) 
270 (42) 
 Rash maculo-papular 
21 (14) 
60 (12) 
81 (13) 
 Rash macular 
15 (10) 
56 (11) 
71 (11) 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
VERSION 4 
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Table 2 
Overall Safety Population: Treatment-Emergent Adverse Events Reported 
by ≥ 10% of Patients 
Primary System Organ Class 
      Preferred Term 
IV Studiesa 
N = 146 
Oral Studiesb 
N = 491 
Total 
N = 637 
Musculoskeletal and connective 
tissue disorders 
78 (53) 
249 (51) 
327 (51) 
 Back pain 
27 (18) 
88 (18) 
115 (18) 
 Arthralgia 
17 (12) 
72 (15) 
89 (14) 
 Pain in extremity 
21 (14) 
66 (13) 
87 (14) 
Respiratory, thoracic and 
mediastinal disorders 
87 (60) 
228 (46) 
315 (49) 
 Cough 
32 (22) 
94 (19) 
126 (20) 
 Dyspnea 
31 (21) 
80 (16) 
111 (17) 
Infections and infestations 
48 (33) 
244 (50) 
292 (46) 
 Upper respiratory tract infection 
12 (8) 
94 (19) 
106 (17) 
Psychiatric disorders 
32 (22) 
151 (31) 
183 (29) 
 Insomnia 
14 (10) 
89 (18) 
103 (16) 
 
Source: \biostatistics\MLNM9708\IB\2014\Tables\T14.1.3-TEAE_Pct10_Pooled and 
\biostatistics\MLNM9708\IB\2014\Tables\T14.6.2-TEAE_AESI_Rash; data cutoff 27 March 2014. 
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. 
A subject counts once for each preferred term and system organ class.  Percentages use the number of treated 
subjects as the denominator. 
a Studies C16001 and C16002. 
b Studies C16003, C16004, C16005, C16006, C16007, C16008, C16009, C16013, C16015, C16017, C16018, and 
TB-MC010034. 
1.2.6 
Relapsed and/or Refractory Multiple Myeloma 
The development of MLN9708 in patients with RRMM includes 2 Phase 1 dose-escalation 
single-agent studies (Studies C16003 and C16004). 
Across these studies, 120 patients were treated, 60 in each study (Study C16003 with the twice-
weekly schedule and Study C16004 with the weekly schedule).  The MTD in Study C16003 was 
2 mg/m2 twice-weekly dosing based on DLTs of macular rash and thrombocytopenia (platelet 
count = 10 x 109/L).  The MTD in Study C16004 was 2.97 mg/m2 given weekly based on DLTs 
of diarrhea, nausea, vomiting, and erythema multiforme. 
At the data cut-off, with 3 patients remaining on study, the median number of cycles 
administered in Study C16003 was 4 (range 1-61) with 33 (55%) patients treated for ≥4 cycles, 
17 (28%) for ≥8 cycles, and 11 (18%) for ≥12 cycles.  Across all patients treated, including 
above and below the MTD, dose reductions were needed once in 57% of patients, with 
≥2 reductions needed in 20% of patients. 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
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At the data cut-off, all patients in Study C16004 have discontinued treatment.  The median 
number of cycles administered was 2 (range 1-24) with 19 (32%) patients treated for ≥4 cycles, 
12 (20%) for ≥8 cycles, and 2 (3%) for ≥12 cycles.  Across all patients treated including above 
and below the MTD, dose reductions were needed once in 33% of patients, with ≥2 reductions 
needed in 13% of patients. 
Final study results suggest that single-agent MLN9708 has anti-tumor activity in heavily 
pretreated MM patients, with durable responses/disease control, and is generally well 
tolerated(Richardson et al. 2014, Kumar et al. 2014). 
1.2.7 
Newly Diagnosed Multiple Myeloma (NDMM) 
Three Phase I/II studies are being conducted with MLN9708 in combination with standard anti-
myeloma regimens; 2 in combination with LenDex (Studies C16005 [Berdeja et al. 2011, 
Richardson et al. 2012 (a), Richardson et al. 2012 (b), Kumar et al. 2013] and C16008 
[Richardson et al. 2012 (a)]) and 1 in combination with MP (Study C16006 [San Miguel et al. 
2012]).  Study C16014 is a randomized, placebo-controlled Phase III study of MLN9708 or 
placebo in combination with LenDex.  Please refer to the MLN9708 IB and SMA for further 
information. 
1.2.8 
Rationale for the Study 
The use of autologous stem cell transplantation, proteasome inhibitors, and immunomodulatory 
drugs has transformed the treatment landscape of patients with multiple myeloma (Jemal et al. 
2010, National Comprehensive Cancer Network. 2010, Kumar et al. 2008).  Despite these 
advances, the vast majority of patients will eventually relapse and succumb to their disease.  In 
patients with particular high-risk features, such as those with abnormalities of chromosome 17p, 
circulating plasma cells, extra medullary disease, and short remission duration following 
aggressive induction/stem cell transplantation the outcome is especially poor with progression-
free survival of less than 2 years (Richardson et al. 2011, Drake et al. 2010, Kapoor et al. 2009, 
Neben et al. 2012, Jimenez-Zepeda et al. 2012).  Allogeneic (using donor stem cells) stem cell 
transplantation is an appropriate treatment option in these high-risk patients. 
Allogeneic stem cell transplant can achieve better control of multiple myeloma, but carries a 
higher mortality as a consequence of complications related to graft-versus-host disease (GVHD) 
(Kumar et al. 2011).  In GVHD, donor cells recognize the recipient as a foreign object and mount 
an immune reaction.  Haploidentical blood or marrow stem cell transplantation has historically 
been limited by unacceptable rates of GVHD, graft failure, and nonrelapse mortality.  As a 
result, patients with this type of transplantation were previously excluded from this protocol.  
However, modern transplant techniques have remarkably reduced GVHD and have led to the 
increasing utilization of haploidentical donors.  The feasibility of haploidentical transplantation 
has dramatically expanded the donor pool, making allogeneic transplantation available for the 
vast majority of patients (McCurdy and Fuchs 2015, Kanate et al 2015).  With the introduction of 
Protocol Amendment 3, haploidentical allogeneic transplantion is allowed. 
Proteasome inhibitors have an anti-myeloma effect and are often used as either initial treatment 
or at relapse in patients with multiple myeloma.  Proteasome inhibitors have also been shown in 
pre-clinical and clinical models to stimulate allogeneic immune cells to eliminate myeloma cells 


 
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STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
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and at the same time reduce the incidence and severity of GVHD (Koreth et al. 2009, El Cheik et 
al. 2008, Kroger et al. 2006).  The use of proteasome inhibitors after stem cell transplant can 
therefore prolong remissions after transplant and reduce the incidence of GVHD. 
This study investigates the role of MLN 9708 as maintenance in patients that undergo allogeneic 
stem cell transplant for high-risk multiple myeloma and in patients with multiple myeloma that 
undergo allogeneic stem cell transplant due to relapsing after an autologous stem cell transplant. 
2. 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
The primary objectives of this study are to assess the: 
 Maximum-tolerated dose (MTD) of MLN9708 in this patient population 
 Safety of MLN9708 when used as maintenance after allogeneic stem cell transplant for 
multiple myeloma. 
2.2 
Secondary Objectives 
The secondary objectives of this study are to determine the: 
 Progression-free survival (PFS) at 2 years after initiation of maintenance therapy 
 Overall survival (OS) at 2 years after allogeneic stem cell transplant 
 Incidence of graft-versus-host disease (GVHD) in patients receiving allogeneic stem cell 
transplant and maintenance with MLN9708 
 Effect of MLN9708 on immune effector cells after allogeneic stem cell transplant. 
3. 
STUDY PATIENT POPULATION AND DISCONTINUATION 
3.1 
Inclusion Criteria 
Patients must meet the following criteria in order to be included in the research study: 
1. Symptomatic multiple myeloma or asymptomatic myeloma with myeloma-related organ 
damage diagnosed according to standard criteria in patients who received allogeneic 
transplant due to high-risk prognostic features, such as, but not limited to: 
- Chromosome 17p, partial deletion (del(17p), t(4;14), t(14;16), t(14;20) 
- Plasma cell leukemia 
- Progression-free survival of less than 2 years after autologous stem cell transplant 


 
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STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
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2. Evidence of engraftment of neutrophils (absolute neutrophil count [ANC] 
>1000 cells/mm3) and platelets (platelets >60,000 cells/mm3 [dose escalation phase] and 
>50,000 cells/mm3 [dose expansion phase]) 
3. Achievement of at least a PR prior to allogeneic stem cell transplant. 
4. Adequate liver function defined as: 
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 x the 
upper limit of normal (ULN) 
- Total bilirubin ≤2.0 x ULN 
5. Adequate renal function defined as creatinine clearance ≥30 mL/min, estimated or 
calculated. 
6. Aged ≥18 and ≤70 years, at time of enrollment 
7. Ability to swallow oral medication 
8. Absence of gastrointestinal symptoms that precludes oral intake and absorption of 
MLN9708 (nausea, vomiting, diarrhea, malabsorption) 
9. Off antibiotics and amphotericin B formulations, voriconazole or other anti-fungal 
therapy for the treatment of proven, probable or possible infections (defined in 
accordance with the European Organization for Research and Treatment of 
Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of 
Allergy and Infectious Diseases Mycoses Study Group [EORTC/MSG] criteria) 
10. Eastern Cooperative Oncology Group (ECOG) Performance Status score of ≤ 2 
(Appendix A) 
11. Life expectancy ≥3 months 
12. Male patients with female partners of childbearing potential and female patients of 
childbearing potential are required to use two forms of acceptable contraception, 
including one barrier method, during their participation in the study and for 90 days 
following last dose of study drug.  Male patients must also refrain from donating sperm 
during their participation in the study (Appendix C). 
13. Ability to understand the nature of this study, comply with the study procedures, and 
willingly give written informed consent before performance of any study related 
procedure not part of standard medical care, with the understanding that consent may be 
withdrawn by the patient at any time without prejudice to future medical care. 
3.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
3. Patients who have progressive disease when compared to pre-transplant staging as 
defined by IMWG Uniform Response criteria for Multiple Myeloma (see Appendix E). 
4. Umbilical cord blood transplant 


 
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STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
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5. Patients with > Grade 2 peripheral neuropathy with pain, or ≥ Grade 3 peripheral 
neuropathy per National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) Version 4.0 
6. Patients with uncontrolled bacterial, viral, or fungal infections 
7. New York Heart Association (NYHA) Class III or IV heart failure uncontrolled angina, 
severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute 
ischemia or active conduction system abnormalities (see Appendix B).  Prior to study 
entry, any electrocardiogram (ECG) abnormality at Screening has to be documented by 
the Investigator as not medically relevant. 
8. Patients who are pregnant (positive beta-human chorionic gonadotropin [β-HCG]) or 
breastfeeding 
9. Most recent chemotherapy ≤21 days and ≤ Grade 1 chemotherapy-related side effects, 
with the exception of alopecia 
10. Use of a study drug ≤21 days or 5 half-lives (whichever is shorter) prior to the first dose 
of MLN9708.  For study drugs for which 5 half-lives is ≤21 days, a minimum of 10 days 
between termination of the study drug and administration of MLN9708 is required. 
11. Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) 
administered ≤14 days or limited field radiation for palliation ≤7 days prior to starting 
study drug or has not recovered from side effects of such therapy 
12. Major surgical procedures ≤14 days of beginning study drug, or minor surgical 
procedures ≤7 days.  No waiting is required following port-a-cath placement. 
13. Ongoing or active systemic infection.  Known diagnosis of human immunodeficiency 
virus, hepatitis B, or hepatitis C 
14. Central nervous system involvement 
15. Known allergy to any of the study medications, their analogues, or excipients in the 
various formulations of any agent. 
16. Systemic treatment with strong inhibitors of cytochrome P450 (CYP) 1A2 (CYP1A2) 
(fluvoxamine, enoxacin, ciprofloxacin), moderate inhibitors of CYP1A2 (mexiletine, 
propafenone, and zileuton), strong inhibitors of CYP3A (clarithromycin, telithromycin, 
itraconazole, voriconazole, ketoconazole, posaconazole, and nefazodone), moderate 
CYP3A inhibitors (amprenavir, aprepitant, diltiazem, erythromycin, fosamprenavir, 
grapefruit-containing products including grapefruit juice, and verapamil), or clinically 
significant CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, 
oxcarbazepine, primidone, phenytoin, phenobarbital), or use of Ginkgo biloba or St. 
John’s wort within 14 days before study drug administration in the study. 
17. Presence of other active cancers or history of treatment for invasive cancer ≤5 years.  
Patients with Stage I cancer who have received definitive local treatment and are 
considered unlikely to recur are eligible.  All patients with previously treated in situ 


 
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STUDY DRUG:  MLN9708 
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carcinoma (i.e., non-invasive) are eligible, as are patients with history of non-melanoma 
skin cancer. 
18. Psychological, familial, sociological, or geographical conditions that do not permit 
compliance with the protocol. 
19. Graft versus host disease > Grade 2; or GVHD Grade 1 or Grade 2 which requires > 
0.5 mg/kg methylprednisolone, or equivalent 
3.3 
Discontinuation from Study Treatment 
Patients will be informed that they have the right to withdraw from the study at any time for any 
reason, without prejudice to their medical care.  Patients will be discontinued from study 
treatment for any of the following reasons: 
 
Disease progression 
 
Irreversible or intolerable toxicity or abnormal laboratory values thought to be related to 
drug toxicity 
 
Conditions requiring therapeutic intervention not permitted by the protocol 
 
Intercurrent illness (this will be at the Investigator’s discretion) 
 
Inability of the patient to comply with study requirements or lost to follow-up 
 
Patient requests to discontinue treatment 
 
Patient withdraws consent from the study 
 
Pregnancy 
 
Protocol violation 
At the time of withdrawal, all study procedures outlined for the End of Study visit should be 
completed. The primary reason for patient’s withdrawal from the study should be recorded in the 
source documents and eCRF.  After discontinuation from protocol treatment, patients must be 
followed for AEs for 30 days after their last dose of study drug.  All new AEs occurring during 
this period must be reported and followed until resolution, unless, in the opinion of the 
Investigator, these values are not likely to improve, because of the underlying disease.  In this 
case, the Investigators must record his or her reasoning for this decision in the patients’ medical 
records and as a comment in the electronic Case Report Form (eCRF). 
All patients who have Grade 3 or 4 laboratory abnormalities (per National Cancer Institute 
Common Terminology Criteria for Adverse Events [NCI CTCAE] v4.0; 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE), at the time of discontinuation must be followed 
until the laboratory values have returned to Grade 1 or 2, unless it is, in the opinion of the 
Investigator, not likely that these values are to improve.  In this case, the Investigator must 
record his or her reasoning for making this decision in the patients’ medical records and as a 
comment on the eCRF. 


 
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STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
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4. 
STUDY REGISTRATION 
The patient must willingly consent after being informed of the procedures to be followed, the 
experimental nature of the treatment, potential benefits, alternatives, side-effects, risks, and 
discomforts.  Human protection committee (Institutional Review Board [IRB]) approval of this 
protocol and consent form is required.  Eligible patients who wish to participate in the study will 
be enrolled into the study. 
Registration must occur prior to the initiation of protocol therapy.  Patients eligible to participate 
in the study may be enrolled through the SCRI Innovations Central Enrollment Desk.  The 
enrollment desk may be reached by calling (877) MY-1-SCRI.  Registration may be done via fax 
1-866-346-1062 Monday through Friday, 8:30 a.m. to 4:30 p.m., Central Standard Time.  Patient 
registration will be confirmed via email within 24 hours, or by the next business day. 
5. 
STUDY DESIGN 
This is a Phase II, open-label, multicenter, non-randomized study to determine the feasibility of 
MLN9708 as maintenance after allogeneic stem cell transplant for multiple myeloma.  Patients 
will be enrolled between Days 45 and 120 after allogeneic transplant and will receive MLN9708 
on Days 1, 8, and 15 of each 28-day cycle for 6 cycles.  Up to 18 patients will be enrolled in the 
dose-escalation phase to define the MTD of MLN9708.  An additional 20 patients will be 
enrolled in the expansion phase at the MTD. 
Up to 5 study sites are planned in the United States. 
Dosing will start at 2.3 mg.  If acceptable tolerability is demonstrated, escalations will be made 
to 3 mg and to the maximum-planned dose (MPD) of 4 mg.  Once the MTD/MPD is determined, 
enrollment into the expansion phase will proceed at that dose.  The study schema is presented in 
Figure 1. 
 


 
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STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
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Figure 1 
Study Schema 
Dose Escalation – Until the MTD/MPD is reached 
 
Dose Expansion 
 
 
Cohort 3 
 
20 Additional Patients 
 
Cohort 2 
4 mg Single 
Weekly Dose 
 
Dose expansion at the 
MTD/MPD 
 
Cohort 1 
3 mg Single 
Weekly Dose 
 
 
 
2.3 mg Single 
Weekly Dose 
 
 
 
 
 
 
 
 
 
MTD = Maximum-tolerated dose 
MPD = Maximum-planned dose 
 
5.1 
Treatment Plan 
All protocol-specific criteria for administration of study drug must be met and documented 
before drug administration.  Study drug will be administered or dispensed only to eligible 
patients under the supervision of the investigator or identified subinvestigator(s).  Patients should 
be monitored for toxicity, as necessary, and doses of MLN9708 should be modified as needed to 
accommodate patient tolerance to treatment; this may include symptomatic treatment, dose 
interruptions, and adjustments of MLN9708 dose. 
MLN9708 will be administered orally as monotherapy.  Dosing will start at 2.3 mg.  If 
acceptable tolerability is demonstrated, escalations will be made to 3 mg and to the MPD of 
4 mg.  Once the MTD is determined, enrollment of an additional 20 patients into the expansion 
phase will proceed at that dose. 
MLN9708 will be given on an empty stomach, with no food and fluids except for water and 
prescribed medications for 2 hours before and 1 hour after each dose.  Each dose of MLN9708 
will be given orally with approximately 8 oz (240 mL) of water.  Missed doses can be taken as 
soon as the patient remembers as long as the next scheduled dose is at least 72 hours from that 
point in time.  A double dose should not be taken to make up for a missed dose.  If the patient 
vomits after taking a dose, the patient should not be given a repeat dose, rather dosing should 
resume at the time of the next scheduled dose. 
The capsules should not be chewed, broken, or opened for administration.  Patients should be 
monitored for toxicity as necessary, and doses of MLN9708 should be modified on the basis of 
the patient’s tolerability.  This may include symptomatic treatment, dose interruptions, and/or 
adjustments of the MLN9708 dose.  More conservative dose escalation, evaluation of alternative 
dosing, and expansion of an existing dose level are all permissible following discussions between 


 
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STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
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the Study Chair, Millennium, and the Investigators, if such measures are needed for patient 
safety or for a better understanding of the dose-related toxicity or exposure of MLN9708. 
No routine prophylactic antiemetics will be given.  However, antiemetics may be administered 
prior to treatment based on the patient’s susceptibility to nausea and vomiting at the 
investigator’s discretion, and may be given prophylactically afterwards. 
5.1.1 
Dose Escalation Procedure 
The actual number of dose cohorts to be explored in this study will depend upon the MTD and 
the observed safety profile of MLN9708. 
The 3 + 3 Dose-Escalation Design 
Using a 3 + 3 dose escalation design, each cohort will enroll up to 6 evaluable patients.  
Evaluation of a cohort of at least 3 patients completing 1 cycle of treatment (28 days) is required 
prior to proceeding to the next dose level.  Dose escalation decisions will take into account the 
safety profile of prior dose groups.  Intrapatient dose escalation will not be allowed. 
The 3 + 3 dose escalation procedure is presented in Table 3. 
 
Table 3 
Dose Escalation (3 + 3) Design 
Number of Patients with a DLT 
Action 
0 of 3 patients 
Escalate to next dose level as shown in Figure 1 
1 of 3 patients 
Accrue 3 additional evaluable patients at the current dose 
level (for a total of up to 6 evaluable patients)a 
1 of 6 patients 
Escalate to the next dose level as shown in Figure 1 
2 or more patients in a dose level group of 
up to 6 patients 
The MTD has been exceeded. 
 
DLT = Dose-limiting toxicity 
a For a patient to be considered “evaluable,” he or she must have met the minimum safety evaluation requirements of the study, 
and/or experienced a DLT. 
 
5.1.2 
Dose-Limiting Toxicity 
Toxicity will be assessed utilizing the NCI CTCAE v4.0, unless otherwise specified. 
A toxicity will be considered dose-limiting if it occurs during the first cycle (28 days) of 
treatment with MLN9708 and deemed at least possibly related to therapy per treating physician’s 
discretion.  Patients who experience a dose-limiting toxicity (DLT) in the first cycle of therapy 
will discontinue treatment with MLN9708.  Dose-limiting toxicities will be defined as the 
following: 
 Grade 4 neutropenia for >7 days, or febrile neutropenia 
 Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia associated with bleeding 


 
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STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
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 Grade 3 or 4 non-hematologic toxicity with the following exceptions: 
- alopecia 
- Grade 3 rash, nausea, diarrhea, and vomiting, if controlled to ≤ Grade 2 with 
standard supportive care within 72 hours 
 Treatment delay of ≥14 days due to unresolved toxicity 
 For patients with ALT, ALP and bilirubin below ULN at enrollment: Hy’s law:  
Hepatocellular injury (defined as ALT >2 x ULN and (ALT/ULN)/(alkaline phosphatase 
[ALP]/ULN) >5) and bilirubin >2 x ULN or jaundice ± ALK <2 x ULN 
 For patients with ALT, ALP and/or bilirubin above ULN at enrolment:  Increase of 3x 
above baseline level. 
 
Determination of Dose-Limiting Toxicities 
The patient population used for determination of DLTs will consist of patients who have met the 
minimum safety evaluation requirements of the study, and/or who have experienced a DLT.  
Minimum safety requirements will be met if, during Cycle 1 of treatment, the patient receives all 
(3 of 3) scheduled doses of MLN9708, completes all required safety evaluations, and is observed 
for at least 28 days following the first dose of MLN9708.  An isolated laboratory abnormality 
could also be considered criteria for seriousness (e.g., results in hospitalization or considered 
medically significant). 
Patients who discontinue treatment early due to disease progression or withdrawal will be asked 
to have all end-of-treatment safety evaluations performed as described in the protocol (see 
Section 7.5).  If a patient withdraws from treatment during Cycle 1 due to any reason other than a 
DLT and does not meet the minimum requirements for inclusion in the MTD-determining 
population described above, that patient will be replaced. 
5.1.3 
Maximum-Tolerated Dose 
The MTD is the highest dose at which ≤1 of 6 patients experience a DLT during 1 cycle 
(28 days) of therapy.  If 2 or more patients in a dosing group of ≤6 patients experience a DLT, 
the MTD has been exceeded.  If 2 or more patients in a doses group of up to 6 patients 
experience a DLT and only 3 patients were evaluated at the previous (i.e., next lower) dose, then 
an additional 3 patients will be evaluated at this next lower dose and if zero or one have DLTs 
then this previous dose level is declared the MTD. 
5.1.4 
Expansion after Determination of the Maximum-Tolerated Dose 
Once the MTD is determined, the MTD cohort of patients will be expanded with an additional 
20 patients to further characterize the safety and clinical benefits of maintenance with MLN9708 
after allogeneic stem cell transplant.  If the MTD is not reached, the expansion will proceed at 
the MPD. 


 
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STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
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5.2 
Treatment Duration 
The total duration of the study from first patient enrolled to last patient out is planned to be 
approximately 3 years. 
Based on tolerability, patients will receive 6 cycles of MLN9708 as maintenance therapy 
following an allogeneic stem cell transplant. 
5.3 
Concomitant Medications 
Patients will be instructed not to take any additional medications during the course of the study 
without prior consultation with the research team.  At each visit, the patient will be asked about 
any new medications he is taking or has taken after the start of the study drug. 
5.3.1 
Permitted Concomitant Medications and Procedures 
The following medications and procedures are permitted during the study: 
 Antiemetics, including 5-HT3 serotonin receptor antagonists, may be used prior to 
treatment based on the patient’s susceptibility to nausea and vomiting 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 (e.g., granulocyte colony stimulating factor [G-CSF], granulocyte 
macrophage-colony stimulating factor [GM-CSF], recombinant erythropoietin) are 
permitted in Cycle 1 of the dose escalation phase if the patient has a neutrophil value that 
meets DLT criteria and after Cycle 1 of the dose escalation phase. Their use should 
follow published guidelines and/or institutional practice.  
 Erythropoietin will be allowed in this study according to standard clinical practice.  Their 
use should follow published guidelines and/or institutional practice. 
 Patients should be transfused with red cells and platelets in Cycle 1 of the dose escalation 
phase if the patient has a platelet value that meets DLT criteria and as clinically indicated 
and according to institutional guidelines. 
 Antiviral therapy such as acyclovir may be administered if medically appropriate. 
 Concomitant treatment with bisphosphonates will be permitted, as appropriate. 
 Patients who experience worsening neuropathy from baseline may be observed for 
recovery, and have dose reductions/delays as indicated in the protocol, and any 
supportive therapy or intervention may be initiated as appropriate at the discretion of the 
investigator. 
 Supportive measures consistent with optimal patient care may be given throughout the 
study. 
Other medications considered necessary for the patient’s safety and well-being may be given at 
the discretion of the Investigator with the exception of those listed in Section 5.3.2. 


 
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 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
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5.3.2 
Prohibited Concomitant Medications and Procedures 
The following treatments are prohibited while in this study: 
 No other investigational therapy should be given to patients. 
 Systemic treatment with any of the following metabolizing enzyme inhibitors is not 
permitted in this study.  A DDI with a strong inhibitor would increase MLN2238 exposure: 
o Strong inhibitors of CYP1A2: fluvoxamine, ciprofloxacin, and enoxacin 
o Moderate inhibitors of CYP1A2: mexiletine, propafenone, and zileuton 
o Strong inhibitors of CYP3A: clarithromycin, telithromycin, itraconazole, 
voriconazole, ketoconazole, posaconazole and nefazodone 
o Moderate inhibitors of CYP3A: amprenavir, aprepitant, diltiazem, erythromycin, 
fosamprenavir, grapefruit-containing products (including grapefruit juice), and 
verapamil 
 Systemic treatment with any of the following metabolizing enzyme inducers is not 
permitted in this study: 
o Clinically significant CYP3A inducers: rifampin, rifapentine, rifabutin, 
carbamazepine, oxcarbazepine, primidone, phenytoin, and phenobarbital 
For the most updated information, visit the following website:  
http://medicine.iupui.edu/clinpharm/ddis/. 
 Herbal preparations/medications are not allowed throughout the study.  These herbal 
medications include, but are not limited to: St. John’s wort, kava, ephedra (ma huang), 
gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng.  
Patients should stop using these herbal medications 7 days prior to first dose of study drug. 
The following procedures are prohibited during the study: 
 No anticancer agents should be given to patients.  If such agents are required for a 
patient, then the patient must first be withdrawn from the study.  Adjuvant hormone 
therapy for breast or prostate cancer 
 Radiation therapy (the requirement for local radiation therapy generally indicates disease 
progression). 
 Platelet transfusions to help patients meet eligibility criteria or pre-dose for dosing 
decisions on treatment are not allowed within 3 days before study drug dosing. 
5.4 
Precautions and Restrictions 
Fluid deficits should be corrected before and throughout treatment. 
Nonsteroidal anti-inflammatory drugs (NSAIDs) induced prevalence of nephrotoxicity is 
relatively low; however, given the wide use of these agents many persons are at risk, including 
for example, patients with cardio-renal disease, dehydration, and the aging kidney.  NSAIDs 


 
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STUDY DRUG:  MLN9708 
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should be avoided with impaired renal function given reported NSAID-induced renal failure in 
patients with decreased renal function. 
5.5 
Correlative Studies 
For patients who participate in the exploratory biomarker research component of this study, 
peripheral blood samples will be collected on Days 1 (pre-dose), 4, 8, and 15 of Cycle 1 and Day 
1 (pre-dose) of Cycle 2.  Participating patients will include 3 patients at each dose level and 5 
additional patients at the MTD. 
Immune analysis from the peripheral blood will include: 
 CD3+, CD4+, CD8+, CD45+, CD19+ and CD56+/CD16+ cells by fluorescence-activated 
cell sorting 
 Regulatory T cells by intracellular staining of FoxP3 and surface staining of CD4+ and 
CD25+ cells 
 Inflammatory cytokines including IL-1β, IL-6, IL-8, IL-10 and TNF-α 
Participating sites will process the samples, analyse them, and report data for the flow cytometric 
analysis.  Samples for cytokine analysis will be shipped to a central laboratory for analysis.  For 
shipment, handling, etc. of the correlative testing blood samples blood, see the Study Manual. 
6. 
DOSE MODIFICATIONS 
If toxicity occurs, the toxicity will be graded utilizing the NCI CTCAE v4.0, and appropriate 
supportive care treatment will be administered to decrease the signs and symptoms thereof.  
Dose adjustments will be based on the organ system exhibiting the greatest degree of toxicity. 
Study drug will be delayed if patients develop > Grade 2 GVHD and until GVHD is ≤ Grade 2.  
If GVHD severity returns to ≤ Grade 2, study drug can be restarted at the initial dose.  If GVHD 
recurs, hold dose until GVHD is ≤ Grade 2 and restart at next lower dose level.  GVHD stopping 
criteria during administration of study drug includes the development of Grade 3 or 4 GVHD in 
more 80%, 70%, or 60% of the first 10, 20, or 30 patients enrolled, respectively.  Patients that do 
not complete one cycle of maintenance because of GVHD will be replaced.  Criteria for GVHD 
are presented in Appendix F. 
6.1 
Dose Modifications Due to Hematologic Toxicity 
Dose reductions or holds and initiation of supportive care are allowed as clinically indicated by 
the treating physician.  Patients whose treatment is delayed due to toxicity will discontinue study 
drug or will proceed with the next cycle of treatment when toxicity has improved (as long as the 
toxicity resolves within 3 weeks) according to the dose modifications below.  Treatment with 
MLN9708 will be held in any patient experiencing a DLT as described in Section 5.1.2 at any 
time during the study.  Patients who experience a DLT in the first cycle of therapy will be 
discontinued from treatment with MLN9708.  Dose modifications following treatment-related 
toxicity in subsequent cycleswill be according to the dose modifications below. 
Dose reductions for toxicity will be allowed.  For patients in the first cohort, MLN9708 may be 
delayed, but not reduced.  For patients in Cohorts 2 and 3, doses will first be delayed and then 


 
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STUDY DRUG:  MLN9708 
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reductions will be allowed based on clinical judgment of the treatment physician (see Figure 1).  
If persistent toxicity occurs despite dose delays and/or reductions, the patient will be removed 
from the study. 
Any patients who require a treatment delay of more than 3 weeks due to treatment-related 
toxicity will be discontinued from study treatment, unless the treating physician and the Study 
Chair agree that continued treatment at lower doses is in the best interest of the patient. 
6.1.1 
Recommended MLN9708 Criteria for Beginning or Delaying a Subsequent 
Treatment Cycle & Dose Modifications for Treatment Associated Toxicity on 
Day 1 of a New Cycle 
Treatment with MLN9708 will use a cycle length of 28 days. For a new cycle of treatment to 
begin, the patient must meet the following criteria: 
 ANC must be ≥ 1,000/mm3. 
 Platelet count must be ≥ 40,000/mm3. 
 All other nonhematologic toxicity (except for alopecia) must have resolved to ≤ Grade 1 
or to the patient’s baseline condition 
If the patient fails to meet the above-cited criteria for initiation of the next cycle of treatment, 
dosing should be delayed for 1 week. At the end of that time, the patient should be re-evaluated 
to determine whether the criteria have been met. If the patient continues to fail to meet the 
above-cited criteria, delay therapy and continue to reevaluate. The maximum delay before 
treatment should be discontinued will be 3 weeks or at the discretion of the Principal 
Investigator. 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
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Table 4 
Dose Modifications Due to Hematologic Toxicities within a Treatment Cycle 
(Day 8 and Day 15 of a Treatment Cycle) 
Event 
Actiond 
Neutropenia (ANC) 
 
ANC <0.5 x 109/L (Grade 4) or 
febrile neutropenia 
Hold dose until recovery to ≤ Grade 2 [ANC 1.0 x 
109/L], then resume MLN9708 at one lower dose 
levela (if applicableb).  Note: If resolved in ≤5 days, 
then resume without a dose reduction. 
Recurrence of  
ANC <0.5 x 109/L (Grade 4) or 
febrile neutropenia 
Holda dose until ANC recovery to ≤ Grade 2 [ANC 
1.0 x 109/L], then resume MLN9708 at one lower 
dose levela (if applicableb). 
Thrombocytopenia 
 
Platelets <30 x 109/L 
 
 
Hold dose until improvement to platelets 30 x 109/L  
 
 If resolved in ≤5 days, then resume without a 
dose reductionc. 
 
 If resolved in >5 days but <3 weeks, then resume 
dose at one lower dose levelc (if applicableb). 
 
a Hold MLN9708 treatment; do at least weekly CBC with differential until toxicity resolves (ANC recovery 1.0 x 109/L and 
platelets 30 x 109/L). 
b Patients on 2.3 mg of MLN9708 will not undergo a dose reduction.  
c Re-treatment criteria = ANC recovery 1.0 x 109/L and platelets 30 x 109/L. 
d Any patient who requires a treatment delay of more than 3 weeks due to treatment-related toxicity will be discontinued from 
study treatment, unless the treating Investigator and Study Chair agree that continued treatment at lower doses is in the best 
interest of the patient.ANC = absolute neutrophil count, CBC = complete blood count. 
 
6.2 
Dose Modifications due to Non-Hematologic Toxicity 
The dose reduction guidelines for non-hematologic toxicities are presented in Table 5. 
 
Table 5 
Dose Reductions for Grade 3 or 4 Non-Hematologic Toxicities 
Criteria 
Action 
Peripheral Neuropathy: 
Newly developed Grade 1 peripheral 
neuropathy with pain, 
≥ Grade 2 peripheral neuropathy 
Hold MLN9708 until resolution to ≤ Grade ≤ 1 
without pain or baseline 
Grade 2 neuropathy with pain or 
Grade 3 peripheral neuropathy 
Hold MLN9708 until resolution to Grade ≤ 1 
without pain or baseline. 
Reduce MLN9708 to next lower dose (if 
applicable*) upon recovery. 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
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Criteria 
Action 
Grade 4 peripheral neuropathy 
Discontinue MLN9708. 
Grade 2 rash and/or pruritis 
Follow at least weekly. See Section 6.3.4 Specific 
Recommendations for Management of Clinical 
Events 
Grade 3 Non-Hematologic 
Toxicities or recurrent Grade 3 
Non-Hematologic Toxicities that do 
not recover to Grade ˂ 1 or baseline 
within 4 weeks 
MLN9708 therapy should be withheld until 
symptoms have resolved to ≤ Grade 1 or baseline.  
Reduce MLN9708 to next lower dose (if 
applicable*) upon recovery.  Note:  a dose level 
reduction will be made either on the basis of 
within-cycle or for a subsequent cycle criteria, but 
not for both from the same cycle. 
Grade 4 Non-Hematologic 
Toxicities 
Discontinue MLN9708.  Upon toxicity recovery, if 
the patient has received clinical benefit from 
therapy with MLN9708, the Investigator and the 
Study Chair may consider restarting therapy. 
*Patients on 2.3 mg of MLN9708 will not undergo a dose reduction. 
6.3 
Specific Recommendations for Management of Clinical Events 
Adverse drug reactions such as thrombocytopenia, diarrhea, fatigue, nausea, vomiting, and rash 
have been associated with MLN9708 treatment. Management guidelines regarding these events 
are outlined below. Further details of management of MLN9708 AEs are described in Section 6 
of the MLN9708 IB. 
6.3.1 
Prophylaxis against Risk of Infection 
Antiviral therapy such as acyclovir or valacyclovir may be initiated as clinically indicated and 
per institutional standards.  Other antivirals are also acceptable.  Patients who do not receive 
antiviral therapy should be made aware of risks, such as reactivation of herpes zoster and herpes 
simplex viruses. 
6.3.2 
Nausea and/or Vomiting 
Standard anti-emetics including 5-hydroxytryptamine 3 serotonin receptor antagonists are 
recommended for emesis if it occurs once treatment is initiated based on the patient’s 
susceptibility to nausea and vomiting; prophylactic anti-emetics may also be considered at the 
discretion of the investigator.  Fluid deficit should be corrected before initiation of study drug 
and during treatment. 
6.3.3 
Diarrhea 
Prophylactic antidiarrheals will not be used in this protocol.  However, diarrhea should be 
managed according to clinical practice, including the administration of antidiarrheals once 
infectious causes are excluded.  Fluid intake should be maintained to avoid dehydration.  Fluid 
deficit should be corrected before initiation of treatment and during treatment. 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
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6.3.4 
Erythematous Rash With or Without Pruritus 
Rash has been reported with MLN9708.  As with bortezomib, rash with or without pruritus has 
been reported with MLN9708, primarily at the higher doses tested.  The rash may range from 
some erythematous areas, macular and/or small papular bumps that may or may not be pruritic 
over a few areas of the body, to a more generalized eruption that is predominately on the trunk or 
extremities.  Rash has been most commonly characterized as maculopapular or macular.  To 
date, when it does occur, rash is most commonly reported within the first 3 cycles of therapy.  
The rash is often transient, self-limiting, and is typically Grade 1 to 2 in severity.   
Symptomatic measures such as antihistamines or corticosteroids (oral or topical) have been 
successfully used to manage rash and have been used prophylactically in subsequent cycles.  The 
use of a topical, IV, or oral steroid (10mg of prednisone/day) is permitted.  Management of a 
Grade 3 rash may require intravenous antihistamines or corticosteroids.  Administration of 
MLN9708 (and/or other causative agent if given in combination) should be modified per 
protocol and re-initiated at a reduced level from where rash was noted (also, per protocol). 
In line with clinical practice, dermatology consult and biopsy of Grade 3 or higher rash or any 
SAE involving rash is recommended.  Prophylactic measures should also be considered if a 
patient has previously developed a rash (eg, using a thick, alcohol-free emollient cream on dry 
areas of the body or oral or topical antihistamines).  .  In the event of rash, a skin biopsy is 
suggested to assess etiology. 
A rare risk is Stevens-Johnson syndrome, a severe, life-threatening or deadly rash with skin 
peeling and mouth sores, which should be managed symptomatically according to standard 
medical practice.  In the case of rash, punch biopsies for histopathological analysis are 
encouraged at the discretion of the Investigator. 
6.3.5 
Thrombocytopenia 
Thrombocytopenia has been reported with MLN9708.  Blood counts should be monitored 
regularly as outlined in the protocol with additional testing obtained according to standard 
clinical practice.  Thrombocytopenia may be severe but has been manageable with platelet 
transfusions according to standard clinical practice.  MLN9708 administration should be 
modified as noted as per dose modification recommendations in the protocol when 
thrombocytopenia occurs (see Table 4).  Therapy can be reinitiated at a reduced level upon 
recovery of platelet counts.  A rare risk is thrombotic thrombocytopenic purpura, a rare blood 
disorder where blood clots form in small blood vessels throughout the body characterized by 
thrombocytopenia, petechiae, fever, or possibly more serious signs and symptoms.  Thrombotic 
thrombocytopenic purpura should be managed symptomatically according to standard medical 
practice. 
6.3.6 
Neutropenia 
Neutropenia has been reported with MLN9708.  Blood counts should be monitored regularly as 
outlined in the protocol with additional testing obtained according to standard clinical practice.  
Neutropenia may be severe but has been manageable with G‑CSF according to standard clinical 
practice.  MLN9708 administration should be modified as noted as per dose modification 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
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recommendations in the protocol when neutropenia occurs (see Table 4).  Therapy can be 
reinitiated at a reduced level upon recovery of ANCs. 
6.3.7 
Fluid Deficit 
Dehydration should be avoided since MLN9708 may cause vomiting, diarrhea, and dehydration.  
Acute renal failure has been reported in patients treated with MLN9708, commonly in the setting 
of the previously noted gastrointestinal toxicities and dehydration..  Fluid deficit should be 
corrected before initiation of study drug and during treatment.   
6.3.8 
Hypotension 
Symptomatic hypotension and orthostatic hypotension have been reported with MLN9708.  
Blood pressure should be closely monitored while the patient is on study treatment and fluid 
deficit should be corrected as needed, especially in the setting of concomitant symptoms such as 
nausea, vomiting, diarrhea, or anorexia.  Patients taking medications and/or diuretics to manage 
their blood pressure (for either hypotension or hypertension) should be managed according to 
standard clinical practice, including considerations for dose adjustments of their concomitant 
medications during the course of the study.  Fluid deficit should be corrected before initiation of 
study drug and during treatment to avoid dehydration. 
6.3.9 
Posterior Reversible Encephalopathy Syndrome 
One case of posterior reversible encephalopathy syndrome, which ultimately resolved, has been 
reported with MLN9708.  This condition is characterized by headache, seizures and visual loss, 
as well as abrupt increase in blood pressure.  Diagnosis may be confirmed by magnetic 
resonance imaging (MRI).  If the syndrome is diagnosed or suspected, symptom-directed 
treatment should be maintained until the condition is reversed by control of hypertension or other 
instigating factors. 
6.3.10 
Transverse Myelitis 
Transverse myelitis has also been reported with MLN9708. It is not known if MLN9708 causes 
transverse myelitis; however, because it happened to a patient receiving MLN9708, the 
possibility that MLN9708 may have contributed to transverse myelitis cannot be excluded. 
7. 
STUDY ASSESSMENTS AND EVALUATIONS 
7.1 
Overview 
All patients should visit the study center on the days specified within this protocol.  The 
complete Schedule of Assessments for this study is shown in Appendix D. 
Informed consent must be obtained ≤28 days prior to initiation of treatment and before any 
protocol-specific procedures are performed.  The Baseline visit physical examination including 
vital signs, medical history, ECOG performance status, complete blood counts (CBC), 
differential and platelets, comprehensive metabolic profile (CMP), urinalysis, and PT/aPTT/INR 
should be done ≤7 days prior to initiation of treatment.  However, if these initial examinations 
are obtained within 72 hours of first study drug administration they do not have to be repeated on 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
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Day 1 of Cycle 1.  A pregnancy test must be performed within 72 hours of first study drug 
administration. 
7.2 
Baseline Study Assessments 
The following information will be collected and procedures will be performed for each patient at 
Baseline ≤7 days prior to initiation of treatment unless otherwise noted: 
 Written informed consent prior to any other study-related procedures (≤28 days of first 
study drug treatment) 
 Medical history including: 
- Review of systems 
- Prior treatments for all significant conditions, including neuropathy 
- ECOG performance status prior to conditioning for allogeneic transplant 
- Pre allogeneic transplant overall comorbidity index 
- Transplant history including 
 Conditioning regimens including total dose and start and end dates 
 Type of transplant (syngeneic, autologous or allogeneic; bone marrow 
versus peripheral blood stem cells; match related versus matched 
unrelated) 
 Date of transplant 
 Date of engraftment of white cells and platelets 
 Number of allogeneic CD34+ cells received (record for allogeneic 
transplant only) 
 Graft versus host disease prophylaxis 
 Post-transplant infections 
- Prior systemic therapy for multiple myeloma with start and end dates and best 
overall response to therapy 
- Prior radiation therapy for multiple myeloma with total dose, start and end dates 
- Prior surgeries for multiple myeloma and date 
 Physical examination, including a neurological evaluation, measurements of height (first 
visit), weight, and vital signs (resting heart rate, blood pressure [BP], respiratory rate, and 
oral temperature) 
 ECOG performance status (see Appendix A) 
 Acute GVHD assessment with overall grade (see Appendix F) 
 Chronic GVHD assessment with overall grade (see Appendix F) 
 12-lead ECGs in triplicate approximately 5 minutes apart 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
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 Chest X-ray 
 Concomitant medication review of all medications taken within 21 days of first planned 
study drug administration for conditions other than GVHD 
 Concomitant medication review specifically for GVHD prophylaxis since receiving the 
allogeneic transplant 
 CBC, including 3-part differential (total neutrophil count including bands, lymphocytes, 
monocytes) hemoglobin, hematocrit, and platelets 
 CMP to include: glucose, blood urea nitrogen (BUN), creatinine (creatinine clearance 
calculated by Cockcroft-Gault), sodium, potassium, chloride, calcium, phosphorus, 
magnesium, carbon dioxide (CO2), ALT, AST, ALP, lactate dehydrogenase (LDH), uric 
acid, total bilirubin, total protein, and albumin 
 Urinalysis (dipstick) 
 Coagulation tests:  prothrombin time (PT), activated partial thromboplastin time (aPTT), 
and International Normalized Ratio (INR) 
 Serum or urine pregnancy test for women of childbearing status (must be performed 
within 72 hours prior to the initiation of treatment) 
 Disease assessments: 
- Bone marrow aspirate and biopsy including: 
 Quantify percent myeloma cell involvement 
 Obtain bone marrow aspirate for cytogenetics [i.e., diploidy, del(13)] and 
include number of metaphases analyzed 
 Mutations detected in fluorescent in situ hybridization (FISH) studies [i.e., 
t(4:14); t(11:14); del(17p)] 
 If available, provide MRD by flow cytometry 
- Skeletal survey (lateral radiograph of the skull, anteroposterior and lateral views 
of the spine, and anteroposterior views of the pelvis, ribs, femora, and humeri) 
≤28 days of first study drug treatment. 
- Serum free light chains (SFLC) 
- Serum protein electrophoresis (SPEP) and serum protein immunofixation to 
determine M-protein 
- Urine protein electrophoresis (UPEP), urine protein immunofixation (requires a 
24-hour urine collection), and total protein in urine 
- Serum quantitative immunoglobulins 
- Serum β2 microglobulin 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
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- Known plasmacytomas, utilize same modality used to assess original disease (i.e., 
PET, MRI, CT, etc) 
 Gene expression profile analysis, if available (prior to bone marrow transplant and prior 
to enrolment) 
7.3 
Study Treatment Assessments 
7.3.1 
All Cycles Day 1 (± 2 days) 
 Medical history update 
 Physical examination including a neurological evaluation, measurement of weight, and 
vital signs 
 ECOG performance status 
 Acute GVHD assessment with overall score 
 Chronic GVHD assessment with overall score 
 AE assessment 
 Concomitant medication review of all medications taken for conditions other than GVHD 
 Concomitant medication review specifically for GVHD prophylaxis since receiving the 
allogeneic transplant 
 Percentage chimerism conducted per institutional guidelines 
 CBC including 3-part differential (total neutrophil count including bands, lymphocytes, 
monocytes) hemoglobin, hematocrit, and platelets 
 CMP to include: glucose, BUN, creatinine (creatinine clearance calculated by Cockcroft-
Gault), sodium, potassium, chloride, calcium, phosphorus, magnesium, CO2, ALT, AST, 
ALP, LDH, uric acid, total bilirubin, total protein, and albumin 
 Urinalysis (dipstick; if abnormal microscopic performed as clinically indicated) 
 PT/aPTT/INR 
 Biomarker blood sample collection for flow cytometry (conducted and reported by 
participating sites) and cytokine analysis (conducted by a central laboratory) (Cycles 1 
and 2 only for patients participating in the exploratory biomarker research) 
7.3.2 
Cycle 1 Days 4, 8, and 15 
 Physical examination (symptom directed) (Days 8 and 15 only) 
 AE assessment (Days 4, 8, and 15) 
 Concomitant medication review of all medications taken for conditions other than GVHD 
(Days 4, 8 and 15) 
 Concomitant medication review specifically for GVHD prophylaxis since receiving the 
allogeneic transplant (Days 4, 8 and 15) 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
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 Acute GVHD assessment with overall score, only for patients who have onset of GVHD 
post allogeneic transplant (Days 8 and 15 only) 
 Chronic GVHD assessment with overall score, only for patients who have onset of 
GVHD post allogeneic transplant (Days 8 and 15 only) 
 CBC, including 3-part differential (total neutrophil count including bands, lymphocytes, 
monocytes) hemoglobin, hematocrit, and platelets (Days 8 and 15 only) 
 CMP to include: glucose, BUN, creatinine (creatinine clearance calculated by Cockcroft-
Gault), sodium, potassium, chloride, calcium, phosphorus, magnesium, CO2, ALT, AST, 
ALP, LDH, uric acid, total bilirubin, total protein, and albumin (Days 8 and 15 only) 
 Urinalysis (dipstick; if abnormal microscopic performed as clinically indicated) (Days 8 
and 15 only) 
 Biomarker blood sample collection for flow cytometry (conducted and reported by 
participating sites) and cytokine analysis (conducted by a central laboratory) (Days 4, 8 
and 15 for patients participating in the exploratory research) 
7.3.3 
Cycles 2 through 6 Days 8 and 15 
 AE assessment 
 Concomitant medication review of all medications taken for conditions other than GVHD 
 Concomitant medication review specifically for GVHD prophylaxis since receiving the 
allogeneic transplant 
 Acute GVHD assessment with overall score, only for patients who have onset of GVHD 
post allogeneic transplant 
 Chronic GVHD assessment with overall score, only for patients who have onset of 
GVHD post allogeneic transplant 
 CBC, including 3-part differential (total neutrophil count including bands, lymphocytes, 
monocytes) hemoglobin, hematocrit, and platelets 
7.4 
Response Assessments 
Patients will be re-evaluated for response to treatment after 2 cycles of treatment.  Response will 
be assessed at 8-week intervals (±1 week) during study treatment.  Patients with progressive 
disease (PD) or unacceptable toxicity should be discontinued from the study; patients with stable 
disease (SD) or response to therapy will continue treatment through 6 cycles. 
The following assessments will be performed as clinically indicated: 
 Bone marrow aspirate and biopsy (to confirm CR only) including: 
- Quantify percent myeloma cell involvement 
- Obtain bone marrow aspirate for cytogenetics [i.e., diploidy, del 13] and include 
number of metaphases analyzed 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
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- Mutations detected in FISH studies [i.e., t(4:14); t(11:14); del 17p] 
- If available, provide MRD by flow cytometry 
 SFLC 
 SPEP and serum protein immunofixation to determine M-protein 
 UPEP, urine protein immunofixation (requires a 24-hour urine collection), and total 
protein in urine 
 Serum quantitative immunoglobulins 
 Known plasmacytomas, utilize same modality used to assess original disease (i.e., PET, 
MRI, CT, etc) 
Above response assessment will be performed every 3 months for 2 years after completion of 
maintenance therapy until disease progression. 
7.5 
End-of-Treatment Visit 
Patients are permitted to continue maintenance treatment with MLN9708 through 6 cycles.  
Patients may be discontinued before the end of 6 cycles due to disease progression, unacceptable 
toxicity, or the decision to discontinue treatment by the patient or the study physician.  After 
withdrawal from or completion of protocol treatment, patients must be followed for any new 
AEs for 30 calendar days after the last dose of study drug. 
Thirty days (±3 days) days after completion of the planned study treatment period or early 
discontinuation, the following tests and observations will be conducted: 
 Update of medical history 
 Physical examination including a neurological evaluation, measurement of weight, and 
vital signs 
 ECOG performance status 
 Acute GVHD assessment with overall score 
 Chronic GVHD assessment with overall score 
 AE assessment 
 Concomitant medication review of all medications taken for conditions other than GVHD 
 Concomitant medication review specifically for GVHD prophylaxis since receiving the 
allogeneic transplant 
 CBC, including 3-part differential (total neutrophil count including bands, lymphocytes, 
monocytes) hemoglobin, hematocrit, and platelets 
 CMP to include: glucose, BUN, creatinine (creatinine clearance calculated by Cockcroft-
Gault), sodium, potassium, chloride, calcium, phosphorus, magnesium, CO2, ALT, AST, 
ALP, LDH, uric acid, total bilirubin, total protein, and albumin 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
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 Urinalysis (dipstick; if abnormal microscopic performed as clinically indicated) 
 Disease assessment: 
- Bone marrow aspirate and biopsy (to confirm CR only) including: 
 Quantify percent myeloma cell involvement 
 Obtain bone marrow aspirate for cytogenetics [i.e., diploidy, del 13] and 
include number of metaphases analyzed 
 Mutations detected in FISH studies [i.e., t(4:14); t(11:14); del 17p] to 
confirm CR 
 If available, provide MRD by flow cytometry 
- SFLC 
- SPEP and serum protein immunofixation to determine M-protein 
- UPEP, urine protein immunofixation (requires a 24-hour urine collection), and 
total protein in urine 
- Serum quantitative immunoglobulins 
- Known plasmacytomas, utilize same modality used to assess original disease (i.e., 
PET, MRI, CT, etc) 
7.6 
Follow-up 
Please see Appendix D. 
8. 
DRUG FORMULATION, AVAILABILITY, ADMINISTRATION, AND 
TOXICITY INFORMATION 
8.1 
MLN9708 
Investigational Product 
Dosage Form and Strength 
Manufacturer 
MLN9708 
2.3, 3.0, and 4.0mg 
Millennium Pharmaceuticals, 
Inc 
 
8.1.1 
Labeling, Packaging, and Supply 
MLN9708 is an anticancer drug and as with other potentially toxic compounds caution should be 
exercised when handling MLN9708 capsules. 
MLN9708 will be supplied for oral administration by Millennium Pharmaceuticals, Inc.  
Capsules will be supplied color-coded by strength and will be individually packaged in blisters 
with a paper backing for child resistance. 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
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The study drug will be labeled and handled as open-label material, and packaging labels will 
fulfill all requirements specified by governing regulations.  The immediate packaging will 
contain a statement to conform with US Food and Drug Administration (FDA) Investigational 
New Drug (IND) requirements as follows: Caution: New Drug - Limited by Federal (or United 
States) law to investigational use. 
All study drugs must be kept in a secure place under appropriate storage conditions.  MLN9708 
capsules should be stored unopened at 2 to 8ºC (36 to 46ºF).  The capsules are individually 
packaged in cold form foil-foil blisters in a child-resistant package.  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. 
The SCRI Innovations must be granted access on reasonable request to check drug storage, 
dispensing procedures, and accountability records. 
8.1.2 
Storage and Handling 
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 protective clothing should be 
worn during cleanup and return of broken capsules and powder to minimize skin contact. 
The area should be ventilated and the site washed with soap and water after material pick-up is 
complete. The material should be disposed of as hazardous medical waste in compliance with 
federal, state, and local regulations. 
In case of contact with the powder (e.g., from a broken capsule), skin should be washed 
immediately with soap and copious amounts of water for at least 15 minutes. In case of contact 
with the eyes, copious amounts of water should be used to flush the eyes for at least 15 minutes. 
Medical personnel should be notified. Patients are to be instructed on proper storage, 
accountability, and administration of MLN9708, including that MLN9708 is to be taken as intact 
capsules. 
8.1.3 
 Study Compliance 
Study drug will be administered or dispensed only to eligible patients under the supervision of 
the investigator or identified sub-investigator(s).  The appropriate study personnel will maintain 
records of study drug receipt and dispensing. 
8.1.4 
Preparation and Administration of MLN9708 
Patients will receive their study medication at the study site.  The batch number of the study drug 
dispensed to the patient should be entered on the eCRF, if applicable. 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
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MLN9708 will be given on an empty stomach, with no food and fluids except for water and 
prescribed medications for 2 hours before and 1 hour after each dose.  Each dose of MLN9708 
will be given with approximately 8 oz (240 mL) of water.  If the patient vomits after taking a 
dose, another dose should not be given that day, but dosing should resume at the time of the next 
scheduled dose. 
8.1.5 
Precautions and Risks Associated with Handling MLN9708 
MLN9708 drug product is a cytotoxic anticancer drug.  As with other potentially toxic 
compounds, caution should be exercised when handling MLN9708.  Please refer to published 
guidelines regarding the proper handling and disposal of cytotoxic agents. 
MLN9708 capsules must be administered as intact capsules and are not intended to be opened or 
manipulated in any way. 
8.1.6 
Potential Risks and Benefits 
Please refer to the current MLN9708 Investigator’s Brochure (IB) and its Safety Management 
Attachment (SMA) provided by Millennium. 
MLN9708 is a modified dipeptide boronic acid proteasome inhibitor similar to b, 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 (Chow et al. 2012, Assouline et al. 2012, Lonial et al. 2012, Kumar et al. 2012 (a), Kumar 
et al. 2012 (b), Richardson et al. 2012 (c), San Miguel et al. 2012). 
8.2 
Accountability for All Study drugs 
The Principal Investigator (or designee) is responsible for accountability of all used and unused 
study drug supplies at the site. 
All study drug inventories must be made available for inspection by the Sponsor or its 
representatives and regulatory agency inspectors upon request. 
At the end of the study, all SCRI Innovations Drug Accountability Record Form(s) will be 
completed by the site and sent to the SCRI Innovations Regulatory Department.  Study drug 
supplies must not be destroyed unless prior approval has been granted by the Sponsor or its 
representative.  Please contact SCRI Innovations regarding disposal of any study drug. 
8.3 
MLN9708 Destruction 
Investigational 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. 


 
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9. 
RESPONSE EVALUATIONS AND MEASUREMENTS 
Response and progression will be evaluated in this study using the International Myeloma 
Working Group Uniform Response Criteria (see Appendix E). 
 
CR 
 
Complete Response 
sCR 
subcategory: stringent complete response 
VGPR  
Very good partial response 
PR 
 
Partial response 
SD 
 
Stable disease 
PD 
 
Progressive disease 
 
All response categories (CR, sCR, VGPR, PR, PD) require two consecutive assessments made at 
any time before the institution of any new therapy, as well as no known evidence of progressive 
or new bone lesions if radiographic studies were performed.  Radiographic studies are not 
required to satisfy these response requirements.  Bone marrow assessments are not required to be 
confirmed by repeat testing. 
Complete response should be confirmed with a bone marrow biopsy for morphology and a bone 
marrow aspiration for flow cytometry, FISH, and cytogenetics performed locally.  Additional 
confirmatory studies include SPEP, UPEP, immunofixation of blood and urine, and SFLC (see 
Appendix D). 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Statistical Design 
This is an open-label, multicenter, non-randomized study to determine the feasibility of 
MLN9708 as maintenance after allogeneic stem cell transplant for multiple myeloma.  Patients 
will be enrolled between Days 45 and 120 after allogeneic transplant and will receive MLN9708 
on Days 1, 8, and 15 of each 28-day cycle for 6 cycles. 
10.2 
Sample Size Considerations 
For the dose-escalation phase of the study, a minimum of 2 and a maximum of 6 patients will be 
enrolled in each of 3 cohorts.  Therefore, the maximum number of patients to determine the 
MTD will be 18.  When the MTD is determined, an additional 20 patients will be enrolled in the 
expansion phase at either the MTD or the MPD. 
10.3 
Analysis Population 
The following analysis populations will be used: 


 
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 The Safety population will consist of all patients who received at least one dose of 
MLN9708.  This population will be used in all safety summaries. 
 The Efficacy Evaluable population will consist of all patients with measurable or 
evaluable disease at baseline who receive at least 1 dose of MLN9708 and undergo at 
least one post-baseline disease assessment. In addition, patients who discontinued the 
study prior to their first post-baseline disease assessment due to death or progressive 
disease will also be included in the Efficacy Evaluable population. 
10.4 
Data Analysis 
Descriptive statistics, including mean, median, standard deviations and ranges for all continuous 
measures will be tabulated and reported.  Percentages and frequencies for all categorical 
measures will also be presented. 
10.4.1 
Demographics and Baseline Characteristics 
Demographic data and baseline disease characteristics will be summarized using descriptive 
statistics. 
10.4.2 
Efficacy Analysis 
 PFS, defined as the time from the first day of study drug administration (Day 1) to 
disease progression as defined by the International Myeloma Working Group Uniform 
Response Criteria (see Appendix E), or death on study.  Patients who are alive and free 
from disease progression will be censored at the date of last tumor assessment. 
 OS, defined as the time from the first day of study drug administration (Day 1) or death 
on study.  Patients who are alive will be censored at the date of last known date alive. 
Progression-free survival and OS (efficacy secondary endpoints) estimates will be generated 
using Kaplan-Meier methods, both for all patients enrolled and those patients receiving the 
MTD.  Two-year PFS and OS estimates with 95% confidence intervals (CIs), and median PFS 
and OS with 95% CIs, will be generated and reported accordingly. 
The effect of MLN9708 on immune effector cells after allogeneic stem cell transplant will be 
analyzed by examining the difference in the actual change from baseline at Cycle 1 Day 4, Cycle 
1 Day 8, Cycle 1 Day 15, and Cycle 2 Day 1, and the percentage change from baseline at Cycle 1 
Day 4, Cycle 1 Day 8, Cycle 1 Day 15, and Cycle 2 Day 1, among those patients participating in 
the biomarker research component. Each analysis will be performed within dose level and total 
patients. 
The following parameters will be examined: 
 CD3+, CD4+, CD8+, CD45+, CD19+ and CD56+/CD16+ cell counts,  
by fluorescence-activated cell sorting 
 Regulatory T cell counts by intracellular staining of FoxP3,  
and surface staining of CD4+ and CD25+ cells 
 Inflammatory cytokine concentrations of IL-1β, IL-6, IL-8, IL-10 and TNF-α. 


 
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For each parameter, the actual change from baseline and the percentage change from baseline, at 
each time point, will be analyzed using the two-sided Wilcoxon signed-rank procedure to test 
whether either the change is statistically different from zero.  
The significance level will be set at 10%, and there will be no adjustment to the alpha level for 
multiple comparisons. The rationale for the reporting of p-values in these analyses is for 
hypothesis-generating purposes only. 
10.4.3 
Safety Analysis 
Safety will be assessed through the analysis of the reported incidence of treatment-emergent 
AEs.  Treatment-emergent AEs are those with an onset on or after the initiation of therapy, and 
will be graded according to NCI CTCAE v4.0. 
The AEs will be coded using Medical Dictionary for Regulatory Activities, and summarized 
using system organ class and preferred term by dose level for all patients in the Safety 
Population.  In addition, summaries of serious AEs (SAEs), AEs leading to treatment 
discontinuation, AEs by maximum NCI CTCAE grade, and AEs related to study treatment will 
also be presented by dose level. 
Safety of MLN9708 when used in this indication (primary endpoint) will be evaluated as 
follows: Toxicity profile data will include AEs, laboratory parameters, vital signs, and other 
protocol-specified tests that are deemed critical to the safety evaluation.  Safety data will be 
tabulated for all patients who receive any amount of study medication.  Adverse events will be 
tabulated by system organ class, preferred term, severity, and relation to treatment.  The 
tabulation of laboratory parameters will indicate the normal range of each parameter.  Each 
analyte value will be classified as falling above, below, or within the normal range. 
Incidence of GVHD (safety secondary endpoint) will reported in a manner consistent with the 
AE reporting previously described. 
10.4.4 
Planned Interim Analysis 
Data will be reviewed by the Investigator and Study Chair before advancing to the next cohort, 
but formal interim analyses will not be performed. 
11. 
SAFETY REPORTING AND ANALYSES 
Safety assessments will consist of monitoring and recording protocol-defined AEs and SAEs, 
measurement of protocol-specified hematology, clinical chemistry, and urinalysis variables, 
measurement of protocol-specified vital signs, and other protocol-specified tests that are deemed 
critical to the safety evaluation of the study drug. 
The Principal Investigator is responsible for recognizing and reporting AEs to the SCRI 
Innovations Safety Department (see Section 11.1.7).  It is the Sponsor’s responsibility to report 
relevant SAEs to the applicable local, national, or international regulatory bodies.  In addition, 
Investigators must report SAEs and follow-up information to their responsible IRB according to 
the policies of that IRB. 


 
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The Principal Investigator is also responsible for ensuring that every staff member involved in 
the study is familiar with the content of this section. 
11.1 
Definitions 
11.1.1 
Pretreatment Event Definition 
A pretreatment event is any untoward medical occurrence in a patient or subject who has signed 
informed consent to participate in a study but before administration of any study medication; it 
does not necessarily have to have a causal relationship with study participation. 
11.1.2 
Adverse Events 
Adverse event means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  An AE (also known as adverse experience) can 
be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or 
disease temporarily associated with the use of a drug, without any judgement about causality.  
This includes any newly occurring event, or a previous condition that has increased in severity or 
frequency since the administration of study drug.  An AE can arise with any use of the drug (e.g., 
off-label use, use in combination with another drug) and with any route of administration, 
formulation, dose or including overdose. 
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline. 
11.1.3 
Serious Adverse Event 
An AE or a suspected adverse reaction is considered “serious” if it results in any of the 
following outcomes: 
 Death 
 A life-threatening AE (refers to an AE in which the patient was at risk of death at 
the time of the event.  It does not refer to an event which hypothetically might have 
caused death if it were more severe) 
 Inpatient hospitalization of at least 24-hours or prolongation of existing 
hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
 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 
one of the outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in hospitalization, or development of drug dependency or drug 


 
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abuse; any organism, virus, or infectious particle (eg, prion protein transmitting Transmissible 
Spongiform Encephalopathy), pathogenic or nonpathogenic, is considered an infectious agent.   
It is important to distinguish between “serious” and “severe” AE, as the terms are not 
synonymous.  Severity is a measure of intensity; however, an AE of severe intensity need not 
necessarily be considered serious.  Seriousness serves as the guide for defining regulatory 
reporting obligations.  “Serious” is a regulatory definition and is based on patient/event outcome 
or action usually associated with events that pose a threat to a patient’s life or vital functions.  
For example, nausea which persists for several hours may be considered severe nausea, but may 
not be considered an SAE.  On the other hand, a stroke which results in only a limited degree of 
disability may be considered only a mild stroke, but would be considered an SAE.  Severity and 
seriousness should be independently assessed when recording AEs on the eCRF and SAEs on the 
SAE Report Form. 
11.1.4 
Adverse Event of Special Interest Definition 
Adverse Events of Special Interest (AESIs) are a subset of AEs that are to be reported to 
Millennium on a quarterly basis by the sponsor-investigator. Millennium will provide the current 
list of AESIs and updates to the list will be distributed to the sponsor-investigator as appropriate. 
11.1.5 
Adverse Reaction 
An adverse reaction means any AE caused by a drug.  Adverse reactions are a subset of all 
suspected adverse reactions where there is a reason to conclude that the drug caused the event. 
11.1.6 
Suspected Adverse Reaction 
Suspected adverse reaction means any AE for which there is a reasonable possibility that the 
drug caused the AE.  Reasonable possibility means that there is evidence to suggest a causal 
relationship between the drug and the AE.  A suspected adverse reaction implies a lesser degree 
of certainty about causality than adverse reaction, which means any adverse event caused by a 
drug. 
11.1.7 
Recording and Reporting of Adverse Events 
Recording of Adverse Events 
All AEs of any patient during the course of the research study will be recorded in the eCRF, and 
the Investigator will give his or her opinion as to the relationship of the AE to the study drug 
treatment (i.e., whether the event is related or unrelated to study drug administration). 
All AEs should be documented.  A description of the event, including its date of onset and 
resolution, whether it constitutes an SAE or not, any action taken (e.g., changes to study 
treatment), and outcome, should be provided, along with the Investigator’s assessment of 
causality (i.e., the relationship to the study treatment[s]).  For an AE to be a suspected treatment-
related event there should be at least a reasonable possibility of a causal relationship between the 
protocol treatment and the AE.  Adverse events will be graded according to the NCI CTCAE 
v4.0, and changes will be documented. 
If the AE is serious, it should be reported immediately to SCRI Innovations Safety Department.  
Other untoward events occurring in the framework of a clinical study are to be recorded as AEs 


 
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(i.e., AEs that occur prior to assignment of study treatment that are related to a protocol-
mandated intervention, including invasive procedures such as biopsies, medication washout, or 
no treatment run-in). 
Any clinically significant signs and symptoms; abnormal test findings; changes in physical 
examination; hypersensitivity; and other measurements that occur will be reported as an AE, and 
collected on the relevant eCRF screen. 
Test findings will be reported as an AE if: the test result requires an adjustment in the study 
drug(s) or discontinuation of treatment, and/ or test findings require additional testing or surgical 
intervention, a test result or finding is associated with accompanying symptoms, or a test result is 
considered to be an AE by the Investigator. 
Reporting Period for Adverse Events 
All AEs regardless of seriousness or relationship to MLN9708 treatment (called study 
treatment), spanning from the start of study treatment, until 30 calendar days after 
discontinuation or completion of study treatment as defined by the clinical study for that patient, 
are to be recorded on the corresponding screen(s) included in the eCRF. 
All AEs resulting in discontinuation from the study should be followed until resolution or 
stabilization.  All new AEs occurring during this period must be reported and followed until 
resolution unless, in the opinion of the Investigator, the AE or laboratory abnormality/ies are not 
likely to improve because of the underlying disease.  In this case, the Investigators must record 
his or her reasoning for this decision in the patient’s medical record and as a comment on the 
eCRF screen. 
After 30 days of completion of protocol-specific treatment or discontinuation, only AEs, SAEs, 
or deaths assessed by the Investigator as treatment related are to be reported. 
11.1.8 
Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the patient, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means will be 
reported appropriately.  Each reported AE or SAE will be described by its duration (i.e., start and 
end dates), regulatory seriousness criteria if applicable, suspected relationship to the study drug 
(see following guidance), and actions taken.  For serious pretreatment events, the investigator 
must determine both the intensity of the event and the relationship of the event to study 
procedures. 
To ensure consistency of AE and SAE causality assessments, Investigators should apply the 
following general guideline: 
YES:  There is a plausible temporal relationship between the onset of the AE and 
administration of the study medication, and the AE cannot be readily explained by the 
patient’s clinical state, intercurrent illness, or concomitant therapies, and/or the AE 
follows a known pattern of response to the study drug, and/or the AE abates or resolves 
upon discontinuation of the study drug or dose reduction and, if applicable, reappears 
upon re-challenge. 


 
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NO:  Evidence exists that the AE has an etiology other than the study drug (e.g., pre-
existing medical condition, underlying disease, intercurrent illness, or concomitant 
medication), and/or the AE has no plausible temporal relationship to study drug 
administration (e.g., cancer diagnosed 2 days after first dose of study drug). 
11.2 
Serious Adverse Event Reporting by Investigators 
Adverse events classified by the treating Investigator as serious require expeditious handling and 
reporting to SCRI Innovations Safety Department in order to comply with regulatory 
requirements.  Determination of life-threatening or serious is based on the opinion of either the 
Sponsor or the Investigator. 
Serious AEs may occur at any time from the start of study treatment through 30 days after the 
last dose of study drug.  The SCRI Innovations Safety Department must be notified of all 
SAEs, regardless of causality, within 24 hours of the first knowledge of the event by the 
treating physician or research personnel. 
To report a SAE, the SAE Report Form should be completed with the necessary information. 
The SAE report should be sent to SCRI Innovations Safety Department via fax or e-mail using 
the using the following contact information (during both business and non-business hours): 
SCRI Innovations Safety Department 
Safety Dept. Fax #:      1-866-807-4325 
Safety Dept. Email:     CANN.SAE@ scri-innovations.com 
Transmission of the SAE report should be confirmed by the site personnel submitting the report. 
Follow-up information for SAEs and information on non-serious AEs that become serious should 
also be reported to SCRI Innovations Safety Department as soon as it is available; these reports 
should be submitted using the SCRI Innovations SAE Report Form. 
Investigators must report SAEs and follow-up information to their responsible IRB according to 
the policies of the responsible IRB. 
11.3 
Recording of Adverse Events and Serious Adverse Events 
11.3.1 
Diagnosis versus Signs and Symptoms 
All AEs should be recorded individually in the patient’s own words (verbatim) unless, in the 
opinion of the Investigator or designated physician, the AEs constitute components of a 
recognized condition, disease, or syndrome.  In the latter case, the condition, disease, or 
syndrome should be named rather than each individual sign or symptom.  If a constellation of 
signs and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at 
the time of reporting, each individual event should be recorded as an AE or SAE as appropriate 
on the relevant form(s) (SAE Report Form and/or AE eCRF screen).  If a diagnosis is 
subsequently established, it should be reported as follow-up information is available.  If a 
diagnosis is determined subsequent to the reporting of the constellation of symptoms, the 
signs/symptoms should be updated to reflect the diagnosis. 


 
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Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors), should not be reported as an 
SAE. 
11.3.2 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient evaluation 
time points.  Such events should only be recorded once on the SAE Report Form and/or the AE 
eCRF screen.  If a persistent AE becomes more severe or lessens in severity, it should be 
recorded on a separate SAE Report Form and/or AE eCRF screen. 
A recurrent AE is one that occurs and resolves between patient evaluation time points, and 
subsequently recurs.  All recurrent AEs should be recorded on an SAE Report Form and/or AE 
eCRF screen. 
11.3.3 
Abnormal Laboratory Values 
If an abnormal laboratory value or vital sign is associated with clinical signs and/or symptoms, 
the sign or symptom should be reported as an AE or SAE, and the associated laboratory value or 
vital sign should be considered additional information that must be collected on the relevant 
eCRF screen.  If the laboratory abnormality is a sign of a disease or syndrome, only the diagnosis 
needs to be recorded on the SAE Report Form or AE eCRF screen. 
Abnormal laboratory values will be reported as an AE if: the laboratory result requires an 
adjustment in the study drug(s) or discontinuation of treatment, and/ or laboratory findings 
require additional testing or surgical intervention, a laboratory result or finding is associated with 
accompanying symptoms, or a laboratory result is considered to be an AE by the Investigator. 
11.3.4 
Deaths 
Deaths that occur during the protocol-specified AE reporting period that are attributed by the 
Investigator solely to progression of disease will be recorded on the “Study Discontinuation” 
eCRF screen.  All other on study deaths, regardless of attribution, will be recorded on an SAE 
Report Form and expeditiously reported to the SCRI Innovations Safety Department. 
When recording a SAE with an outcome of death, the event or condition that caused or 
contributed to the fatal outcome should be recorded as the single medical concept on the SAE 
Report Form and Adverse Event screen of the eCRF.  If the cause of death is unknown and 
cannot be ascertained at the time of reporting, record “Death NOS” on the eCRF Adverse Event 
screen.  During post-study survival follow-up, deaths attributed to progression of disease will be 
recorded only on the “After Progressive Disease Follow-Up” eCRF screen. 
11.3.5 
Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization of >24 hours or prolongation of pre-existing 
hospitalization should be documented and reported as an SAE unless specifically instructed 
otherwise in this protocol.  There are some hospitalizations that do not require reporting as an 
SAE. 


 
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Treatment within or admission to the following facilities is not considered to meet the criteria of 
“inpatient hospitalization” (although if any other SAE criteria are met, the event must still be 
treated as an SAE and immediately reported): 
 Emergency Department or Emergency Room 
 Outpatient or same-day surgery units 
 Observation or short-stay unit 
 Rehabilitation facility 
 Hospice or skilled nursing facility 
 Nursing homes, Custodial care or Respite care facility 
Hospitalization during the study for a pre-planned surgical or medical procedure (one which was 
planned prior to entry in the study), does not require reporting as a SAE to the SCRI Innovations 
Safety Department. 
11.3.6 
Pre-Existing Medical Conditions 
A pre-existing medical condition is one that is present at the start of the study.  Such conditions 
should be recorded on the General Medical History eCRF screen.  A pre-existing medical 
condition should be recorded as an AE or SAE only if the frequency, severity, or character of the 
condition worsens during the study.  When recording such events on an SAE Report Form and/or 
AE eCRF screen, it is important to convey the concept that the pre-existing condition has 
changed by including applicable descriptors. 
11.3.7 
New Cancers 
The development of a new primary cancer should be regarded as an AE and will generally meet 
at least one of the seriousness criteria (see Section 11.1.3).  New primary cancers are those that 
are not the primary reason for the administration of the study treatment and have developed after 
the inclusion of the patient into the study.  They do not include metastases of the original cancer.  
Symptoms of metastasis or the metastasis itself should not be reported as an AE/SAE, as they are 
considered to be disease progression. 
11.3.8 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies 
If a patient becomes pregnant while enrolled in the study, a Pregnancy Form should be 
completed and faxed to the SCRI Innovations Safety Department.  SCRI Innovations Safety 
Department should be notified expeditiously, irrespective of whether or not it meets the criteria 
for expedited reporting.  Abortions (spontaneous, accidental, or therapeutic) must also be 
reported to SCRI Innovations Safety Department. 
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, this must be reported to the SCRI Innovations Safety Department immediately.  Every 
effort should be made to follow the pregnancy for the final pregnancy outcome. 
Congenital anomalies/birth defects always meet SAE criteria, and should therefore be 
expeditiously reported as an SAE, using the previously described process for SAE reporting.  A 


 
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Pregnancy Form should also have been previously completed, and will need to be updated to 
reflect the outcome of the pregnancy. 
11.3.9 
MLN9708 Overdose 
Symptomatic and non-symptomatic overdose must be reported in the eCRF.  Any accidental or 
intentional overdose with the study treatment that is symptomatic, even if not fulfilling a 
seriousness criterion, is to be reported to the SCRI Innovations Safety Department no greater 
than 24 hours from first knowledge of the event using the corresponding screens in the eCRF and 
following the same process described for SAE reporting (see Section 11.2) if the overdose is 
symptomatic. 
Five cases of overdose are described in the IB.  No significant information was identified 
concerning MLN9708 overdose.  The AEs reported with these cases were the same type as seen 
in the population receiving the appropriately prescribed dose. 
11.4 
Sponsor Serious Adverse Event Reporting Requirements 
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, SCRI Innovations Safety Department on behalf of 
the sponsor-investigator, is responsible for reporting serious adverse events (SAEs) to any 
regulatory agency and to the sponsor- investigator’s EC or IRB.    
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. 
SCRI Innovations Safety Department will forward SAE information to Millennium 
Pharmaceuticals, Inc., within 1 business day of SCRI Innovations Safety Department personnel 
becoming aware of the SAE. 


 
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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 
 
SCRI Innovations is responsible for reporting relevant SAEs to the competent authority, other 
applicable regulatory authorities, and participating Investigators, in accordance with 
International Conference on Harmonisation guidelines and FDA regulations. 
11.4.1 
Procedures for Reporting AESIs 
AEs may be spontaneously reported by the patient and/or in response to an open question from 
study personnel or revealed by observation, physical examination, or other diagnostic 
procedures.  Any clinically relevant deterioration in laboratory assessments or other clinical 
finding is considered an AE.  When possible, signs and symptoms indicating a common 
underlying pathology should be noted as one comprehensive event.  For nonserious AEs 
(including AESIs), the investigator must determine both the intensity of the event and the 
relationship of the event to study drug administration. 
11.4.2 
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 11.4).  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 11.4).  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 G) 
11.4.3 
Sponsor Assessment of Unexpected 
The Sponsor is responsible for assessing an AE or suspected AE as “unexpected”. 
An AE or suspected adverse reaction is considered “unexpected” when the following conditions 
occur: 
 Event(s) is not mentioned in the IB (or current US Package Insert) 
 Event(s) is not listed at the specificity or severity that has been observed 


 
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 An event(s) is not consistent with the General Investigative Plan or in the current 
application 
 Includes AEs or Suspected Adverse Reactions that may be anticipated from the 
pharmacological properties of the study drug, or that occur with members of the drug 
class, but that have previously been observed under investigation 
When applicable, an unexpected AE may also apply to an event that is not listed in the current IB 
or an event that may be mentioned in the IB, but differs from the event because of greater 
severity or specificity. 
Known as Suspected Unexpected Serious Adverse Reactions (SUSAR), these events suspected 
(by the Investigator or Sponsor) to be related to the study drug, are unexpected (not listed in the 
IB), and are serious (as defined by the protocol) and require expedient submission to relevant 
health authorities within 7 days (fatal or life-threatening event) or 15 days (all serious events), or 
as defined by law.  The term SUSAR is used primarily in the reporting of events to regulatory 
authorities. 
Expected AEs are those events that are listed or characterized in the current IB. 
11.4.4 
Sponsor Reporting for Clinical Studies Under an Investigational New Drug 
Application 
Sponsor-investigator must also provide Millennium Pharmacovigilance with a copy of all 
communications with applicable regulatory authorities related to the study product(s) as soon as 
possible but no later than 4 calendar days of such communication. 
Millennium Pharmacovigilance or Designee 
SAE and Pregnancy Reporting Contact Information 
FAX Number 1-800-963-6290 
Email: TakedaOncoCases@cognizant.com 
12. 
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS 
This research study will be conducted according to the standards of Good Clinical Practice 
(GCP) outlined in the International Congress on Harmonisation (ICH) E6 Tripartite Guideline 
and the Code of Federal Regulations (CFR) Title 21 part 312, applicable government regulations, 
institutional research policies and procedures and any other local applicable regulatory 
requirement(s).  The investigator will be thoroughly familiar with the appropriate use of the 
study drug as described in the protocol and Investigator’s Brochure.  Essential clinical 
documents will be maintained to demonstrate the validity of the study and the integrity of the 
data collected.  Master files should be established at the beginning of the study, maintained for 
the duration of the study and retained according to the appropriate regulations. 
12.1 
Institutional Review Board Approval 
The clinical study protocol, informed consent form (ICF), IB, available safety information, 
patient documents (e.g., study diary), patient recruitment procedures (e.g., advertisements), 


 
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information about payments (i.e., Principal Investigator payments) and compensation available 
to the patients and documentation evidencing the Principal Investigator’s qualifications should 
be submitted to the IRB for ethical review and approval if required by local regulations, prior to 
the study start. 
The Principal Investigator/Sponsor and/or designee will follow all necessary regulations to 
ensure appropriate, initial, and on-going, IRB study review.  The Principal Investigator/Sponsor 
(as appropriate) must submit and, where necessary, obtain approval from the IRB for all 
subsequent protocol amendments and changes to the informed consent document.  Investigators 
will be advised by the Sponsor or designee whether an amendment is considered substantial or 
non-substantial and whether it requires submission for approval or notification only to an IRB. 
Safety updates for MLN9708, will be prepared by the Sponsor or its representative as required, 
for distribution to the Investigator(s) and submission to the relevant IRB. 
12.2 
Regulatory Approval 
As required by local regulations, the Sponsor will ensure all legal aspects are covered, and 
approval of the appropriate regulatory bodies obtained, prior to study initiation.  If required, the 
Sponsor will also ensure that the implementation of substantial amendments to the protocol and 
other relevant study documents happen only after approval by the relevant regulatory authorities. 
12.3 
Informed Consent 
Informed consent is a process by which a patient voluntarily confirms his or her willingness to 
participate in a particular study after having been informed of all aspects of the study that are 
relevant to the patient's decision to participate.  Informed consent is documented by means of a 
written, signed, and dated ICF. 
The ICF will be submitted for approval to the IRB that is responsible for review and approval of 
the study.  Each consent form must include all of the relevant elements currently required by the 
FDA, as well as local county authority or state regulations and national requirements. 
Before recruitment and enrollment into the study, each prospective candidate will be given a full 
explanation of the research study.  Once the essential information has been provided to the 
prospective candidate, and the Investigator is sure that the individual candidate understands the 
implications of participating in this research study, the candidate will be asked to give consent to 
participate in the study by signing an ICF.  A notation that written informed consent has been 
obtained will be made in the patient’s medical record.  A copy of the ICF, to include the patient’s 
signature, will be provided by the Investigator to the patient. 
If an amendment to the protocol substantially alters the study design or the potential risks to the 
patients, the patient’s consent to continue participation in the study should be obtained. 
Millennium requests that informed consent documents be reviewed by Millennium or designee 
prior to IRB/IEC submission.   


 
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12.3.1 
Confidentiality 
12.3.1.1 Patient Confidentiality 
Confidentiality of patient’s personal data will be protected in accordance with the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA).  HIPAA regulations require that, 
in order to participate in the study, a patient must sign an authorization form for the study that he 
or she has been informed of following: 
 What protected health information (PHI) will be collected from patients in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 That health information may be further disclosed by the recipients of the information, and 
that if the information is disclosed the information may no longer be protected by federal 
or state privacy laws 
 The information collected about the research study will be kept separate from the 
patient’s medical records, but the patient will be able to obtain the research records after 
the conclusion of the study 
 Whether the authorization contains an expiration date 
 The rights of a research patient to revoke his or her authorization 
In the event that a patient revokes authorization to collect or use his or her PHI, the Investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization.  For patients that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (i.e., that the patient is alive) at the 
end of their scheduled study period. 
In compliance with ICH GCP guidelines and applicable parts of 21 CFR it is a requirement that 
the Investigator and institution permit authorized representatives of Sponsor, the regulatory 
authorities, Millennium, and the IRB direct access to review the patient’s original medical 
records at the site for verification of study-related procedures and data.  
Measures to protect confidentiality include: only a unique study number and initials will identify 
patients in the eCRF or other documents submitted to the Sponsor.  This information, together 
with the patient’s date of birth, will be used in the database for patient identification.  Patient 
names or addresses will not be entered in the eCRF.  No material bearing a patient’s name will 
be kept on file by Sponsor.  Patients will be informed of their rights within the ICF. 
12.3.1.2 Investigator and Staff Information 
Personal data of the Investigators and sub-Investigators may be included in the SCRI Innovations 
database, and shall be treated in compliance with all applicable laws and regulations.  When 
archiving or processing personal data pertaining to the Investigator or sub Investigator, SCRI 
Innovations shall take all appropriate measures to safeguard and prevent access to this data by 
any unauthorized party. 


 
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12.4 
Financial Information 
The finances for this clinical study will be subject to a separate written agreement between the 
SCRI Innovations and applicable parties.  Any Investigator financial disclosures as applicable to 
21CFR Part 54 shall be appropriately provided. 
12.5 
Investigator Compliance 
The investigator will conduct the study in compliance with the protocol given approval/favorable 
opinion by the IRB/IEC and the appropriate regulatory authority(ies).  Changes to the protocol 
will require approval from Millennium and written IRB/IEC approval/favorable opinion prior to 
implementation, except when the modification is needed to eliminate an immediate hazard(s) to 
patients.  The IRB/IEC may provide, if applicable regulatory authority(ies) permit, expedited 
review and approval/favorable opinion for minor change(s) in ongoing studies that have the 
approval /favorable opinion of the IRB/IEC.  The investigator will submit all protocol 
modifications to Millennium and the regulatory authority(ies) in accordance with the governing 
regulations.  
Any departures from the protocol must be fully documented in the source documents.   
13. 
RESEARCH RETENTION AND DOCUMENTATION OF THE STUDY 
13.1 
Amendments to the Protocol 
Amendments to the protocol shall be planned, documented, and signature authorized prior to 
implementation. 
If an amendment to the protocol is required, the amendment will be originated and documented 
by the Sponsor.  All amendments require review and approval of all pharmaceutical companies 
and the Principal Investigator supporting the study.  The written amendment must be reviewed 
and approved by the Sponsor, and submitted to the IRB at the Investigator’s facility for the 
board’s approval. 
Amendments specifically involving change to study design, risk to patient, increase to dosing or 
exposure, patient number increase, addition or removal of new tests or procedures, shall be 
reviewed and approved by the IRB of record for the Investigator’s facility. 
The amendment will be submitted formally to the FDA or other regulatory authorities by the 
Sponsor as applicable and IRB approval obtained, and specifically when an increase to dosing or 
patient exposure and/or patient number has been proposed; or, when the addition or removal of 
an Investigator is necessitated. 
Items requiring a protocol amendment with IRB and/or FDA or other regulatory authorities 
approval which include but are not limited to the following: 
 Change to study design 
 Risk to patient 
 Increase to dose or patient exposure to drug 


 
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 Patient number increase 
 Addition or removal of tests and / or procedures 
 Addition/removal of a new Principal Investigator. 
It should be further noted that, if an amendment to the protocol substantially alters the study 
design or the potential risks to the patients, their consent to continue participation in the study 
should be obtained. 
13.2 
Documentation Required to Initiate the Study 
Before the study may begin certain documentation required by FDA regulations and ICH GCP 
must be provided by the Investigator.  The required documentation should be submitted to: 
SCRI Development Innovations 
3322 West End Avenue, Suite 900 
Nashville, TN  37203 
Documents at a minimum required to begin a study in the US include, but are not limited to, the 
following: 
 A signature-authorized protocol and contract 
 A copy of the official IRB approval of the study and the IRB members list 
 Current Curricula Vitae for the Principal Investigator and any associate Investigator(s) 
who will be involved in the study 
 Indication of appropriate accreditation for any laboratories to be used in the study and a 
copy of the normal ranges for tests to be performed by that laboratory 
 Original Form FDA 1572 (Statement of Investigator), appropriately completed and 
signed 
 A copy of the IRB-approved consent form (and patient information sheet, if applicable) 
containing permission for audit by representatives of  SCRI-Innovations, the IRB, and the 
FDA and other regulatory agencies (as applicable) 
 Financial disclosure forms for all Investigators listed on Form FDA 1572 (if applicable) 
 Site qualification reports, where applicable 
 Verification of Principal Investigator acceptability from local and/or national debarment 
list(s)  
13.3 
Study Documentation and Storage 
The Principal Investigator must maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties and should ensure that all persons assisting in the conduct of the study 
are informed of their obligations.  All persons authorized to make entries and/or corrections on 
the eCRFs are to be included on this document.  All entries in the patient’s eCRF are to be 
supported by source documentation where appropriate. 
Source documents are the original documents, data, records, and certified copies of original 
records of clinical findings, observations, and activities from which the patient’s eCRF data are 


 
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obtained.  These can include, but are not limited to, hospital records, clinical and office charts, 
laboratory, medico-technical department and pharmacy records, diaries, microfiches, ECG 
traces, copies or transcriptions certified after verification as being accurate and complete, 
photographic negatives, microfilm or magnetic media, X-rays, and correspondence. 
The Principal Investigator and each study staff member is responsible for maintaining a 
comprehensive and centralized filing system  (e.g., regulatory binder or investigator study file 
[ISF]) of all study-related (essential) documentation, suitable for inspection at any time by 
representatives from the Sponsor and/or applicable regulatory authorities.  The ISF must consist 
of those documents that individually or collectively permit evaluation of the conduct of the study 
and the quality of the data produced.  The ISF should contain as a minimum all relevant 
documents and correspondence as outlined in ICH GCP Section 8 and 21 CFR Part 312.57, 
including key documents such as the IB and any amendments, protocol and any amendments, 
signed ICFs, copies of completed CRFs, IRB approval documents, Financial Disclosure forms, 
patient identification lists, enrollment logs, delegation of authority log, staff qualification 
documents, laboratory normal ranges, records relating to the study drug including accountability 
records.  Drug accountability records should, at a minimum, contain information regarding 
receipt, shipment, and disposition.  Each form of drug accountability record, at a minimum, 
should contain Principal Investigator name, date drug shipped/received, date, quantity and 
batch/code, or lot number for identity of each shipment.  In addition, all original source 
documents supporting entries in the eCRF must be maintained and be readily available. 
The Sponsor shall maintain adequate investigational product records and financial interest 
records as per 21CFR Part 54.6 and Part 312.57 for no less than 2 years after the last marketing 
application has been approved by FDA; or, in the event that the marketing application has not 
been approved by FDA, for no less than 2 years after the last shipment / delivery of the drug for 
investigational use is discontinued and FDA has been notified of the discontinuation. 
The Investigator shall maintain adequate records of drug disposition, case histories, and any 
other study-related records as per 21 CFR Part 312.62 for no less than 2 years after the last 
marketing application has been approved by FDA; or, in the event that the marketing application 
has not been approved by FDA, for no less than 2 years after the last shipment / delivery of the 
drug for investigational use is discontinued and FDA has been notified of the discontinuation. 
To enable evaluations and/or audits from regulatory authorities or from the Sponsor or its 
representative, the Investigator additionally agrees to keep records, including the identity of all 
participating patients (sufficient information to link records e.g., eCRF records, and medical 
records), all original, signed ICFs, and copies of all eCRF records, SAE Reporting forms, source 
documents, detailed records of treatment disposition, and related essential regulatory documents.  
The documents listed above must be retained by the Investigator for as long as needed to comply 
with national and international regulations (generally 2 years after discontinuing clinical 
development or after the last marketing approval).  Sponsor will notify the 
Investigator(s)/institutions(s) when the study-related records are no longer required. 
If the Investigator relocates, retires, or for any reason withdraws from the study, both the 
Sponsor and its representative should be prospectively notified.  The study records must be 
transferred to an acceptable designee, such as another Investigator, another institution, or to the 


 
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Sponsor.  The Investigator must obtain the Sponsor’s written permission before disposing of any 
records, even if retention requirements have been met.  All study files will be maintained by the 
Sponsor throughout the study, and will be transferred to the Sponsor at the conclusion of the 
study. 
13.4 
Data Collection 
The study eCRF is the primary data collection instrument for the study.  Case report forms will 
be completed using the English language and should be kept current to enable the Sponsor to 
review the patients’ status throughout the course of the study. 
In order to maintain confidentiality, only study number, patient number, initials and date of birth 
will identify the patient in the eCRF.  If the patient’s name appears on any other document (e.g., 
laboratory report), it must be obliterated on the copy of the document to be supplied to SCRI and 
replaced instead with the patient number and patient’s initials.  The Investigator will maintain a 
personal patient identification list (patient numbers with corresponding patient identifiers) to 
enable records to be identified and verified as authentic.  Patient data/information will be kept 
confidential, and will be managed according to applicable local, state, and federal regulations. 
All data requested in the eCRF system must be supported by and be consistent with the patient’s 
source documentation.  All missing data must be explained.  When a required laboratory test, 
assessment, or evaluation has not been done or an “Unknown” box is not an option on the eCRF, 
a note should be created verifying that the field was “Not Done” or “Unknown”.  For any entry 
errors made, the error(s) must be corrected, and a note explaining the reason for change should 
be provided. 
The Investigator will electronically sign and date the patient eCRF casebook indicating that the 
data in the eCRF has been assessed.  Each completed eCRF will be signed and dated by the 
Principal Investigator, once all data for that patient is final. 
13.5 
Study Monitoring, Auditing, and Inspecting 
The Investigator will permit study-related monitoring, quality audits, and inspections by the 
Sponsor or its representative(s), government regulatory authorities, and the IRB of all study-
related documents (e.g., source documents, regulatory documents, data collection instruments, 
case report forms).  The Investigator will ensure the capability for inspections of applicable 
study-related facilities.  The Investigator will ensure that the study monitor or any other 
compliance or Quality Assurance reviewer is given access to all study-related documents and 
study-related facilities. 
At the Sponsor’s discretion, Source Document Verification may be performed on all data items 
or a percentage thereof. 
Participation as an Investigator in this study implies the acceptance of potential inspection by 
government regulatory authorities, the IRB and the Sponsor or its representative(s). 
13.6 
Quality Assurance and Quality Control 
Each study site shall be required to have Standard Operating Procedures to define and ensure 
quality assurance/control processes for study conduct, data generation & collection, recording of 
data/documentation and reporting according to the protocol, GCP and any applicable local, 
national or international regulations. 


 
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13.7 
Disclosure and Publication Policy 
All information provided regarding the study, as well as all information collected/documented 
during the course of the study, will be regarded as confidential.  The Sponsor reserves the right 
to release literature publications based on the results of the study.  Results from the study will be 
published/presented as per the Sponsor’s publication strategy. 
13.8 
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. 
13.9 
Product Complaints 
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product.  Individuals who 
identify a potential product complaint situation should immediately contact MedComm Solutions 
(see below) and report the event.  Whenever possible, the associated product should be 
maintained in accordance with the label instructions pending further guidance from a Millennium 
Quality representative.


 
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For Product Complaints 
call MedComm Solutions at 
877-674-3784 (877 MPI DRUG) 
(US and International) 
Product complaints in and of themselves are not AEs.  If a product complaint results in an SAE, 
an SAE form should be completed and sent to Millennium Pharmacovigilance (refer to 
Section 11.4). 
13.10 
Closure of the Study 
This study may be prematurely terminated, if in the opinion of the investigator or Millennium, 
there is sufficient reasonable cause.  Written notification documenting the reason for study 
termination will be provided to the investigator or Millennium by the terminating party.   
Circumstances that may warrant termination include, but are not limited to: 
 Determination of unexpected, significant, or unacceptable risk to patients 
 Failure to enter patients at an acceptable rate 
 Insufficient adherence to protocol requirements 
 Insufficient, incomplete and/or unevaluable data 
 Determination of efficacy based on interim analysis 
 Plans to modify, suspend or discontinue the development of the drug. 
13.11 
Record Retention 
The investigator will maintain all study records according to the ICH-GCP and applicable 
regulatory requirement(s). 
14. 
USE OF INFORMATION 
All information regarding MLN9708 supplied by Millennium to the investigator is privileged 
and confidential information.  The investigator agrees to use this information to accomplish the 
study and will not use it for other purposes without consent from Millennium.  It is understood 
that there is an obligation to provide Millennium with complete data obtained during the study.  
The information obtained from the clinical study will be used toward the development of 
MLN9708 and may be disclosed to regulatory authority(ies), other investigators, corporate 
partners, or consultants as required. 
Upon completion of the clinical study and evaluation of results by Millennium, the hospital or 
institution and/or investigator may publish or disclose the clinical trial results pursuant to the 
terms contained in the applicable Clinical Trial Agreement.    
 


 
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15. 
REFERENCES 
Assouline et al. 2012 
Assouline S, Chang J, Rifkin R, Hui A-M, Gupta N, Yu J, et al. Once-weekly MLN9708, an 
investigational proteasome inhibitor, in patients with relapsed/refractory lymphoma: Results of a 
phase 1 dose-escalation study [abstract]. Presented at17th Annual Congress of the European 
Hematology Association; 2012 June 14-17; Amsterdam, the Netherlands. Abstract 1063. 
Berdeja et al. 2011 
Berdeja JG, Richardson PG, Lonial S, Niesvizky R, Hui A-M, Berg D, et al. Phase 1/2 study of 
oral MLN9708, a novel, investigational proteasome inhibitor, in combination with lenalidomide 
and dexamethasone in patients with previously untreated multiple myeloma (MM) [abstract]. 
Blood (ASH Annual Meeting Abstracts). 2011;118(21):223. Abstract 479. 
Chow et al. 2012 
Chow LQ, Infante JR, Siu LL, Sullivan D, Kauh JS, DiBacco A, et al. MLN9708, an 
investigational proteasome inhibitor, in patients with solid tumors; Updated phase 1 results 
[abstract]. Presented at the Multidisciplinary Head and Neck Cancer Symposium; 2012 Jan 26-
28; Phoenix, AZ. Abstract 203. 
Drake et al. 2010 
Drake M, Iacobelli S, van Biezen A, et al.  Primary plasma cell leukemia and autologous stem 
cell transplantation.  Haematologica. 2010;95(5):804-9. 
El Cheik et al. 2008 
El Cheik 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: 455-458. 
Filipovich et al. 2005 
Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, 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. Biology of Blood and 
Marrow Transplantation 2005;11(12):945-56. 
Gupta et al. 2011 
Gupta, N., M. Saleh, and K. Venkatakrishnan. Flat-Dosing Versus BSA-Based Dosing for 
MLN9708, An Investigational Proteasome Inhibitor: Population Pharmacokinetic (PK) Analysis 
of Pooled Data From 4 Phase-1 Studies in 53rd ASH Annual Meeting and Exposition. 2011. San 
Diego, CA. 


 
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Harousseau et al. 2008 
Harousseau JL, Dreyling M, ESMO Guidelines Working Group. Multiple myeloma: ESMO 
clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2008;19 Suppl 
2:ii55-7. 
Huang et al. 2007 
Huang SY, Yao M, Tang JL, Lee WC, Tsay W, Cheng AL, et al. Epidemiology of multiple 
myeloma in Taiwan: increasing incidence for the past 25 years and higher prevalence of 
extramedullary myeloma in patients younger than 55 years. Cancer. 2007;110(4):896-905. 
Jemal et al. 2010 
Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60(5):277-
300. 
Jimenez-Zepeda et al. 2012 
Jimenez-Zepeda V, Mikhael J, Winter J, et al.  Second autologous stem cell transplanatation as 
salvage therapy for multiple myeloma: impact on progression-free and overall survival.  Biol 
Blood Marrow Transplant. 2012;18:773-9. 
Kanate et al 2015 
Kanate AS, Mussetti A, Kharfan-Dabaja MA, Ahn KW, DiGilio A, Beitinjaneh A, et al. 
Reduced-intensity transplantation for lymphomas using haploidentical related donors versus 
HLA-matched unrelated donors. Blood. 2015 Dec 15. Pii: blood-2015-09-671834. (Epub ahead 
of print) 
Kapoor et al. 2009 
Kapoor P, Kumar S, Fonseca R, et al.  Impact of risk stratification on outcome among patients 
with multiple myeloma receiving initial therapy with lenalidomide and dexamethasone.  Blood. 
2009;114:518-21. 
Koreth et al. 2009 
Koreth J, Alyea E, Murphy W, et al.  Proteasome inhibition and allogeneic hematopoietic stem 
cell transplantation: A review.  Biol Blood Marrow Transplant. 2009;15:1502-12. 
Kroger et al. 2006 
Kroger N, Zabelina T, Ayuk F, et al.  Bortezomib after dose-reduced allogeneic stem cell 
transplantation for multiple myeloma to enhance or maintain remission status.  Exp Hematol 
2006; 34(6): 770-775. 
Kumar et al. 2008 
Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, et al. Improved 
survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111(5):2516-20. 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
VERSION 4 
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Kumar et al. 2011 
Kumar S, Bensinger WI, Reeder CB, et al. Weekly dosing of the investigational oral proteasome 
inhibitor MLN9708 in patients with relapsed and/or refractory multiple myeloma: Results from a 
phase 1 dose-escalation study. Blood. 2011;118(21). Abstract 816. 
Kumar et al. 2011 
Kumar S, Zhang M, Li P, et al.  Trends in allogeneic stem cell transplantation for multiple 
myeloma: a CIBMTR analysis.  Blood. 2011;118:1979-88. 
Kumar et al. 2012 (a) 
Kumar, S., et al. Oral weekly MLN9708, an investigational proteasome inhibitor, in combination 
with lenalidomide and dexamethasone in patients (pts) with previously untreated multiple 
myeloma (MM): A phase I/II study in ASCO Annual Meeting. 2012. Chicago, Illinois. 
Kumar et al. 2012 (b) 
Kumar, S. et al. A Phase 1/2 Study of Weekly MLN9708, an Investigational Oral Proteasome 
Inhibitor, in Combination with Lenalidomide and Dexamethasone in Patients with Previously 
Untreated Multiple Myeloma (MM) in 54th ASH Annual Meeting and Exposition. 2012. Atlanta, 
Georgia. 
Kumar et al. 2013 
Kumar S., Niesvizky R, Berdeja J, et al. Safety and Pharmacokinetics of Weekly MLN9708, an 
Investigational Oral Proteasome Inhibitor, Alone and in Combination Clinical Lymphoma 
Myeloma and Leukemia 2013;13(Supplement 1):S154; abstr P-230. 
Kumar et al. 2014 
Kumar S., et al. Weekly dosing of the investigational oral proteasome inhibitor MLN9708 in 
patients (pts) with relapsed/refractory multiple myeloma (MM). Blood. 2014; first edition 
(prepublished online 09 June 2014). 
Landgren and Weiss. 2009 
Landgren O, Weiss BM. Patterns of monoclonal gammopathy of undetermined significance and 
multiple myeloma in various ethnic/racial groups: support for genetic factors in pathogenesis. 
Leukemia. 2009;23(10):1691-7. 
Lonial et al. 2012 
Lonial, S Baz RC, Wang M, Talpaz M, Liu G, Berg D, et al. Phase I study of twice-weekly 
dosing of the investigational oral proteasome inhibitor MLN9708 in patients (pts) with relapsed 
and/or refractory multiple myeloma (MM) [abstract]. Presented at: ASCO Annual Meeting; 2012 
Jun 1-5; Chicago, Illinois. Abstract 8017. 
McCurdy and Fuchs 2015 
McCurdy SR, Fuchs EJ. Comparable Outcomes for Hematologic Malignancies after HLA-
Haploidentical Transplantation with Posttransplantation Cyclophosphamide and HLA-Matched 


 
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STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
VERSION 4 
Page 73 of 86 
Transplantation. Adv Hematology. 2015, Article ID 431923, 9 pages, 
http://dx.doi.org/10.1155/2015/431923 
National Comprehensive Cancer Network. 2010 
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: 
Adult Cancer Pain, v 2010. Available from 
http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. 
Neben et al. 2012 
Neben K, Lokhorst H, Jauch A, et al.  Administration of bortezomib before or after autologous 
stem cell transplantation improves outcomes in multiple myeloma patients with deletion 17p.  
Blood. 2012;119:940-8. 
Palumbo and Anderson. 2011 
Palumbo A, Anderson K. Multiple myeloma. N Engl J Med. 2011;364(11):1046-60. 
Przepiorka et al. 1995 
Przepiorka D, Weisdorf D, Martin P, et al. Consensus conference on acute GvHD grading.  Bone 
Marrow Transplant. 1995;15:825-8. 
Qiu et al. 2008 
Qiu L, Wang Y, Qi P, Zou D, Zhao Y, Qi J. Clinical Epidemiological Study on Multiple 
Myeloma in China: A 18-Year Retrospective Study in a Representative Center [abstract]. 
Presented at 50th ASH Annual Meeting and Exposition; 2008 Dec 6-9, San Francisco, CA. 
Abstract 2723. 
Richardson et al. 2011 
Richardson PG, Berdeja JG, Niesvizky R, Lonial S, Roy V, Parameswaran H, et al. 
Investigational agent MLN 9708, an oral proteasome inhibitor, in patients with relapsed and/or 
refractory multiple myeloma: Results for the expansion cohorts of a phase 1 dose escalation 
study. Blood (ASH Annual Meeting) 2011; 118: Abstract 301. 
Richardson et al. 2012 (a) 
Richardson P, Berdeja J, Niesvizky R, et al. MLN9708, an investigational proteasome inhibitor, 
combined with lenalidomide and dexamethasone in previously untreated multiple myeloma 
patients: evaluation of weekly and twice-weekly dosing regimens. In: 17th Congress of European 
Hematology Association (EHA). Amsterdam, The Netherlands; 2012. 
Richardson et al. 2012 (b) 
Richardson P, Berdeja J, Niesvizky R, et al. Oral weekly MLN9708, an investigational 
proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients (pts) with 
previously untreated multiple myeloma (MM): A phase 1/2 study. In: Annual Meeting of the 
American Society of Clinical Oncology (ASCO); 2012 1-5 June; Chicago, IL. 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
VERSION 4 
Page 74 of 86 
Richardson et al. 2012 (c) 
Richardson, P.G., et al. MLN9708, an investigational proteasome inhibitor, in combination with 
lenalidomide and dexamethasone in previously untreated multiple myeloma patients (pts): 
Evaluation of weekly and twice-weekly dosing in 17th EHA Annual Congress. 2012. Amsterdam, 
the Netherlands. 
Richardson et al. 2014 
Richardson PG, Baz R, Wang M, et al. Phase 1 study of twice-weekly dosing of investigational 
oral proteasome inhibitor MLN9708 in patients with relapsed and/or refractory multiple 
myeloma. Blood 2014;first edition (prepublished online 11 June 2014). 
San Miguel et al. 2012 
San Miguel J, Hajek R, Spicka I, Chen C, Gutierrez E, Schusterbauer C, et al. Oral MLN9708, 
an investigational proteasome inhibitor, in combination with melphalan and prednisone in 
patients with previously untreated multiple myeloma: a phase 1 study [abstract]. Presented at: 
17th Annual Congress of the European Hematology Association; 2012 June 14-17; Amsterdam, 
the Netherlands. Abstract 0293. 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
VERSION 4 
Page 75 of 86 
16. 
APPENDICES 
 
Appendix A: ECOG Performance Status Criteria 
 
ECOG Performance Status Scale 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able to carry 
on all pre-disease performance without 
restriction. 
 
100 
Normal, no complaints, no evidence of 
disease. 
 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  Restricted in 
physically strenuous activity, but 
ambulatory and able to carry out work of a 
light or sedentary nature (e.g., light 
housework, office work). 
 
80 
Normal activity with effort; some signs or 
symptoms of disease. 
 
70 
Cares for self, unable to carry on normal 
activity or to do active work. 
2 
In bed << 50% of the time.  Ambulatory and 
capable of all self-care, but unable to carry 
out any work activities.  Up and about more 
than 50% of waking hours. 
 
60 
Requires occasional assistance, but is able 
to care for most of his/her needs. 
 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >> 50% of the time.  Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours. 
 
40 
Disabled, requires special care and 
assistance 
 
30 
Severely disabled, hospitalization 
indicated.  Death no imminent. 
4 
100% bedridden.  Completely disabled.  
Cannot carry on any self-care.  Totally 
confined to bed or chair. 
 
20 
Very sick, hospitalization indicated.  Death 
not imminent. 
 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead 
0 
Dead 


 
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STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
VERSION 4 
Page 76 of 86 
 
Appendix B: New York Heart Association (NYHA) Classification of Cardiac Disease 
The following table presents the NYHA classification of cardiac disease. 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations of physical 
activity.  Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea, or anginal pain. 
No objective evidence of 
cardiovascular disease. 
II 
Patients with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity results in 
fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
minimal cardiovascular 
disease. 
III 
Patients with cardiac disease resulting in marked limitation of physical 
activity.  They are comfortable at rest.  Less than ordinary activity causes 
fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to carry on any physical 
activity without discomfort.  Symptoms of heart failure or the anginal 
syndrome may be present even at rest.  If any physical activity is undertaken, 
discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease. 
Source:  The Criteria Committee of the New York Heart Association.  Nomenclature and Criteria for Diagnosis of 
Diseases of the Heart and Great Vessels.  9th Ed. Boston, MA:  Little, Brown & Co; 1994:253-256. 
 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
VERSION 4 
Page 77 of 86 
Appendix C: Guidelines for Women of Childbearing Potential and Fertile Male Patients 
It is not known what effects MLN9708 has on human pregnancy or development of the 
embryo or fetus.  Therefore, female patients participating in this study should avoid becoming 
pregnant, and male patients should avoid impregnating a female partner.  Nonsterilized female 
patients of reproductive age group and male patients should use effective methods of 
contraception through defined periods during and after study treatment as specified below. 
Female patients must meet 1 of the following criteria:  
 Postmenopausal for at least 1 year before the screening visit, OR 
 Surgically sterile, OR 
 If they are of childbearing potential, agree to practice 2 effective methods of 
contraception, at the same time, from the time of signing the informed consent form 
through 90 days after the last dose of study drug, AND 
 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 [e.g., calendar, ovulation, symptothermal, 
post-ovulation methods] and withdrawal are not acceptable methods of contraception.) 
Male patients, even if surgically sterilized (i.e., status postvasectomy), must agree to 1 of the 
following: 
 Agree to practice effective barrier contraception during the entire study treatment 
period and through 90 days after the last dose of study drug, OR 
 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 (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods] and withdrawal are not acceptable methods of contraception.) 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
VERSION 4 
Page 78 of 86 
Appendix D: MM 42 Schedule of Assessments 
 
 
Procedures 
Pre-TX 
Cycle 1 
Cycle = 28 days 
Cycles 2 to 6 
Cycle = 28 days 
 
Reassess 
Every 
2 Cycles 
(8 weeks) 
 
End of 
Study 
Treatmentr 
Follow-up 
Baseline 
Day 
Day 
Off Study 
Prior to 
Progressions 
After Disease 
Progressiont 
1 
4 
8 
15 
1 (± 2 
days) 
8 
15 
TESTS & OBSERVATIONS 
 
 
Written informed consenta 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical historyb 
X 
X 
 
 
 
X 
 
 
 
X 
X 
 
Physical examinationb,c 
X 
X 
Xc 
Xc 
Xc 
X 
 
 
 
X 
X 
 
ECOG performance statusb 
X 
X 
 
 
 
X 
 
 
 
X 
X 
 
GVHD assessmentd 
X 
X 
 
Xd 
Xd 
X 
Xd 
Xd 
 
X 
X 
 
12-lead ECGe 
X 
 
 
 
 
 
 
 
 
 
 
 
Chest X-ray 
X 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Concomitant medications 
(GVHD and non-GVHD) 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Response assessmentf 
 
 
 
 
 
 
 
 
Xe 
Xe 
Xe 
 
Survival status 
 
 
 
 
 
 
 
 
 
 
 
X 
LABORATORY TESTS 
 
CBC, 3-part diff &plateletsb,g 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
 
CMPb,h 
X 
X 
 
X 
X 
X 
 
 
 
X 
X 
 
Urinalysisb,i 
X 
X 
 
X 
X 
X 
 
 
 
X 
 
 
PT/aPTT/INRb 
X 
X 
 
 
 
X 
 
 
 
 
 
 
Serum or Urine β-HCGj 
X 
 
 
 
 
 
 
 
 
 
 
 
Biomarker blood samplek 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Percentage chimerisml 
 
Xl 
 
 
 
Xl 
 
 
 
 
Xl 
 
DISEASE ASSESSMENTS 
 
Bone Marrow Aspira/Biopsym 
X 
 
 
 
 
 
 
 
Xm 
Xm 
 
 
Skeletal Surveyn 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum free light chain 
X 
 
 
 
 
 
 
 
Xq 
Xq 
Xq 
 
SPEP & immunofixation 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
UPEP & immunofixationo 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
Serum immunoglobulins 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
Serum -2 microglobulin 
X 
 
 
 
 
 
 
 
 
 
 
 
Known plasmacytomasp 
X 
 
 
 
 
 
 
 
X 
X 
X 
 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
VERSION 4 
Page 79 of 86 
a 
Written informed consent must be obtained before any study-related procedure is performed and ≤28 days prior to the initiation of study treatment. 
b 
The Baseline visit physical examination, medical history (see Section 7.2), ECOG performance status, CBC, CMP, PT/aPTT/INR, and urinalysis should be done <7 days 
prior to initiation of treatment.  However, if these initial examinations are obtained ≤72 hours before first study treatment they do not have to be repeated on Day 1 of Cycle 1. 
c 
Physical examinations will include measurements of weight and vital signs (resting heart rate, blood pressure, respiratory rate, oral temperature).  At the Baseline visit only, 
height will also be recorded.  Physical examinations will be done on Day 1 of each cycle.  In addition during Cycle 1 only, patients will have a symptom directed physical 
examination done on Days 4, 8, and 15. 
d 
Acute and chronic GVHD assessment is to be conducted at baseline and Day 1 of every cycle.  Patients that develop GVHD will have the assessment conducted every visit on 
Days 1, 8, and 15 of every cycle. 
e 
Three 12-lead ECGs will be collected approximately 5 minutes apart at the Baseline visit.  Additional ECGs will be done as clinically indicated. 
f 
Patients will be re-evaluated for response to treatment after 2 cycles of treatment.  Response will be assessed at 8-week intervals (±1 week) during study treatment.  Patients 
with progressive disease (PD) or unacceptable toxicity should be discontinued from the study; patients with stable disease (SD) or response to therapy will continue treatment. 
g 
Hematology parameters include the following laboratory tests:  CBC with 3-part differential (total neutrophil count including bands, lymphocytes, monocytes) hemoglobin, 
hematocrit and platelets. 
h 
CMP to include: glucose, BUN, creatinine (creatinine clearance calculated by Cockcroft-Gault), sodium, potassium, chloride, calcium, phosphorus, magnesium, CO2, ALT, 
AST, ALP, LDH, uric acid, total bilirubin, total protein, and albumin. 
i 
A urine dipstick will be done weekly during Cycle 1.  Thereafter, urine dipstick will be done on Day 1 of each 4-week cycle.  If abnormalities are present on urine dipstick, 
additional testing (e.g., microscopic examination, urine protein:creatinine ratio [UPC], etc.) should be done as clinically indicated. 
j 
A serum pregnancy test will be performed only for women of childbearing potential within 72 hours of study drug administration (see Appendix C). 
k 
Biomarker blood samples:  peripheral blood samples will be collected on Days 1 (pre-dose), 4, 8, and 15 of Cycle 1 and on Day 1 (pre-dose) of Cycle 2 only.  Participating 
patients will include 3 patients at each dose level and 5 additional patients at the MTD/MPD. 
l 
Report percentage chimerism conducted by institutional guidelines.  Above provided schedule is preferred, but not required. 
m 
Bone marrow aspirate and biopsy – quantify percent myeloma cell involvement, and obtain bone marrow aspirate for cytogenetics [i.e., diploidy, del(13)] and FISH studies 
[i.e., t(4:14); t(11:14);del(17p)], and at the response assessments to confirm CR only.  If available, provide MRD by flow cytometry at baseline. 
n 
Skeletal survey (lateral radiograph of the skull, anteroposterior and lateral views of the spine, and anteroposterior views of the pelvis, ribs, femora, and humeri) ≤28 days of 
first study drug treatment.  Only repeat if clinically indicated (i.e., bone pain). 
o 
UPEP requires the collection of a 24-hour urine sample. 
p 
Repeat if abnormal at baseline. 
 
q 
All patients will undergo the end of treatment visit assessments listed within 30 days after treatment ends due to completion of the planned study treatment period, or once a 
patient is discontinued due to unacceptable toxicity or decision to discontinue treatment by the patient or the study physician.  If treatment is discontinued because of toxicity 
or any other reason(s) at a treatment visit and no study treatment is administered, that visit may fulfill the End of Treatment Visit.  After withdrawal from or completion of 
protocol treatment, patients must be followed for AEs for 30 calendar days after the last dose of study drug. 
r 
Patients who discontinue study treatment prior to the occurrence of disease progression will be followed every 3 months during years 1 and 2. 
s 
After disease progression is documented, patients will be followed every 3 months during years 1and 2 for survival assessment. 
t 
For known plasmacytomas, utilize the same modality used to assess original disease (i.e., PET, MRI, CT, etc). 
 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
VERSION 4 
Page 80 of 86 
Appendix E: International Myeloma Working Group Uniform Response Criteria 
Response Category 
Definition  
sCR 
Stringent Complete 
Response  
CR criteria as defined below AND 
 
Normal free light chain (FLC)  ratio  
AND 
 
Absence of phenotypically aberrant PCs in bone marrowb 
analyzed by multiparametric flow cytometry 
CR 
Complete Response  
 
Negative immunofixation on the serum and urine  
AND 
 
Disappearance of any soft tissue plasmacytoma(s) 
AND 
 
< 5% plasma cells in bone marrowb. 
 
In case the only measurable disease in a patient with CR at 
baseline is the serum FLC level, a normal FLC ratio of 0.26 to 
1.65 is required additionally to qualify for CR. 
VGPR 
Very Good Partial 
Response  
 
Serum and  urine M-protein detectable by immunofixation but not  
by electrophoresis (PEP) or  ≥90% reduction from baseline 
serum) AND  urine M-protein level <100 mg/  24h 
AND 
 
In case of presence of soft tissue plasmacytoma(s) at baseline, 
disappearance of any soft tissue plasmacytomas 
In case the only measurable disease in a patient with VGPR at 
baseline is the serum FLC level (i.e. no measurable disease in serum 
and urine PEP), a decrease of > 90% in the difference between 
involved and uninvolved FLC levels from baseline is required. 
PR 
Partial Response  
 ≥50% reduction from baseline in serum M-protein   
     AND 
 ≥ 90% reduction from baseline in 24h urinary M-protein OR  
urine M-protein <200 mg/24h    
 
If serum and urine M-protein are non-measureable at baseline, a 
> 50% reduction form baseline in the difference between involved 
and uninvolved FLC levels is required in place of the M-protein 
criteria. 
If serum and urine M-protein are non-measurable, and serum free 
light assay is also non-measurable, >50% reduction from baseline in 
percent plasma cells in bone marrow is required instead of M-
protein measurement, provided baseline plasma cells in bone 
marrow was > 30%.  
AND 
In case of presence of soft tissue plasmacytoma(s) at baseline, a 
reduction in the SPD by >50% is required. 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
VERSION 4 
Page 81 of 86 
Appendix E: International Myeloma Working Group Uniform Response Criteria: Complete Response 
and Other Response Categories (continuation) 
SD  
Not meeting criteria for sCR, CR, VGPR, PR or PD 
PD  
Progressive Disease  
  
Increase of  ≥ 25% from the nadir in at least one of the following criteria: 
 
serum M-protein (absolute increase must be ≥0.5 g/dL and absolute value 
must be ≥1 g/dL) 
 
urine M-protein (absolute increase must be ≥200 mg/24h) 
 
only in patients with non-measurable serum and urine M-protein levels: 
difference in involved and uninvolved FLC levels (absolute increase must be 
>10 mg/L) 
 
Bone marrow plasma cell percentage (absolute % must be ≥10%) 
OR 
 
development of new lytic bone lesions or increase from baseline in size of 
lytic bone lesion(s) 
OR 
 
development of new soft tissue plasmacytoma(s) or definite increase from 
nadir in existing soft tissue plasmacytomas 
OR 
 
development of hypercalcemia (corrected serum calcium >11.5 mg/dL) for 
patients without hypercalcemia at baseline. In case of preexisting 
hypercalcemia at baseline, PD will only be assessed due to the hypercalcemia 
criterion in case the corrected serum calcium level was ≤11.5 mg/dL post-
baseline and increased thereafter beyond 11.5 mg/dL. 
aAll response categories require two consecutive assessments made at any time before the institution of any new therapy; all categories also require no known evidence 
of progressive or new bone lesions if radiographic studies were performed. Radiographic studies are not required to satisfy these response requirements. 
bConfirmation with repeat bone marrow biopsy not needed. 
 
Source:  Kyle RA and Rajkumar SV Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. 
Leukemia 2009. 23:3-9 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
VERSION 4 
Page 82 of 86 
 
Appendix F: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials 
in Acute and Chronic Graft-Versus-Host Disease 
Organ Staging of Acute GVHD 
 
 
Overall Clinical Grading of Acute GVHD 
 
Reference for both tables for acute GVHD:  Przepiorka et al. 1995 
 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
VERSION 4 
Page 83 of 86 
 
Organ Staging of Chronic GVHD 
 
 


 
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STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
VERSION 4 
Page 84 of 86 
 
Reference for chronic GVHD tables:  Filipovich et al. 2005 
 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
VERSION 4 
Page 85 of 86 
Appendix G: Pregnancy Reporting Form 


 
CONFIDENTIAL 
STUDY DRUG:  MLN9708 
 SCRI INNOVATIONS STUDY NUMBER:  MM 42 
FINAL PROTOCOL:  11 APRIL 2014 
 
 
 
 
 
AMENDMENT NUMBER 3:  11 FEBRUARY 2016 
 
 
 
VERSION 4 
Page 86 of 86 
Appendix G: Pregnancy Reporting 
Form
 

SAP_001.pdf: 
 
 
MM 42 
Statistical Analysis Plan 
 
Version 1.0, 06 JAN 2020 
REFERENCE SOP:  CDS-0102 
 
Template ID: ASSOC-DOC-116-SOP [B] 
Page 1 of 11 
Confidential 
 
 
 
 
 
Statistical Analysis Plan Checklist 
for Investigator Initiated Trials 
 
 
 
 
 
 
 
Open-Label Study to Determine the Feasibility of MLN9708 as Maintenance 
after Allogeneic Stem Cell Transplant for Multiple Myeloma, Followed by an 
Expansion Phase at the Maximum-Tolerated Dose (MTD) 
 
Sponsor: 
Sarah Cannon Development Innovations 
(Innovations) 
Study Drug: 
MLN9708 
SCRI Protocol Number: 
MM 42 
Prepared By: 
Innovations 
 
 
 
 
 
 


 
 
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Statistical Analysis Plan 
 
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REFERENCE SOP:  CDS-0102 
 
Template ID: ASSOC-DOC-116-SOP [B] 
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Confidential 
 
 


 
 
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Statistical Analysis Plan Checklist for Investigator Initiated Trials  
History of Changes 
 
This document has undergone the following changes: 
 
Version Number 
Version Date 
Description of Changes 
1.0 
06 JAN 2020 
Original document 
 


 
 
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Statistical Analysis Plan Checklist 
 
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Statistical Analysis Plan Checklist Review and Approval 
 
Approved By: 
 
 
 
 
 
Innovations  
Biostatistician 
David Bass 
 
Date 
 
 
 
 
 
Innovations  
Managerial Peer-Reviewer 
 
 
Date 
 
 
 
 
 
Innovations  
Tier 1 Manager 
 
 
 
 
 
Date 
Innovations  
Study Chair 
 
 
 
Date 
 
 
 
 


 
 
MM 42 
Statistical Analysis Plan Checklist 
 
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1.1 Objectives 
 
Primary Objective: 
Safety of MLN9708 when used as maintenance after allogeneic stem cell transplant for 
multiple myeloma 
Secondary Objectives: 
Maximum-tolerated dose (MTD) of MLN9708 in this patient population 
Progression-free survival (PFS) at 2 years after initiation of maintenance therapy 
Overall survival (OS) at 2 years after allogeneic stem cell transplant 
Incidence of graft-versus-host disease (GVHD) in patients receiving allogeneic stem cell 
transplant and maintenance with MLN9708 
Effect of MLN9708 on immune effector cells after allogeneic stem cell transplant 
1.2 Study Design 
 
Study Type 
 Non-Randomized 
 Randomized (Allocation Ratio:      ) 
Details 
This is a Phase II, open-label, multicenter, non-randomized study to determine the 
feasibility of MLN9708 as maintenance after allogeneic stem cell transplant for multiple 
myeloma. Patients will be enrolled between Days 45 and 120 after allogeneic transplant 
and will receive MLN9708 on Days 1, 8, and 15 of each 28-day cycle for 6 cycles. Up to 
18 patients will be enrolled in the dose-escalation phase to define the MTD of MLN9708. 
An additional 20 patients will be enrolled in the expansion phase at the MTD. 
 
PFS is defined as the time from the first day of study drug administration (Day 1) to 
disease progression as defined by the International Myeloma Working Group Uniform 
Response Criteria (see Appendix E of protocol), or death on study. Patients who are alive 
and free from disease progression will be censored at the date of last tumor assessment. 
 
OS is defined as the time from the first day of study drug administration (Day 1) to death 
on study. Patients who are alive will be censored at the date of last known date alive. 
 
PFS and OS (efficacy secondary endpoints) estimates will be generated using Kaplan-
Meier methods, both for all patients enrolled and those patients receiving the MTD.  
Two-year PFS and OS estimates with 95% confidence intervals (CIs), and median PFS 
and OS with 95% CIs, will be generated and reported accordingly. 
1.3.2 Randomization 
 
Randomization Type: 
 Open-Label           
 Single Blind           
 Double-Blind            
1.4 Timing of Analysis 
 
Planned Interim Analysis 
 Cohort Review / Dose Escalation 
 Safety Review 
 Interim Efficacy/Safety Analysis 
 Independent DMC/DSMB 
 Annual Report / Investigator Brochure (IB) 
 Abstract / Scientific Presentation (Oral/Poster) 
Final Analysis 
As determined by the Study Chair in consultation with the clinical team 


 
 
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1.5 Responsibilities 
 
Trial Statistician: 
Prepare SAP checklist and TFL shells. 
Review deliverables produced by Statistical Programmers. 
PK Statistician: 
N/A 
Independent Statistician: 
N/A 
1.6 Analysis Software 
 
Main statistical analysis: 
SAS Version 9.3 or above 
Other analysis software: 
N/A 
 
 


 
 
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1.7 Coding 
 
 Adverse Events 
 Medical History 
 MedDRA:   
 Version                
 
 Most current release and update coding with new major releases 
 NCI-CTCAE Version v4.0 
 Concomitant Medication 
 Prior Therapy 
 Subsequent/Further Therapy 
 WHO-Drug:   
 Version                
 
 Most current release and update coding with new major releases 
3 Analysis Population 
 
Intent-To-Treat (ITT) Population 
definition: 
 All patients who have started treatment in the study 
 All patients who have been randomized in the study, regardless of whether they have 
received any treatment or not 
 All patients who have been randomized and have started treatment in the study 
 Other definition, specify:       
Per Protocol (PP) Population to 
be used in analysis: 
 Yes          
 No 
If yes, please specify the criteria for exclusion from the PP population:        
Safety (SAF) Population 
definition 
 The Safety population will consist of all patients who received at least one dose of 
MLN9708. 
 Other definition, specify:       
Other Analysis Population 
definition: 
The Efficacy Evaluable population will consist of all patients with measurable or 
evaluable disease at baseline who receive at least 1 dose of MLN9708 and undergo at 
least one post-baseline disease assessment. In addition, patients who discontinued the 
study prior to their first post-baseline disease assessment due to death or progressive 
disease will also be included in the Efficacy Evaluable population. 
4 Baseline Value Definitions 
 
 
Information collected and procedures performed for each patient at ≤7 days prior to 
initiation of treatment. 
5/6 Efficacy 
 
Response Criteria Used: 
 RECIST 1.0          
 RECIST 1.1         
 Cheson 2007 
 Modified RECIST – specify:               
 Other criteria, Specify:  
      International Myeloma Working Group Uniform Response Criteria 
Efficacy Assessment Timepoints: 
Patients will be re-evaluated for response to treatment after 2 cycles of treatment.  
Response will be assessed at 8-week intervals (±1 week) during study treatment.  
Patients with progressive disease (PD) or unacceptable toxicity should be discontinued 
from the study; patients with stable disease (SD) or response to therapy will continue 
treatment through 6 cycles. 
 
 


 
 
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Efficacy Endpoints: 
 
 
Endpoint 
Primary Analysis 
Population 
Other Analysis 
Population 
Primary 
PFS 
Efficacy Evaluable 
      
Secondary 
OS 
Efficacy Evaluable 
      
  
Definition of Terms: 
 
 Response 
 Complete Response + Partial Response as best observed response 
 Complete Response + Partial Response, confirmed with       weeks apart.  
 Other criteria, specify:  
        International Myeloma Working Group Uniform Response Criteria: 
sCR  
(stringent complete response)   
CR  
(complete response) 
VGPR  (very good partial response)    
PR  
(partial response) 
SD  
(stable disease)          
 
PD  
(progressive disease) 
 Clinical Benefit 
 Complete Response + Partial Response + Stable Disease as best observed 
response 
 Complete Response + Partial Response (confirmed with       weeks apart) + 
Stable Disease (at least       weeks from start of treatment)  
 Other criteria, specify:       
 Progression 
As reported by Investigator 
 Subsequent Therapy 
      
 Treatment Failure 
      
Definition of Endpoints: 
Start Date:  
 Date of Randomization         
 Date of First Treatment 
End Date (specify for all pertinent endpoints): 
Progression-Free Survival: Event = Progression or Death  
Situation 
Date of Event or Censoring 
Outcome 
No baseline assessment 
Date of first treatment 
Censored 
PD documented between scheduled visits, 
did not die, and received no subsequent 
therapy 
First date of evaluated 
overall response = PD 
Event 
PD documented between scheduled visits, 
did not die, but received subsequent therapy 
prior to incurring progression event 
Date of last evaluable tumor 
assessment prior to start of 
subsequent therapy 
Censored 
Death while on-study without previous PD, 
and received no subsequent therapy 
Date of death 
Event 
Death while on-study and had previous PD, 
and received no subsequent therapy 
First date of evaluated 
overall response = PD 
Event 


 
 
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Death while on-study without previous PD, 
but received subsequent therapy prior to 
death event 
Date of last evaluable tumor 
assessment prior to start of 
subsequent therapy 
Censored 
Death while on-study and had previous PD, 
but received subsequent therapy prior to PD 
event 
Date of last evaluable tumor 
assessment prior to start of 
subsequent therapy 
Censored 
No progression, no death  
Date of last evaluable tumor 
assessment 
Censored 
Treatment discontinuation for adverse event 
or other non-event reason  
Date of last evaluable tumor 
assessment 
Censored 
Overall Survival: Event = Death 
Situation 
Date of Event or Censoring 
Outcome 
Death, while on-study or follow-up 
Date of death 
Event 
Alive, as of end of study or follow-up 
Date last known alive 
Censored 
Status unknown, as of end of study 
Date last known alive 
Censored 
 Overall Response Rate (ORR) 
Default: Estimates of rates in each treatment arm 
 Difference in rates & 95% confidence interval between treatment arms 
 p-value, specify statistical test:       
 Disease Control Rate (DCR) 
 Clinical Benefit Rate (CBR) 
 Early Progression Rate (EPR) 
 Time To Progression (TTP) 
Default: Estimates of medians in each treatment arm 
 Other quartiles or percentages of survival required, specify:  
   PFS, OS:   2 year PFS and OS with 95% confidence intervals 
 Hazard ratio & 95% confidence interval between treatment arms, unstratified 
 p-value, specify statistical test:       
 Hazard ratio & 95% confidence interval between treatment arms, stratified (specify 
stratification factor(s)):       
 p-value, specify statistical test: 
 Progression-Free Survival 
(PFS) 
 Overall Survival (OS) 
 Duration of Response 
 Duration of Stable Disease 
 Time To Treatment Failure 
(TTF) 
 Other, Specify: 
 
7 Safety 
 
Adverse Events 
Definition of Treatment-Emergent Adverse Event (TEAE):  
Treatment-emergent AEs are those with an onset on or after the initiation of therapy, 
and will be graded according to NCI CTCAE v4.0. 
Laboratory Data 
Data will be summarized by: 
 NCI-CTCAE for CTCAE-gradable parameters, and H/L for non-CTCAE-Gradable 
parameter 
 H/L for all lab parameters 


 
 
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Tier 1 Study – Tables, Figures & Listings 
Standard TFLs 
Table No 
Description 
Variables/Analyses To Be Included 
Subgroup Analyses 
Table 1 
Summary of Patient Disposition 
 Number of patients screened 
 Number of patients randomized 
 Number of patients treated 
 Reason for treatment discontinuation 
 Reason for study withdrawals 
 Other, specify: Patient Deaths;  
                             Time on Study 
      
Table 2 
Summary of Demographic 
Characteristics 
 Age: Mean, SD, Median, Min, Max 
 Age Group:       
 Sex 
 Race 
 ECOG 
 Other, specify:       
      
Table 3 
Summary of Disease History  
 Histology 
 Disease Staging 
 Time from Diagnosis 
 Other, specify: Baseline FISH 
                             Baseline 
Cytogenetics 
      
Table 4 
Summary of Patient Treatment and 
Dose Modifications  
    (reductions, interruptions) 
 
 
Table 5 
Summary of Grade 3+ Adverse Events 
 
 
Table 6 
Summary of Treatment-Related  
Grade 3+ Adverse Events 
 
 
Table 7  
Summary of Serious Adverse Events 
 
 
Table 8 
Summary of Treatment-Related Serious 
Adverse Events 
 
 
Table 9 
Summary of Treatment Related 
Adverse Events Leading to Death 
 
 
Table 10 
Summary of Best Overall Response 
 
 
Table 11 
Summary of Response Over Time 
 
 
Table 12 
Summary of Progression-Free Survival 
    (Kaplan-Meier estimates & 95 CI) 
 
 
Table 13 
Summary of Overall Survival  
    (Kaplan-Meier estimates & 95 CI) 
 
 
Table 14 
Summary of Adverse Events with >= 
5% Frequency    (for: CTGOV) 
 
 
 
 
 


 
 
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Figure 
No 
Description 
Variables/Analyses To Be Included 
Subgroup Analyses 
Figure 1 
Progression-Free Survival 
Timescale to be used on horizontal 
axis: 
 Day  
 Week 
 Month 
 Year 
      
Figure 2 
Overall Survival 
Timescale to be used on horizontal 
axis: 
 Day  
 Week 
 Month 
 Year 
      
 
 
 
 
 
 
 
 
 
 
Listing 
No. 
Title 
Variables/Analyses To Be 
Included 
Subgroup Analyses